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AISC Team B1 5

c1b1328e253176ec4d5eae006538eb5f6301edc3

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PGK1

PGK1 Phosphoglycerate kinase 1 is an enzyme that in humans is encoded by the PGK1 gene. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

PGK1 Phosphoglycerate kinase 1 is an enzyme that in humans is encoded by the PGK1 gene.[1][2][3] # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. [§ 1] - ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

https://www.wikidoc.org/index.php/PGK1

f9213996b173f61d4b310d58dcb8834c0c0dccee

wikidoc

PGM1

PGM1 Phosphoglucomutase-1 is an enzyme that in humans is encoded by the PGM1 gene. The protein encoded by this gene is an isozyme of phosphoglucomutase (PGM) and belongs to the phosphohexose mutase family. There are several PGM isozymes, which are encoded by different genes and catalyze the transfer of phosphate between the 1 and 6 positions of glucose. In most cell types, this PGM isozyme is predominant, representing about 90% of total PGM activity. In red blood cells, PGM2 is a major isozyme. This gene is highly polymorphic. Mutations in this gene cause CDG syndrome type 1t (CDG1T, formerly known as glycogen storage disease type XIV). Alternatively spliced transcript variants encoding different isoforms have been identified in this gene. # Structure The PGM1 gene is localized to the first chromosome, with its specific region being 1p31. The complete PGM1 gene spans over 65 kb and contains 11 exons, and the sites of the two mutations which form the molecular basis for the common PGM1 protein polymorphism lie in exons 4 and 8 and are 18 kb apart. Within this region there is a site of intragenic recombination. There are two alternatively spliced first exons, one of which, exon 1A, is transcribed in a wide variety of cell types; the other, exon 1B, is transcribed in fast muscle tissue. Exon 1A is transcribed from a promoter that has the structural hallmarks of a housekeeping promoter but lies more than 35 kb upstream of exon 2. Exon 1B lies 6 kb upstream of exon 2 within the large first intron of the ubiquitously expressed PGM1 transcript. The fast-muscle form of PGM1 is characterized by 18 extra amino acid residues at its N-terminal end. Sequence comparisons show that exons 1A and 1B are structurally related and have arisen by duplication. PGM1 is a monomeric protein with 562 amino acids and four structural domains arranged in an overall heart shape. The active site is located in the large, centrally located cleft, formed by more than 80 residues. The active site can be segregated into four highly conserved regions that contribute to catalysis and substrate binding. These regions are: the phosphoserine residue that participates in phosphoryl transfer; the metal- binding loop; a sugar-binding loop; and the phosphate-binding site that interacts with the phosphate group of the substrate. The active site cleft of PGM1 relies on all four structural domains of the enzyme for its structural integrity. # Function The biochemical pathways required to utilize glucose as a carbon and energy source are highly conserved from bacteria to humans. PGM1 is an evolutionarily conserved enzyme that regulates one of the most important metabolic carbohydrate trafficking points in prokaryotic and eukaryotic organisms, catalyzing the bi-directional interconversion of glucose 1-phosphate (G-1-P) and glucose 6-phosphate (G-6-P). In one direction, G-1-P produced from sucrose catabolism is converted to G-6-P, the first intermediate in glycolysis. In the other direction, conversion of G-6-P to G-1-P generates a substrate for synthesis of UDP-glucose, which is required for synthesis of a variety of cellular constituents, including cell wall polymers and glycoproteins. PGM1 has been used extensively as a genetic marker for isozyme polymorphism among humans. PGM is known to be post-translationally modified by cytoplasmic glycosylation that does not seem to regulate its enzymatic activity but rather is implicated in the localization of the protein. Glucose 1,6 bisphosphate (Glc-1, 6-P2), a powerful regulator of carbohydrate metabolism, has been demonstrated to be a potent activator of PGM. PGM1 is also modified by phosphorylation on Ser108 as part of its catalytic mechanism. This is shown to be performed by Pak1, a previously identified signaling kinase. # Clinical significance Phosphoglucomutase 1 (PGM1) deficiency is an inherited metabolic disorder in humans (CDG syndrome type 1t, CDG1T). Affected patients show multiple disease phenotypes, including dilated cardiomyopathy, exercise intolerance, and hepatopathy, reflecting the central role of the enzyme in glucose metabolism. The biochemical phenotypes of the PGM1 mutants cluster into two groups: those with compromised catalysis and those with possible folding defects. Relative to the recombinant wild-type enzyme, certain missense mutants show greatly decreased expression of soluble protein and/or increased aggregation. In contrast, other missense variants are well behaved in solution, but show dramatic reductions in enzyme activity, with Kcat/Km often <1.5% of wild-type. Modest changes in protein conformation and flexibility are also apparent in some of the catalytically impaired variants. In the case of the G291R mutant, severely compromised activity is linked to the inability of a key active site serine to be phosphorylated, a prerequisite for catalysis. Our results complement previous in vivo studies, which suggest that both protein misfolding and catalytic impairment may play a role in PGM1 deficiency. # Interactions PGM1 has been shown to interact with S100 calcium binding protein A1 and S100B.

PGM1 Phosphoglucomutase-1 is an enzyme that in humans is encoded by the PGM1 gene.[1][2][3] The protein encoded by this gene is an isozyme of phosphoglucomutase (PGM) and belongs to the phosphohexose mutase family. There are several PGM isozymes, which are encoded by different genes and catalyze the transfer of phosphate between the 1 and 6 positions of glucose. In most cell types, this PGM isozyme is predominant, representing about 90% of total PGM activity. In red blood cells, PGM2 is a major isozyme. This gene is highly polymorphic. Mutations in this gene cause CDG syndrome type 1t (CDG1T, formerly known as glycogen storage disease type XIV). Alternatively spliced transcript variants encoding different isoforms have been identified in this gene.[provided by RefSeq, Mar 2010][3] # Structure The PGM1 gene is localized to the first chromosome, with its specific region being 1p31.[4] The complete PGM1 gene spans over 65 kb and contains 11 exons, and the sites of the two mutations which form the molecular basis for the common PGM1 protein polymorphism lie in exons 4 and 8 and are 18 kb apart. Within this region there is a site of intragenic recombination. There are two alternatively spliced first exons, one of which, exon 1A, is transcribed in a wide variety of cell types; the other, exon 1B, is transcribed in fast muscle tissue. Exon 1A is transcribed from a promoter that has the structural hallmarks of a housekeeping promoter but lies more than 35 kb upstream of exon 2. Exon 1B lies 6 kb upstream of exon 2 within the large first intron of the ubiquitously expressed PGM1 transcript. The fast-muscle form of PGM1 is characterized by 18 extra amino acid residues at its N-terminal end. Sequence comparisons show that exons 1A and 1B are structurally related and have arisen by duplication. [5] PGM1 is a monomeric protein with 562 amino acids and four structural domains arranged in an overall heart shape. The active site is located in the large, centrally located cleft, formed by more than 80 residues. The active site can be segregated into four highly conserved regions that contribute to catalysis and substrate binding.[6] These regions are: the phosphoserine residue that participates in phosphoryl transfer; the metal- binding loop; a sugar-binding loop; and the phosphate-binding site that interacts with the phosphate group of the substrate.[7] The active site cleft of PGM1 relies on all four structural domains of the enzyme for its structural integrity.[8][9] # Function The biochemical pathways required to utilize glucose as a carbon and energy source are highly conserved from bacteria to humans. PGM1 is an evolutionarily conserved enzyme that regulates one of the most important metabolic carbohydrate trafficking points in prokaryotic and eukaryotic organisms, catalyzing the bi-directional interconversion of glucose 1-phosphate (G-1-P) and glucose 6-phosphate (G-6-P). In one direction, G-1-P produced from sucrose catabolism is converted to G-6-P, the first intermediate in glycolysis. In the other direction, conversion of G-6-P to G-1-P generates a substrate for synthesis of UDP-glucose, which is required for synthesis of a variety of cellular constituents, including cell wall polymers and glycoproteins.[10] PGM1 has been used extensively as a genetic marker for isozyme polymorphism among humans. PGM is known to be post-translationally modified by cytoplasmic glycosylation that does not seem to regulate its enzymatic activity but rather is implicated in the localization of the protein.[11] Glucose 1,6 bisphosphate (Glc-1, 6-P2), a powerful regulator of carbohydrate metabolism, has been demonstrated to be a potent activator of PGM. PGM1 is also modified by phosphorylation on Ser108 as part of its catalytic mechanism. This is shown to be performed by Pak1, a previously identified signaling kinase.[12] # Clinical significance Phosphoglucomutase 1 (PGM1) deficiency is an inherited metabolic disorder in humans (CDG syndrome type 1t, CDG1T). Affected patients show multiple disease phenotypes, including dilated cardiomyopathy, exercise intolerance, and hepatopathy, reflecting the central role of the enzyme in glucose metabolism. The biochemical phenotypes of the PGM1 mutants cluster into two groups: those with compromised catalysis and those with possible folding defects. Relative to the recombinant wild-type enzyme, certain missense mutants show greatly decreased expression of soluble protein and/or increased aggregation. In contrast, other missense variants are well behaved in solution, but show dramatic reductions in enzyme activity, with Kcat/Km often <1.5% of wild-type. Modest changes in protein conformation and flexibility are also apparent in some of the catalytically impaired variants. In the case of the G291R mutant, severely compromised activity is linked to the inability of a key active site serine to be phosphorylated, a prerequisite for catalysis. Our results complement previous in vivo studies, which suggest that both protein misfolding and catalytic impairment may play a role in PGM1 deficiency.[13] # Interactions PGM1 has been shown to interact with S100 calcium binding protein A1[14] and S100B.[14]

https://www.wikidoc.org/index.php/PGM1

b1657f0b26a1d05321ffa7d0826d565955a6ee25

wikidoc

PHC1

PHC1 Polyhomeotic-like protein 1 is a protein that in humans is encoded by the PHC1 gene. # Function This gene is a homolog of the Drosophila polyhomeotic gene, which is a member of the Polycomb group of genes. The gene product is a component of a multimeric protein complex that contains EDR2 and the vertebrate Polycomb protein BMH1. The gene product, the EDR2 protein, and the Drosophila polyhomeotic protein share 2 highly conserved domains, named homology domains I and II. These domains are involved in protein-protein interactions and may mediate heterodimerization of the protein encoded by this gene and the EDR2 protein. Mutations in this gene have been associated to cases of primary microcephaly (doi: 10.1093/hmg/ddt072). # Interactions PHC1 has been shown to interact with BMI1 and PHC2.

PHC1 Polyhomeotic-like protein 1 is a protein that in humans is encoded by the PHC1 gene.[1][2] # Function This gene is a homolog of the Drosophila polyhomeotic gene, which is a member of the Polycomb group of genes. The gene product is a component of a multimeric protein complex that contains EDR2 and the vertebrate Polycomb protein BMH1. The gene product, the EDR2 protein, and the Drosophila polyhomeotic protein share 2 highly conserved domains, named homology domains I and II. These domains are involved in protein-protein interactions and may mediate heterodimerization of the protein encoded by this gene and the EDR2 protein.[2] Mutations in this gene have been associated to cases of primary microcephaly (doi: 10.1093/hmg/ddt072). # Interactions PHC1 has been shown to interact with BMI1[1][3] and PHC2.[1][4]

https://www.wikidoc.org/index.php/PHC1

0dd26626313b6d060ecea71f5f52c42a8fb787b3

wikidoc

PHC2

PHC2 Polyhomeotic-like protein 2 is a protein that in humans is encoded by the PHC2 gene. # Function In Drosophila melanogaster, the 'Polycomb' group (PcG) of genes are part of a cellular memory system that is responsible for the stable inheritance of gene activity. PcG proteins form a large multimeric, chromatin-associated protein complex. The protein encoded by this gene has homology to the Drosophila PcG protein 'polyhomeotic' (Ph) and is known to heterodimerize with EDR1 and colocalize with BMI1 in interphase nuclei of human cells. The specific function in human cells has not yet been determined. Two transcript variants encoding different isoforms have been found for this gene. # Interactions PHC2 has been shown to interact with MAPKAPK2, PHC1, BMI1 and MCRS1.

PHC2 Polyhomeotic-like protein 2 is a protein that in humans is encoded by the PHC2 gene.[1][2][3] # Function In Drosophila melanogaster, the 'Polycomb' group (PcG) of genes are part of a cellular memory system that is responsible for the stable inheritance of gene activity. PcG proteins form a large multimeric, chromatin-associated protein complex. The protein encoded by this gene has homology to the Drosophila PcG protein 'polyhomeotic' (Ph) and is known to heterodimerize with EDR1 and colocalize with BMI1 in interphase nuclei of human cells. The specific function in human cells has not yet been determined. Two transcript variants encoding different isoforms have been found for this gene.[3] # Interactions PHC2 has been shown to interact with MAPKAPK2,[4] PHC1,[1][5] BMI1[1] and MCRS1.[5]

https://www.wikidoc.org/index.php/PHC2

3d5efd58e469512a8c8f6844fe739ac32da01e9a

wikidoc

PHF8

PHF8 PHD finger protein 8 is a protein that in humans is encoded by the PHF8 gene. # Function PHF8 belongs to the family of ferrous iron and alpha-ketoglutarate-dependent hydroxylases superfamily., and is active as a histone lysine demethylase with selectivity for the di-and monomethyl states. # Regulation during differentation PHF8 was found to be expressional increased during endothelial differentation and siginifcantly decreased during cardial differentation of murine embryonic stem cells. # Clinical significance Mutations in PHF8 cause Siderius type X-linked mental retardation (XLMR) (OMIM 300263). In addition to moderate intellectual disability, features of the Siderius-Hamel syndrome include facial dysmorphism, cleft lip and/or cleft palate, and in some cases microcephaly. A chromosomal microdeletion on Xp11.22 encompassing all of the PHF8 and FAM120C genes and a part of the WNK3 gene was reported in two brothers with autism spectrum disorder in addition to Siderius-type XLMR and cleft lip and palate. This catalytic activity is disrupted by clinically known mutations to PHF8, which were found to cluster in its catalytic JmjC domain. The F279S mutation of PHF8, found in 2 Finnish brothers with mild intellectual disability, facial dysmorphism and cleft lip/palate, was found to additionally prevent nuclear localisation of PHF8 overexpressed in human cells. The catalytic activity of PHF8 depends on molecular oxygen, a fact considered important with respect to reports on increased incidence of cleft lip/palate in mice that have been exposed to hypoxia during pregnancy. In humans, fetal cleft lip and other congenital abnormalities have also been linked to maternal hypoxia, as caused by e.g. maternal smoking, maternal alcohol abuse or maternal hypertension treatment.

PHF8 PHD finger protein 8 is a protein that in humans is encoded by the PHF8 gene.[1] # Function PHF8 belongs to the family of ferrous iron and alpha-ketoglutarate-dependent hydroxylases superfamily.,[2] and is active as a histone lysine demethylase with selectivity for the di-and monomethyl states.[3] # Regulation during differentation PHF8 was found to be expressional increased during endothelial differentation and siginifcantly decreased during cardial differentation of murine embryonic stem cells.[4] # Clinical significance Mutations in PHF8 cause Siderius type X-linked mental retardation (XLMR) (OMIM 300263).[5][6][7] In addition to moderate intellectual disability, features of the Siderius-Hamel syndrome include facial dysmorphism, cleft lip and/or cleft palate, and in some cases microcephaly.[8][9][10] A chromosomal microdeletion on Xp11.22 encompassing all of the PHF8 and FAM120C genes and a part of the WNK3 gene was reported in two brothers with autism spectrum disorder in addition to Siderius-type XLMR and cleft lip and palate.[11] This catalytic activity is disrupted by clinically known mutations to PHF8, which were found to cluster in its catalytic JmjC domain. The F279S mutation of PHF8, found in 2 Finnish brothers with mild intellectual disability, facial dysmorphism and cleft lip/palate,[10] was found to additionally prevent nuclear localisation of PHF8 overexpressed in human cells.[3] The catalytic activity of PHF8 depends on molecular oxygen,[3] a fact considered important with respect to reports on increased incidence of cleft lip/palate in mice that have been exposed to hypoxia during pregnancy.[12] In humans, fetal cleft lip and other congenital abnormalities have also been linked to maternal hypoxia, as caused by e.g. maternal smoking,[13] maternal alcohol abuse or maternal hypertension treatment.[14]

https://www.wikidoc.org/index.php/PHF8

969fca1f56b8a2f7683d5d3aba282d546ffae424

wikidoc

PIGQ

PIGQ Phosphatidylinositol N-acetylglucosaminyltransferase subunit Q is an enzyme that in humans is encoded by the PIGQ gene. This gene is involved in the first step in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This gene encodes a N-acetylglucosaminyl transferase component that is part of the complex that catalyzes transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI). # Interactions PIGQ has been shown to interact with PIGH, PIGA and PIGC.

PIGQ Phosphatidylinositol N-acetylglucosaminyltransferase subunit Q is an enzyme that in humans is encoded by the PIGQ gene.[1][2][3] This gene is involved in the first step in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This gene encodes a N-acetylglucosaminyl transferase component that is part of the complex that catalyzes transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI).[3] # Interactions PIGQ has been shown to interact with PIGH,[1] PIGA[1] and PIGC.[1]

https://www.wikidoc.org/index.php/PIGQ

523846ab27761ecacc05226af75f7d6769a3ffe0

wikidoc

PIM1

PIM1 Proto-oncogene serine/threonine-protein kinase Pim-1 is an enzyme that in humans is encoded by the PIM1 gene. Pim-1 is a proto-oncogene which encodes for the serine/threonine kinase of the same name. The pim-1 oncogene was first described in relation to murine T-cell lymphomas, as it was the locus most frequently activated by the Moloney murine leukemia virus. Subsequently, the oncogene has been implicated in multiple human cancers, including prostate cancer, acute myeloid leukemia and other hematopoietic malignancies. Primarily expressed in spleen, thymus, bone marrow, prostate, oral epithelial, hippocampus and fetal liver cells, Pim-1 has also been found to be highly expressed in cell cultures isolated from human tumors. Pim-1 is mainly involved in cell cycle progression, apoptosis and transcriptional activation, as well as more general signal transduction pathways. # Gene Located on chromosome 6 (6p21.2), the gene encompasses 5Kb of DNA, including 6 exons and 5 introns. Expression of Pim-1 has been shown to be regulated by the JAK/STAT pathway. Direct binding of transcription factors STAT3 and STAT5 to the Pim-1 promoter results in the transcription of Pim-1. The Pim-1 gene has been found to be conserved in dogs, cows, mice, rats, zebrafish and C. elegans. Pim-1 deficient mice have been shown to be phenotypically normal, indicating that there is redundancy in the function of this kinase. In fact, sequence homology searches have shown that two other Pim-1-like kinases, Pim-2 and Pim-3, are structurally and functionally similar. The Pim-1 gene encodes has multiple translation initiation sites, resulting in two proteins of 34 and 44kD. # Protein structure Human, murine and rat Pim-1 contain 313 amino acids, and have a 94 – 97% amino acid identity. The active site of the protein, ranging from amino acids 38-290, is composed of several conserved motifs, including a glycine loop motif, a phosphate binding site and a proton acceptor site. Modification of the protein at amino acid 67 (lysine to methionine) results in the inactivation of the kinase. # Activation and stabilization Pim-1 is primarily involved in cytokine signaling, and has been implicated in many signal transduction pathways. Because Pim-1 transcription is initiated by STAT3 and STAT5, its production is regulated by the cytokines that regulate the STAT pathway, or STAT factors. These include interleukins (IL-2, IL-3,IL-5, IL-6, IL-7, IL12, IL-15), prolactin, TNFα, EGF and IFNγ, among others. Pim-1 itself can bind to negative regulators of the JAK/STAT pathway, resulting in a negative feedback loop. Although little is known about the post-transcriptional modifications of Pim-1, it has been hypothesized that Hsp90 is responsible for the folding and stabilization of Pim-1, although the exact mechanism has yet to be discovered. Furthermore, the serine/threonine phosphatase PP2 has been shown to degrade Pim-1. # Interactions PIM1 has been shown to interact with: - CBX3, - CDC25A, - Heat shock protein 90kDa alpha (cytosolic), member A1, - NFATC1, - Nuclear mitotic apparatus protein 1, - P21, - SND1 and - RELA. Other known substrates/binding partners of Pim-1 include proteins involved in transcription regulation (nuclear adaptor protein p100, HP-1, PAP-1 and TRAF2 / SNX6), and regulation of the JAK/STAT pathway (SOCS1 and SOCS3). Furthermore, Pim-1 has been shown to be a cofactor for c-Myc, a transcription factor believed to regulate 15% of all genes, and their synergy has been in prostate tumorigenesis. Pim-1 is able to phosphorylate many targets, including itself. Many of its targets are involved in cell cycle regulation. ## Activates - Cdc25C (G1/S positive regulator): Activation results in increased G1 → S - Cdc25C (G2/M positive regulator): Activation results in increased G2 → M ## Deactivates - Bad (Pro-apoptotic protein): Deactivation results in increased cell survival - CKI (G1/S negative regulator): Deactivation results in increased G1 → S - C-TAK1 (Cdc25C inhibitor): Deactivation results in increased G2 → M # Clinical implications Pim-1 is directly involved in the regulation of cell cycle progression and apoptosis, and has been implicated in numerous cancers including prostate cancer, Burkitt’s lymphoma and oral cancer, as well as numerous hematopoietic lymphomas. Single nucleotide polymorphisms in the Pim-1 gene have been associated with increased risk for lung cancer in Korean patients, and have also been found in diffuse large cell lymphomas. As well as showing useful activity against a range of cancers, PIM kinase inhibitors have also been suggested as possible treatments for Alzheimer's disease. PIM expression is sufficient to drive resistance to anti-angiogenic agents in prostate and colon cancer models, although the mechanism is not fully elucidated. # Inhibitors A large number of small molecule inhibitors of PIM1 have been developed. Clinical trial results so far have showed promising anti-cancer activity, but side effects due to insufficient selectivity have proved problematic and research continues to find more potent and selective inhibitors for this target. - AZD1208 - LGH447 - SGI-1776 - TP-3654

PIM1 Proto-oncogene serine/threonine-protein kinase Pim-1 is an enzyme that in humans is encoded by the PIM1 gene.[1][2][3] Pim-1 is a proto-oncogene which encodes for the serine/threonine kinase of the same name. The pim-1 oncogene was first described in relation to murine T-cell lymphomas, as it was the locus most frequently activated by the Moloney murine leukemia virus.[4] Subsequently, the oncogene has been implicated in multiple human cancers, including prostate cancer, acute myeloid leukemia and other hematopoietic malignancies.[5] Primarily expressed in spleen, thymus, bone marrow, prostate, oral epithelial, hippocampus and fetal liver cells, Pim-1 has also been found to be highly expressed in cell cultures isolated from human tumors.[4] Pim-1 is mainly involved in cell cycle progression, apoptosis and transcriptional activation, as well as more general signal transduction pathways.[4] # Gene Located on chromosome 6 (6p21.2), the gene encompasses 5Kb of DNA, including 6 exons and 5 introns. Expression of Pim-1 has been shown to be regulated by the JAK/STAT pathway. Direct binding of transcription factors STAT3 and STAT5 to the Pim-1 promoter results in the transcription of Pim-1.[4] The Pim-1 gene has been found to be conserved in dogs, cows, mice, rats, zebrafish and C. elegans. Pim-1 deficient mice have been shown to be phenotypically normal, indicating that there is redundancy in the function of this kinase.[4] In fact, sequence homology searches have shown that two other Pim-1-like kinases, Pim-2 and Pim-3, are structurally and functionally similar.[4] The Pim-1 gene encodes has multiple translation initiation sites, resulting in two proteins of 34 and 44kD.[4] # Protein structure Human, murine and rat Pim-1 contain 313 amino acids, and have a 94 – 97% amino acid identity.[4] The active site of the protein, ranging from amino acids 38-290, is composed of several conserved motifs, including a glycine loop motif, a phosphate binding site and a proton acceptor site.[4] Modification of the protein at amino acid 67 (lysine to methionine) results in the inactivation of the kinase.[4] # Activation and stabilization Pim-1 is primarily involved in cytokine signaling, and has been implicated in many signal transduction pathways. Because Pim-1 transcription is initiated by STAT3 and STAT5, its production is regulated by the cytokines that regulate the STAT pathway, or STAT factors. These include interleukins (IL-2, IL-3,IL-5, IL-6, IL-7, IL12, IL-15), prolactin, TNFα, EGF and IFNγ, among others.[4] Pim-1 itself can bind to negative regulators of the JAK/STAT pathway, resulting in a negative feedback loop. Although little is known about the post-transcriptional modifications of Pim-1, it has been hypothesized that Hsp90 is responsible for the folding and stabilization of Pim-1, although the exact mechanism has yet to be discovered.[4] Furthermore, the serine/threonine phosphatase PP2 has been shown to degrade Pim-1. # Interactions PIM1 has been shown to interact with: - CBX3,[6] - CDC25A,[7] - Heat shock protein 90kDa alpha (cytosolic), member A1,[8] - NFATC1,[9] - Nuclear mitotic apparatus protein 1,[10] - P21,[11] - SND1[12] and - RELA.[13] Other known substrates/binding partners of Pim-1 include proteins involved in transcription regulation (nuclear adaptor protein p100, HP-1, PAP-1 and TRAF2 / SNX6), and regulation of the JAK/STAT pathway (SOCS1 and SOCS3).[4] Furthermore, Pim-1 has been shown to be a cofactor for c-Myc, a transcription factor believed to regulate 15% of all genes, and their synergy has been in prostate tumorigenesis.[14] Pim-1 is able to phosphorylate many targets, including itself. Many of its targets are involved in cell cycle regulation. ## Activates - Cdc25C (G1/S positive regulator): Activation results in increased G1 → S[4] - Cdc25C (G2/M positive regulator): Activation results in increased G2 → M[4] ## Deactivates - Bad (Pro-apoptotic protein): Deactivation results in increased cell survival[4] - CKI (G1/S negative regulator): Deactivation results in increased G1 → S[4] - C-TAK1 (Cdc25C inhibitor): Deactivation results in increased G2 → M[4] # Clinical implications Pim-1 is directly involved in the regulation of cell cycle progression and apoptosis, and has been implicated in numerous cancers including prostate cancer, Burkitt’s lymphoma and oral cancer, as well as numerous hematopoietic lymphomas. Single nucleotide polymorphisms in the Pim-1 gene have been associated with increased risk for lung cancer in Korean patients, and have also been found in diffuse large cell lymphomas.[15] As well as showing useful activity against a range of cancers, PIM kinase inhibitors have also been suggested as possible treatments for Alzheimer's disease.[16] PIM expression is sufficient to drive resistance to anti-angiogenic agents in prostate and colon cancer models, although the mechanism is not fully elucidated.[17] # Inhibitors A large number of small molecule inhibitors of PIM1 have been developed. Clinical trial results so far have showed promising anti-cancer activity, but side effects due to insufficient selectivity have proved problematic and research continues to find more potent and selective inhibitors for this target.[18][19][20][21][22][23][24] - AZD1208 - LGH447 - SGI-1776 - TP-3654

https://www.wikidoc.org/index.php/PIM1

d8d27f3c328083ade9cb780c4413a7faa467eb01

wikidoc

PIN1

PIN1 Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 is an enzyme that in humans is encoded by the PIN1 gene. Pin 1, or peptidyl-prolyl cis/trans isomerase (PPIase), isomerizes only phospho-Serine/Threonine-Proline motifs. The enzyme binds to a subset of proteins and thus plays a role as a post phosphorylation control in regulating protein function. Studies have shown that the deregulation of Pin1 may play a pivotal role in various diseases. Notably, the up-regulation of Pin1 is implicated in certain cancers, and the down-regulation of Pin1 is implicated in Alzheimer's disease. Inhibitors of Pin1 may have therapeutic implications for cancer and immune disorders. # Discovery The gene encoding Pin1 was identified in 1996 as a result of a genetic/biochemical screen for proteins involved in mitotic regulation. It was found to be essential for cell division in some organisms. By 1999, however, it was apparent that Pin1 knockout mice had a surprisingly mild phenotype, indicating that the enzyme was not required for cell division per se. Further studies later found that loss of Pin1 in mice displays are not only neuronal degenerative phenotypes but also several abnormalities, similar to those of cyclin D1-null mice, suggesting the conformation changes mediated by Pin1 may be crucial for cell normal function. # Activation Phosphorylation of Ser/Thr-Pro motifs in substrates is required for recognition by Pin1. Pin is a small protein at 18 kDa and does not have a nuclear localization or export signal. However, 2009, Lufei et al. reported that Pin1 has putative novel nuclear localization signal (NLS) and Pin1 interacts with importin α5 (KPNA1). Substrate interactions and a WW domain determine subcellular distribution. Expression is induced by growth signals from E2F transcription factors. Expression levels fluctuate in normal, but not in cancerous cells. Expression is often associated with cell proliferation. Postranslational modifications such as phosphorylation on Ser16 inhibit the ability of Pin1 to bind substrate, and this inhibitory process may be altered during oncogenesis. It is hypothesized, but not proven, that Pin1 might also be regulated by proteolytic pathways. # Function Pin1 activity regulates the outcome of proline-directed kinase (e.g. MAPK, CDK or GSK3) signalling and consequently regulates cell proliferation (in part through control of cyclin D1 levels and stability) and cell survival. The precise effects of Pin1 depend upon the system: Pin1 accelerates dephosphorylation of Cdc25 and Tau, but protects phosphorylated cyclin D from ubiquitination and proteolysis. Recent data also implicate Pin1 as playing an important role in immune responses, at least in part by increasing the stability of cytokine mRNAs by influencing the protein complexes to which they bind. Pin1 has been hypothesized to act as a molecular timer. # Interactions PIN1 has been shown to interact with: - C-jun, - CDC25C, - CDC27, - CSNK2A2, - Casein kinase 2, alpha 1, - DAB2, - eNOS, - FOXO4, - MPHOSPH1, - MYT1, - Mothers against decapentaplegic homolog 2, - Mothers against decapentaplegic homolog 3 - P53, - PKMYT1, - PLK1, - SUPT5H, and - Wee1-like protein kinase.

PIN1 Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 is an enzyme that in humans is encoded by the PIN1 gene.[1][2] Pin 1, or peptidyl-prolyl cis/trans isomerase (PPIase), isomerizes only phospho-Serine/Threonine-Proline motifs. The enzyme binds to a subset of proteins and thus plays a role as a post phosphorylation control in regulating protein function. Studies have shown that the deregulation of Pin1 may play a pivotal role in various diseases. Notably, the up-regulation of Pin1 is implicated in certain cancers, and the down-regulation of Pin1 is implicated in Alzheimer's disease. Inhibitors of Pin1 may have therapeutic implications for cancer and immune disorders. # Discovery The gene encoding Pin1 was identified in 1996 as a result of a genetic/biochemical screen for proteins involved in mitotic regulation. It was found to be essential for cell division in some organisms. By 1999, however, it was apparent that Pin1 knockout mice had a surprisingly mild phenotype, indicating that the enzyme was not required for cell division per se. Further studies later found that loss of Pin1 in mice displays are not only neuronal degenerative phenotypes but also several abnormalities, similar to those of cyclin D1-null mice, suggesting the conformation changes mediated by Pin1 may be crucial for cell normal function. # Activation Phosphorylation of Ser/Thr-Pro motifs in substrates is required for recognition by Pin1. Pin is a small protein at 18 kDa and does not have a nuclear localization or export signal. However, 2009, Lufei et al. reported that Pin1 has putative novel nuclear localization signal (NLS) and Pin1 interacts with importin α5 (KPNA1).[3] Substrate interactions and a WW domain determine subcellular distribution. Expression is induced by growth signals from E2F transcription factors. Expression levels fluctuate in normal, but not in cancerous cells. Expression is often associated with cell proliferation. Postranslational modifications such as phosphorylation on Ser16 inhibit the ability of Pin1 to bind substrate, and this inhibitory process may be altered during oncogenesis. It is hypothesized, but not proven, that Pin1 might also be regulated by proteolytic pathways. # Function Pin1 activity regulates the outcome of proline-directed kinase (e.g. MAPK, CDK or GSK3) signalling and consequently regulates cell proliferation (in part through control of cyclin D1 levels and stability) and cell survival. The precise effects of Pin1 depend upon the system: Pin1 accelerates dephosphorylation of Cdc25 and Tau, but protects phosphorylated cyclin D from ubiquitination and proteolysis. Recent data also implicate Pin1 as playing an important role in immune responses, at least in part by increasing the stability of cytokine mRNAs by influencing the protein complexes to which they bind. Pin1 has been hypothesized to act as a molecular timer.[4] # Interactions PIN1 has been shown to interact with: - C-jun,[5] - CDC25C,[6][7][8] - CDC27,[6][8] - CSNK2A2,[9] - Casein kinase 2, alpha 1,[9] - DAB2,[10] - eNOS,[11] - FOXO4,[12] - MPHOSPH1,[13] - MYT1,[14] - Mothers against decapentaplegic homolog 2,[15] - Mothers against decapentaplegic homolog 3[15] - P53,[16][17] - PKMYT1,[6] - PLK1,[6][8] - SUPT5H,[18] and - Wee1-like protein kinase.[6]

https://www.wikidoc.org/index.php/PIN1

924c6f34e0f43dc9cdba752f537da5e3fda721bf

wikidoc

PKLR

PKLR Pyruvate kinase isozymes R/L is an enzyme that in humans is encoded by the PKLR gene. The protein encoded by this gene is a pyruvate kinase that catalyzes the production of pyruvate and ATP from phosphoenolpyruvate. Defects in this enzyme, due to gene mutations or genetic variations, are the common cause of chronic hereditary nonspherocytic hemolytic anemia (CNSHA or HNSHA). Alternatively spliced transcript variants encoding distinct isoforms have been described. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

PKLR Pyruvate kinase isozymes R/L is an enzyme that in humans is encoded by the PKLR gene.[1][2] The protein encoded by this gene is a pyruvate kinase that catalyzes the production of pyruvate and ATP from phosphoenolpyruvate. Defects in this enzyme, due to gene mutations or genetic variations, are the common cause of chronic hereditary nonspherocytic hemolytic anemia (CNSHA or HNSHA). Alternatively spliced transcript variants encoding distinct isoforms have been described.[2] # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. [§ 1] - ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

https://www.wikidoc.org/index.php/PKLR

482ddb35fe2e3510bc0ee76708b793b3f5203014

wikidoc

PKM2

PKM2 Pyruvate kinase isozymes M1/M2 (PKM1/M2), also known as pyruvate kinase muscle isozyme (PKM), pyruvate kinase type K, cytosolic thyroid hormone-binding protein (CTHBP), thyroid hormone-binding protein 1 (THBP1), or opa-interacting protein 3 (OIP3), is an enzyme that in humans is encoded by the PKM2 gene. PKM2 is an isoenzyme of the glycolytic enzyme pyruvate kinase. Depending upon the different metabolic functions of the tissues, different isoenzymes of pyruvate kinase are expressed. PKM2 is expressed in some differentiated tissues, such as lung, fat tissue, retina, and pancreatic islets, as well as in all cells with a high rate of nucleic acid synthesis, such as normal proliferating cells, embryonic cells, and especially tumor cells. # Structure Two isozymes are encoded by the PKM gene: PKM1 and PKM2. The M-gene consists of 12 exons and 11 introns. PKM1 and PKM2 are different splicing products of the M-gene (exon 9 for PKM1 and exon 10 for PKM2) and solely differ in 23 amino acids within a 56-amino acid stretch (aa 378-434) at their carboxy terminus. # Function Pyruvate kinase catalyzes the last step within glycolysis, the dephosphorylation of phosphoenolpyruvate to pyruvate, and is responsible for net ATP production within the glycolytic sequence. In contrast to mitochondrial respiration, energy regeneration by pyruvate kinase is independent from oxygen supply and allows survival of the organs under hypoxic conditions often found in solid tumors. The involvement of this enzyme in a variety of pathways, protein–protein interactions, and nuclear transport suggests its potential to perform multiple nonglycolytic functions with diverse implications, although multidimensional role of this protein is as yet not fully explored. However, a functional role in angiogenesis the so-called process of blood vessel formation by interaction and regulation of Jmjd8 has been shown. # Localization ## Tissue The PKM1 isozyme is expressed in organs that are strongly dependent upon a high rate of energy regeneration, such as muscle and brain. ## Subcellular PKM2 is a cytosolic enzyme that is associated with other glycolytic enzymes, i.e., hexokinase, glyceraldehyde 3-P dehydrogenase, phosphoglycerate kinase, phosphoglyceromutase, enolase, and lactate dehydrogenase within a so-called glycolytic enzyme complex. However, PKM2 contains an inducible nuclear localization signal in its C-terminal domain. The role of PKM2 within the nucleus is complex, since pro-proliferative but also pro-apoptotic stimuli have been described. On the one hand, nuclear PKM2 was found to participate in the phosphorylation of histone 1 by direct phosphate transfer from PEP to histone 1. On the other hand, nuclear translocation of PKM2 induced by a somatostatin analogue, H2O2, or UV light has been linked with caspase-independent programmed cell death. # Clinical significance ## Bi-functional role within tumors PKM2 is expressed in most human tumors. Initially, a switch from PKM1 to PKM2 expression during tumorigenesis was discussed. These conclusions, however, were the result of misinterpretation of western blots that had used PKM1-expressing mouse muscle as the sole non-cancer tissue. In clinical cancer samples, solely an up-regulation of PKM2, but no cancer specificity, could be confirmed. In contrast to the closely homologous PKM1, which always occurs in a highly active tetrameric form and which is not allosterically regulated, PKM2 may occur in a tetrameric form but also in a dimeric form. The tetrameric form of PKM2 has a high affinity to its substrate phosphoenolpyruvate (PEP), and is highly active at physiological PEP concentrations. When PKM2 is mainly in the highly active tetrameric form, which is the case in differentiated tissues and most normal proliferating cells, glucose is converted to pyruvate under the production of energy. Meanwhile, the dimeric form of PKM2 is characterized by a low affinity to its substrate PEP and is nearly inactive at physiological PEP concentrations. When PKM2 is mainly in the less active dimeric form, which is the case in tumor cells, all glycolytic intermediates above pyruvate kinase accumulate and are channelled into synthetic processes, which branch off from glycolytic intermediates such as nucleic acid-, phospholipid-, and amino acid synthesis. Nucleic acids, phospholipids, and amino acids are important cell building-blocks, which are greatly needed by highly proliferating cells, such as tumor cells. Due to the key position of pyruvate kinase within glycolysis, the tetramer:dimer ratio of PKM2 determines whether glucose carbons are converted to pyruvate and lactate under the production of energy (tetrameric form) or channelled into synthetic processes (dimeric form). In tumor cells, PKM2 is mainly in the dimeric form and has, therefore, been termed Tumor M2-PK. The quantification of Tumor M2-PK in plasma and stool is a tool for early detection of tumors and follow-up studies during therapy. The dimerization of PKM2 in tumor cells is induced by direct interaction of PKM2 with different oncoproteins (pp60v-src, HPV-16 E7, and A-Raf). The physiological function of the interaction between PKM2 and HERC1 as well as between PKM2 and PKCdelta is unknown). However, the tetramer:dimer ratio of PKM2 is not stationary value. High levels of the glycolytic intermediate fructose 1,6-bisphosphate induce the re-association of the dimeric form of PKM2 to the tetrameric form. As a consequence, glucose is converted to pyruvate and lactate with the production of energy until fructose 1,6-bisphosphate levels drop below a critical value to allow dissociation to the dimeric form. This regulation is termed metabolic budget system. Another activator of PKM2 is the amino acid serine. The thyroid hormone 3,3´,5-triiodi-L-tyhronine (T3) binds to the monomeric form of PKM2 and prevents its association to the tetrameric form. In tumor cells, the increased rate of lactate production in the presence of oxygen is termed the Warburg effect. Genetic manipulation of cancer cells so that they produce adult PKM1 instead of PKM2 reverses the Warburg effect and reduces the growth rate of these modified cancer cells. Accordingly, cotransfection of NIH 3T3 cells with gag-A-Raf and a kinase dead mutant of PKM2 reduced colony whereas cotransfection with gag-A-Raf and wild type PKM2 led to a doubling of focus formation. The dimeric form of PKM2 has been observed to have protein kinase activity in tumor cells. It is able to bind to and phosphorylate the histone H3 of chromatin in cancer cells, thereby having a role in the regulation of gene expression. This modification of histone H3 and the resulting involvement in gene expression regulation can be a cause of tumor cell proliferation. The pyruvate kinase activity of PKM2 can be promoted by SAICAR (succinylaminoimidazolecarboxamide ribose-5′-phosphate), an intermediate in purine biosynthesis. In cancer cells, glucose starvation leads to a rise in SAICAR levels and the subsequent stimulation of pyruvate kinase activity of PKM2. This allows for the completion of the glycolytic pathway to produce pyruvate and, therefore, survival under glucose deprivation. In addition, an abundance of SAICAR can modify glucose absorption and lactate production in cancer cells. However, it has been shown that SAICAR binding also sufficiently stimulates the protein kinase activity of PKM2 in tumor cells. In turn, the SAICAR-PKM2 complex can potentially phosphorylate a number of other protein kinases using PEP as the phosphate donor. Many of these proteins contribute to the regulation of cancer cell proliferation. Specifically, PKM2 can be a component in mitogen-activated protein kinase (MAPK) signaling, which is associated with increased cell proliferation if functioning improperly. This provides a potential link between SAICAR-activated PKM2 and cancer cell growth. ## Natural mutations and carcinogenesis Two missense mutations, H391Y and K422R, of PKM2 were found in cells from Bloom syndrome patients prone to developing cancer. Results show that, despite the presence of mutations in the inter-subunit contact domain, the K422R and H391Y mutant proteins maintained their homotetrameric structure, similar to the wild-type protein, but showed a loss of activity of 75 and 20%, respectively. H391Y showed a 6-fold increase in affinity for its substrate phosphoenolpyruvate and behaved like a non-allosteric protein with compromised cooperative binding. However, the affinity for phosphoenolpyruvate was lost significantly in K422R. Unlike K422R, H391Y showed enhanced thermal stability, stability over a range of pH values, a lesser effect of the allosteric inhibitor Phe, and resistance toward structural alteration upon binding of the activator (fructose 1,6-bisphosphate) and inhibitor (Phe). Both mutants showed a slight shift in the pH optimum from 7.4 to 7.0. The co-expression of homotetrameric wild type and mutant PKM2 in the cellular milieu resulting in the interaction between the two at the monomer level was substantiated further by in vitro experiments. The cross-monomer interaction significantly altered the oligomeric state of PKM2 by favoring dimerisation and heterotetramerization. In silico study provided an added support in showing that hetero-oligomerization was energetically favorable. The hetero-oligomeric populations of PKM2 showed altered activity and affinity, and their expression resulted in an increased growth rate of Escherichia coli as well as mammalian cells, along with an increased rate of polyploidy. These features are known to be essential to tumor progression. Further, cells stably expressing exogenous wild- or mutant-PKM2 (K422R or H391Y) or co-expressing both wild and mutant (PKM2-K422R or PKM2-H391Y), were assessed for cancer metabolism and tumorigenic potential. Cells co-expressing PKM2 and mutant (K422R or H391Y) showed significantly aggressive cancer metabolism, compared to cells expressing either wild or mutant PKM2 independently. A similar trend was observed for oxidative endurance, tumorigenic potential, cellular proliferation and tumor growth. These observations signify the dominant negative nature of these mutations. Remarkably, PKM2-H391Y co-expressed cells showed a maximal effect on all the studied parameters. Such a dominant negative impaired function of PKM2 in tumor development is not known; also evidencing for the first time the possible predisposition of BS patients with impaired PKM2 activity to cancer, and the importance of studying genetic variations in PKM2 in future to understand their relevance in cancer in general. ## Regulatory circuits Cancer cells are characterized by a reprogramming of energy metabolism. Over the last decade, understanding of the metabolic changes that occur in cancer has increased dramatically, and there is great interest in targeting metabolism for cancer therapy. PKM2 plays a key role in modulating glucose metabolism to support cell proliferation. PKM2, like other PK isoforms, catalyzes the last energy-generating step in glycolysis, but is unique in its capacity to be regulated. PKM2 is regulated on several cellular levels, including gene expression, alternative splicing and post-translational modification. In addition, PKM2 is regulated by key metabolic intermediates and interacts with more than twenty different proteins. Hence, this isoenzyme is an important regulator of glycolysis and additional functions in other novel roles that have recently emerged. Recent evidence indicates that intervening in the complex regulatory network of PKM2 has severe consequences on tumor cell proliferation, indicating the potential of this enzyme as a target for tumor therapy. ## Bacterial pathogenesis With the yeast two-hybrid system, gonococcal Opa proteins were found to interact with PKM2. The results suggest that direct molecular interaction with the host metabolic enzyme PKM2 is required for the acquisition of pyruvate and for gonococcal growth and survival. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

PKM2 Pyruvate kinase isozymes M1/M2 (PKM1/M2), also known as pyruvate kinase muscle isozyme (PKM), pyruvate kinase type K, cytosolic thyroid hormone-binding protein (CTHBP), thyroid hormone-binding protein 1 (THBP1), or opa-interacting protein 3 (OIP3), is an enzyme that in humans is encoded by the PKM2 gene.[1][2][3][4] PKM2 is an isoenzyme of the glycolytic enzyme pyruvate kinase. Depending upon the different metabolic functions of the tissues, different isoenzymes of pyruvate kinase are expressed. PKM2 is expressed in some differentiated tissues, such as lung, fat tissue, retina, and pancreatic islets, as well as in all cells with a high rate of nucleic acid synthesis, such as normal proliferating cells, embryonic cells, and especially tumor cells.[5][6][7][8][9][10][11] # Structure Two isozymes are encoded by the PKM gene: PKM1 and PKM2. The M-gene consists of 12 exons and 11 introns. PKM1 and PKM2 are different splicing products of the M-gene (exon 9 for PKM1 and exon 10 for PKM2) and solely differ in 23 amino acids within a 56-amino acid stretch (aa 378-434) at their carboxy terminus.[12][13] # Function Pyruvate kinase catalyzes the last step within glycolysis, the dephosphorylation of phosphoenolpyruvate to pyruvate, and is responsible for net ATP production within the glycolytic sequence. In contrast to mitochondrial respiration, energy regeneration by pyruvate kinase is independent from oxygen supply and allows survival of the organs under hypoxic conditions often found in solid tumors.[14] The involvement of this enzyme in a variety of pathways, protein–protein interactions, and nuclear transport suggests its potential to perform multiple nonglycolytic functions with diverse implications, although multidimensional role of this protein is as yet not fully explored. However, a functional role in angiogenesis the so-called process of blood vessel formation by interaction and regulation of Jmjd8 has been shown.[15][16] # Localization ## Tissue The PKM1 isozyme is expressed in organs that are strongly dependent upon a high rate of energy regeneration, such as muscle and brain.[17][18][19] ## Subcellular PKM2 is a cytosolic enzyme that is associated with other glycolytic enzymes, i.e., hexokinase, glyceraldehyde 3-P dehydrogenase, phosphoglycerate kinase, phosphoglyceromutase, enolase, and lactate dehydrogenase within a so-called glycolytic enzyme complex.[19][20][21][22] However, PKM2 contains an inducible nuclear localization signal in its C-terminal domain. The role of PKM2 within the nucleus is complex, since pro-proliferative but also pro-apoptotic stimuli have been described. On the one hand, nuclear PKM2 was found to participate in the phosphorylation of histone 1 by direct phosphate transfer from PEP to histone 1. On the other hand, nuclear translocation of PKM2 induced by a somatostatin analogue, H2O2, or UV light has been linked with caspase-independent programmed cell death.[23][24][25] # Clinical significance ## Bi-functional role within tumors PKM2 is expressed in most human tumors.[7][10][11] Initially, a switch from PKM1 to PKM2 expression during tumorigenesis was discussed.[26] These conclusions, however, were the result of misinterpretation of western blots that had used PKM1-expressing mouse muscle as the sole non-cancer tissue. In clinical cancer samples, solely an up-regulation of PKM2, but no cancer specificity, could be confirmed.[27] In contrast to the closely homologous PKM1, which always occurs in a highly active tetrameric form and which is not allosterically regulated, PKM2 may occur in a tetrameric form but also in a dimeric form. The tetrameric form of PKM2 has a high affinity to its substrate phosphoenolpyruvate (PEP), and is highly active at physiological PEP concentrations. When PKM2 is mainly in the highly active tetrameric form, which is the case in differentiated tissues and most normal proliferating cells, glucose is converted to pyruvate under the production of energy. Meanwhile, the dimeric form of PKM2 is characterized by a low affinity to its substrate PEP and is nearly inactive at physiological PEP concentrations. When PKM2 is mainly in the less active dimeric form, which is the case in tumor cells, all glycolytic intermediates above pyruvate kinase accumulate and are channelled into synthetic processes, which branch off from glycolytic intermediates such as nucleic acid-, phospholipid-, and amino acid synthesis.[17][18][19] Nucleic acids, phospholipids, and amino acids are important cell building-blocks, which are greatly needed by highly proliferating cells, such as tumor cells. Due to the key position of pyruvate kinase within glycolysis, the tetramer:dimer ratio of PKM2 determines whether glucose carbons are converted to pyruvate and lactate under the production of energy (tetrameric form) or channelled into synthetic processes (dimeric form).[17][18][19] In tumor cells, PKM2 is mainly in the dimeric form and has, therefore, been termed Tumor M2-PK. The quantification of Tumor M2-PK in plasma and stool is a tool for early detection of tumors and follow-up studies during therapy. The dimerization of PKM2 in tumor cells is induced by direct interaction of PKM2 with different oncoproteins (pp60v-src, HPV-16 E7, and A-Raf).[20][21][28][29][30] The physiological function of the interaction between PKM2 and HERC1 as well as between PKM2 and PKCdelta is unknown).[31][32] However, the tetramer:dimer ratio of PKM2 is not stationary value. High levels of the glycolytic intermediate fructose 1,6-bisphosphate induce the re-association of the dimeric form of PKM2 to the tetrameric form. As a consequence, glucose is converted to pyruvate and lactate with the production of energy until fructose 1,6-bisphosphate levels drop below a critical value to allow dissociation to the dimeric form. This regulation is termed metabolic budget system.[18][19][33] Another activator of PKM2 is the amino acid serine.[18] The thyroid hormone 3,3´,5-triiodi-L-tyhronine (T3) binds to the monomeric form of PKM2 and prevents its association to the tetrameric form.[34] In tumor cells, the increased rate of lactate production in the presence of oxygen is termed the Warburg effect. Genetic manipulation of cancer cells so that they produce adult PKM1 instead of PKM2 reverses the Warburg effect and reduces the growth rate of these modified cancer cells.[26] Accordingly, cotransfection of NIH 3T3 cells with gag-A-Raf and a kinase dead mutant of PKM2 reduced colony whereas cotransfection with gag-A-Raf and wild type PKM2 led to a doubling of focus formation.[35] The dimeric form of PKM2 has been observed to have protein kinase activity in tumor cells. It is able to bind to and phosphorylate the histone H3 of chromatin in cancer cells, thereby having a role in the regulation of gene expression.[36] This modification of histone H3 and the resulting involvement in gene expression regulation can be a cause of tumor cell proliferation.[36] The pyruvate kinase activity of PKM2 can be promoted by SAICAR (succinylaminoimidazolecarboxamide ribose-5′-phosphate), an intermediate in purine biosynthesis. In cancer cells, glucose starvation leads to a rise in SAICAR levels and the subsequent stimulation of pyruvate kinase activity of PKM2. This allows for the completion of the glycolytic pathway to produce pyruvate and, therefore, survival under glucose deprivation.[37] In addition, an abundance of SAICAR can modify glucose absorption and lactate production in cancer cells.[37] However, it has been shown that SAICAR binding also sufficiently stimulates the protein kinase activity of PKM2 in tumor cells.[38] In turn, the SAICAR-PKM2 complex can potentially phosphorylate a number of other protein kinases using PEP as the phosphate donor. Many of these proteins contribute to the regulation of cancer cell proliferation. Specifically, PKM2 can be a component in mitogen-activated protein kinase (MAPK) signaling, which is associated with increased cell proliferation if functioning improperly. This provides a potential link between SAICAR-activated PKM2 and cancer cell growth.[38] ## Natural mutations and carcinogenesis Two missense mutations, H391Y and K422R, of PKM2 were found in cells from Bloom syndrome patients prone to developing cancer. Results show that, despite the presence of mutations in the inter-subunit contact domain, the K422R and H391Y mutant proteins maintained their homotetrameric structure, similar to the wild-type protein, but showed a loss of activity of 75 and 20%, respectively. H391Y showed a 6-fold increase in affinity for its substrate phosphoenolpyruvate and behaved like a non-allosteric protein with compromised cooperative binding. However, the affinity for phosphoenolpyruvate was lost significantly in K422R. Unlike K422R, H391Y showed enhanced thermal stability, stability over a range of pH values, a lesser effect of the allosteric inhibitor Phe, and resistance toward structural alteration upon binding of the activator (fructose 1,6-bisphosphate) and inhibitor (Phe). Both mutants showed a slight shift in the pH optimum from 7.4 to 7.0.[39] The co-expression of homotetrameric wild type and mutant PKM2 in the cellular milieu resulting in the interaction between the two at the monomer level was substantiated further by in vitro experiments. The cross-monomer interaction significantly altered the oligomeric state of PKM2 by favoring dimerisation and heterotetramerization. In silico study provided an added support in showing that hetero-oligomerization was energetically favorable. The hetero-oligomeric populations of PKM2 showed altered activity and affinity, and their expression resulted in an increased growth rate of Escherichia coli as well as mammalian cells, along with an increased rate of polyploidy. These features are known to be essential to tumor progression.[40] Further, cells stably expressing exogenous wild- or mutant-PKM2 (K422R or H391Y) or co-expressing both wild and mutant (PKM2-K422R or PKM2-H391Y), were assessed for cancer metabolism and tumorigenic potential. Cells co-expressing PKM2 and mutant (K422R or H391Y) showed significantly aggressive cancer metabolism, compared to cells expressing either wild or mutant PKM2 independently. A similar trend was observed for oxidative endurance, tumorigenic potential, cellular proliferation and tumor growth. These observations signify the dominant negative nature of these mutations. Remarkably, PKM2-H391Y co-expressed cells showed a maximal effect on all the studied parameters. Such a dominant negative impaired function of PKM2 in tumor development is not known; also evidencing for the first time the possible predisposition of BS patients with impaired PKM2 activity to cancer, and the importance of studying genetic variations in PKM2 in future to understand their relevance in cancer in general.[41] ## Regulatory circuits Cancer cells are characterized by a reprogramming of energy metabolism. Over the last decade, understanding of the metabolic changes that occur in cancer has increased dramatically, and there is great interest in targeting metabolism for cancer therapy. PKM2 plays a key role in modulating glucose metabolism to support cell proliferation. PKM2, like other PK isoforms, catalyzes the last energy-generating step in glycolysis, but is unique in its capacity to be regulated. PKM2 is regulated on several cellular levels, including gene expression, alternative splicing and post-translational modification. In addition, PKM2 is regulated by key metabolic intermediates and interacts with more than twenty different proteins. Hence, this isoenzyme is an important regulator of glycolysis and additional functions in other novel roles that have recently emerged. Recent evidence indicates that intervening in the complex regulatory network of PKM2 has severe consequences on tumor cell proliferation, indicating the potential of this enzyme as a target for tumor therapy.[42] ## Bacterial pathogenesis With the yeast two-hybrid system, gonococcal Opa proteins were found to interact with PKM2. The results suggest that direct molecular interaction with the host metabolic enzyme PKM2 is required for the acquisition of pyruvate and for gonococcal growth and survival.[43] # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. [§ 1] - ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

https://www.wikidoc.org/index.php/PKM2

8a8156ca68a2854ae529f331162de286ebb98759

wikidoc

PKN2

PKN2 Serine/threonine-protein kinase N2 is an enzyme that in humans is encoded by the PKN2 gene. # Interactions PKN2 has been shown to interact with: - AKT1, - NCK1, - PTPN13, - Phosphoinositide-dependent kinase-1, and - RHOA. # Further reading - Quilliam LA, Lambert QT, Mickelson-Young LA, Westwick JK, Sparks AB, Kay BK, Jenkins NA, Gilbert DJ, Copeland NG, Der CJ (1997). "Isolation of a NCK-associated kinase, PRK2, an SH3-binding protein and potential effector of Rho protein signaling". J. Biol. Chem. 271 (46): 28772–28776. doi:10.1074/jbc.271.46.28772. PMID 8910519..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - Yu W, Liu J, Morrice NA, Wettenhall RE (1997). "Isolation and characterization of a structural homologue of human PRK2 from rat liver. Distinguishing substrate and lipid activator specificities". J. Biol. Chem. 272 (15): 10030–10034. doi:10.1074/jbc.272.15.10030. PMID 9092545. - Vincent S, Settleman J (1997). "The PRK2 kinase is a potential effector target of both Rho and Rac GTPases and regulates actin cytoskeletal organization". Mol. Cell. Biol. 17 (4): 2247–56. PMC 232074. PMID 9121475. - Cryns VL, Byun Y, Rana A, Mellor H, Lustig KD, Ghanem L, Parker PJ, Kirschner MW, Yuan J (1997). "Specific proteolysis of the kinase protein kinase C-related kinase 2 by caspase-3 during apoptosis. Identification by a novel, small pool expression cloning strategy". J. Biol. Chem. 272 (47): 29449–29453. doi:10.1074/jbc.272.47.29449. PMID 9368003. - Braverman LE, Quilliam LA (1999). "Identification of Grb4/Nckbeta, a src homology 2 and 3 domain-containing adapter protein having similar binding and biological properties to Nck". J. Biol. Chem. 274 (9): 5542–5549. doi:10.1074/jbc.274.9.5542. PMID 10026169. - Flynn P, Mellor H, Casamassima A, Parker PJ (2000). "Rho GTPase control of protein kinase C-related protein kinase activation by 3-phosphoinositide-dependent protein kinase". J. Biol. Chem. 275 (15): 11064–11070. doi:10.1074/jbc.275.15.11064. PMID 10753910. - Sun W, Vincent S, Settleman J, Johnson GL (2000). "MEK kinase 2 binds and activates protein kinase C-related kinase 2. Bifurcation of kinase regulatory pathways at the level of an MAPK kinase kinase". J. Biol. Chem. 275 (32): 24421–24428. doi:10.1074/jbc.M003148200. PMID 10818102. - Koh H, Lee KH, Kim D, Kim S, Kim JW, Chung J (2000). "Inhibition of Akt and its anti-apoptotic activities by tumor necrosis factor-induced protein kinase C-related kinase 2 (PRK2) cleavage". J. Biol. Chem. 275 (44): 34451–34458. doi:10.1074/jbc.M001753200. PMID 10926925. - Gross C, Heumann R, Erdmann KS (2001). "The protein kinase C-related kinase PRK2 interacts with the protein tyrosine phosphatase PTP-BL via a novel PDZ domain binding motif". FEBS Lett. 496 (2–3): 101–104. doi:10.1016/S0014-5793(01)02401-2. PMID 11356191. - Hodgkinson CP, Sale GJ (2002). "Regulation of both PDK1 and the phosphorylation of PKC-zeta and -delta by a C-terminal PRK2 fragment". Biochemistry. 41 (2): 561–569. doi:10.1021/bi010719z. PMID 11781095. - McDonald C, Vacratsis PO, Bliska JB, Dixon JE (2003). "The yersinia virulence factor YopM forms a novel protein complex with two cellular kinases". J. Biol. Chem. 278 (20): 18514–18523. doi:10.1074/jbc.M301226200. PMID 12626518. - Anderson NL, Polanski M, Pieper R, Gatlin T, Tirumalai RS, Conrads TP, Veenstra TD, Adkins JN, Pounds JG, Fagan R, Lobley A (2004). "The human plasma proteome: a nonredundant list developed by combination of four separate sources". Mol. Cell. Proteomics. 3 (4): 311–326. doi:10.1074/mcp.M300127-MCP200. PMID 14718574. - Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP (2004). "Large-scale characterization of HeLa cell nuclear phosphoproteins". Proc. Natl. Acad. Sci. U.S.A. 101 (33): 12130–12135. doi:10.1073/pnas.0404720101. PMC 514446. PMID 15302935. - Yarrow JC, Totsukawa G, Charras GT, Mitchison TJ (2005). "Screening for cell migration inhibitors via automated microscopy reveals a Rho-kinase inhibitor". Chem. Biol. 12 (3): 385–395. doi:10.1016/j.chembiol.2005.01.015. PMID 15797222. - DeGiorgis JA, Jaffe H, Moreira JE, Carlotti CG, Leite JP, Pant HC, Dosemeci A (2005). "Phosphoproteomic analysis of synaptosomes from human cerebral cortex". J. Proteome Res. 4 (2): 306–315. doi:10.1021/pr0498436. PMID 15822905. - Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S (2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Res. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.

PKN2 Serine/threonine-protein kinase N2 is an enzyme that in humans is encoded by the PKN2 gene.[1][2][3] # Interactions PKN2 has been shown to interact with: - AKT1,[4] - NCK1,[5][6] - PTPN13,[7] - Phosphoinositide-dependent kinase-1,[8][9] and - RHOA.[5][10] # Further reading - Quilliam LA, Lambert QT, Mickelson-Young LA, Westwick JK, Sparks AB, Kay BK, Jenkins NA, Gilbert DJ, Copeland NG, Der CJ (1997). "Isolation of a NCK-associated kinase, PRK2, an SH3-binding protein and potential effector of Rho protein signaling". J. Biol. Chem. 271 (46): 28772–28776. doi:10.1074/jbc.271.46.28772. PMID 8910519..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - Yu W, Liu J, Morrice NA, Wettenhall RE (1997). "Isolation and characterization of a structural homologue of human PRK2 from rat liver. Distinguishing substrate and lipid activator specificities". J. Biol. Chem. 272 (15): 10030–10034. doi:10.1074/jbc.272.15.10030. PMID 9092545. - Vincent S, Settleman J (1997). "The PRK2 kinase is a potential effector target of both Rho and Rac GTPases and regulates actin cytoskeletal organization". Mol. Cell. Biol. 17 (4): 2247–56. PMC 232074. PMID 9121475. - Cryns VL, Byun Y, Rana A, Mellor H, Lustig KD, Ghanem L, Parker PJ, Kirschner MW, Yuan J (1997). "Specific proteolysis of the kinase protein kinase C-related kinase 2 by caspase-3 during apoptosis. Identification by a novel, small pool expression cloning strategy". J. Biol. Chem. 272 (47): 29449–29453. doi:10.1074/jbc.272.47.29449. PMID 9368003. - Braverman LE, Quilliam LA (1999). "Identification of Grb4/Nckbeta, a src homology 2 and 3 domain-containing adapter protein having similar binding and biological properties to Nck". J. Biol. Chem. 274 (9): 5542–5549. doi:10.1074/jbc.274.9.5542. PMID 10026169. - Flynn P, Mellor H, Casamassima A, Parker PJ (2000). "Rho GTPase control of protein kinase C-related protein kinase activation by 3-phosphoinositide-dependent protein kinase". J. Biol. Chem. 275 (15): 11064–11070. doi:10.1074/jbc.275.15.11064. PMID 10753910. - Sun W, Vincent S, Settleman J, Johnson GL (2000). "MEK kinase 2 binds and activates protein kinase C-related kinase 2. Bifurcation of kinase regulatory pathways at the level of an MAPK kinase kinase". J. Biol. Chem. 275 (32): 24421–24428. doi:10.1074/jbc.M003148200. PMID 10818102. - Koh H, Lee KH, Kim D, Kim S, Kim JW, Chung J (2000). "Inhibition of Akt and its anti-apoptotic activities by tumor necrosis factor-induced protein kinase C-related kinase 2 (PRK2) cleavage". J. Biol. Chem. 275 (44): 34451–34458. doi:10.1074/jbc.M001753200. PMID 10926925. - Gross C, Heumann R, Erdmann KS (2001). "The protein kinase C-related kinase PRK2 interacts with the protein tyrosine phosphatase PTP-BL via a novel PDZ domain binding motif". FEBS Lett. 496 (2–3): 101–104. doi:10.1016/S0014-5793(01)02401-2. PMID 11356191. - Hodgkinson CP, Sale GJ (2002). "Regulation of both PDK1 and the phosphorylation of PKC-zeta and -delta by a C-terminal PRK2 fragment". Biochemistry. 41 (2): 561–569. doi:10.1021/bi010719z. PMID 11781095. - McDonald C, Vacratsis PO, Bliska JB, Dixon JE (2003). "The yersinia virulence factor YopM forms a novel protein complex with two cellular kinases". J. Biol. Chem. 278 (20): 18514–18523. doi:10.1074/jbc.M301226200. PMID 12626518. - Anderson NL, Polanski M, Pieper R, Gatlin T, Tirumalai RS, Conrads TP, Veenstra TD, Adkins JN, Pounds JG, Fagan R, Lobley A (2004). "The human plasma proteome: a nonredundant list developed by combination of four separate sources". Mol. Cell. Proteomics. 3 (4): 311–326. doi:10.1074/mcp.M300127-MCP200. PMID 14718574. - Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP (2004). "Large-scale characterization of HeLa cell nuclear phosphoproteins". Proc. Natl. Acad. Sci. U.S.A. 101 (33): 12130–12135. doi:10.1073/pnas.0404720101. PMC 514446. PMID 15302935. - Yarrow JC, Totsukawa G, Charras GT, Mitchison TJ (2005). "Screening for cell migration inhibitors via automated microscopy reveals a Rho-kinase inhibitor". Chem. Biol. 12 (3): 385–395. doi:10.1016/j.chembiol.2005.01.015. PMID 15797222. - DeGiorgis JA, Jaffe H, Moreira JE, Carlotti CG, Leite JP, Pant HC, Dosemeci A (2005). "Phosphoproteomic analysis of synaptosomes from human cerebral cortex". J. Proteome Res. 4 (2): 306–315. doi:10.1021/pr0498436. PMID 15822905. - Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S (2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Res. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.

https://www.wikidoc.org/index.php/PKN2

82bf3d9417f8277ed4267ab4f12bec667465ff9d

wikidoc

PLD3

PLD3 Phospholipase D3, also known as PLD3, is a protein that in humans is encoded by the PLD3 gene. PLD3 belongs to the phospholipase D superfamily because it contains the two HKD motifs common to members of the phospholipase D family, however, it has no known catalytic function similar to PLD1 or PLD2. PLD3 is highly expressed in the brain in both humans and mice, and is mainly localized in the endoplasmic reticulum (ER) and the lysosome. PLD3 may play a role in regulating the lysosomal system, myogenesis, late-stage neurogenesis, inhibiting insulin signal transduction, and amyloid precursor protein (APP) processing. The involvement in PLD3 in the lysosomal system and in APP processing and the loss-of-function mutations in PLD3 are thought to be linked to late-onset Alzheimer's disease (LOAD). However, there are also studies that challenge the association between PLD3 and Alzheimer's disease (AD). How APP processing is affected by PLD3 during AD still remains unclear, and its role in the pathogenesis of AD is ambiguous. PLD3 may contribute to the onset of AD by a mechanism other than by influencing APP metabolism, with one proposed mechanism suggesting that PLD3 contributes to the onset of AD by impairing the endosomal-lysosomal system. In 2017, PLD3 was shown to have an association with another neurodegenerative disease, spinocerebellar ataxia. # Genetics PLD3 was first characterized as a human homolog of the HindIII K4L protein in the vaccinia virus, having a DNA sequence 48.1% similar to the viral gene. The PLD3 gene in humans is located at chromosome 19q13.2, with a sequence comprising at least 15 exons and is alternatively spliced at the low GC 5' UTR into 25 predicted transcripts. Translation of the 490 amino acid-long PLD3 protein is initiated around exons 5 to 7, and ends at the stop codon in exon 15. # Structure PLD3 is a 490 amino acid-long type 2 transmembrane protein, unlike PLD1 and PLD2 which do not contain a transmembrane protein domain in their protein structure. The cytosolic N-terminal of the protein faces towards the cytoplasm of the cell, and lacks consensus sites for N-glycosylation. The N-terminus is also predicted to contain a transmembrane domain. The bulk of the protein is located in the ER lumen, containing the C-terminal domain. The C-terminal domain contains seven glycosylation sites along with a prenylation motif and two HXKXXXXD/E (HKD) motifs. In PLD1 and PLD2, this is the catalytic domain or active site of the protein, which is why PLD3 was assigned to the phospholipase D superfamily. However, PLD3 has no known catalytic activity and aside from presence of the HKD motifs, PLD3 has no structural commonalities with PLD1 or PLD2. # Tissue and subcellular distribution Expression of PLD3 in tissues differs with the transcript size of its mRNA. The longer 2200 base pair transcript is ubiquitously expressed in the body, exhibiting higher expression levels in the heart, skeletal muscle, and the brain. Meanwhile, the shorter 1700 base pair transcript is found in abundance in the brain, but at low expression in non-nervous tissue. PLD3 expression is especially pronounced in mature neurons in the mammalian forebrain. High expression of PLD3 is specifically seen in the hippocampus and the frontal, temporal, and occipital lobes in the cerebral cortex. The PLD3 gene is also found with high expression in the cerebellum. Subcellular localization of PLD3 is thought to primarily be in the endoplasmic reticulum (ER), as it has been shown to co-localize with protein disulfide-isomerase, a protein known to be a marker for the ER. PLD3 may also be localized in lysosomes, co-localizing with lysosomal markers LAMP1 and LAMP2 in lysosomes in separate studies. PLD3 was identified as a protein in insulin secretory granules derived from pancreatic beta cells. # Function PLD3 is a member of the phospholipase D protein family, however, it has no known catalytic activity like that of PLD1 and PLD2. PLD3 may play some role in influencing protein processing through the lysosome as well as a regulatory role in lysosomal morphology. Some studies suggest that PLD3 is involved in amyloid precursor protein (APP) processing and regulating amyloid beta (Aβ) levels. Overexpression of wildtype PLD3 is linked to a decrease in intracellular APP and extracellular Aβ isoforms Aβ40 and Aβ42, while a knockdown of PLD3 is linked to an increase in extracellular Aβ40 and Aβ42. PLD3 was implied to be involved in sensing oxidative stress, such that suppressing the PLD3 gene with short hairpin RNA increased the viability of cells exposed to oxidative stress. Increased PLD3 expression was shown to increase myotube formation in differentiated mouse myoblasts in vitro, and ER stress which also increases myotube formation was also shown to increase PLD3 expression. Decreasing PLD3 expression meanwhile decreases myotube formation. These findings suggest a possible role of PLD3 in myogenesis, although its exact mechanism of action remains unknown. Overexpression of PLD3 in mouse myoblasts in vitro may inhibit Akt phosphorylation and block signal transduction during insulin signalling. PLD3 may be involved in the later stages of neurogenesis, contributing to processes associated with neurotransmission, target cell innervation, and neuronal survival. Elevated expression of PLD3 was found to be one of the consistent factors that contribute to the self-renewal activity of hematopoietic stem cell populations, suggesting a possible role of PLD3 in the mechanism behind the maintenance of durable, long-term self-renewing cell populations. # Interactions The human progranulin protein (PGRN), encoded by the human granulin gene (GRN), is co-expressed with and interacts with PLD3 accumulated on neuritic plaques in AD brains. PLD3 may interact with APP and amyloid beta, as some studies indicate that PLD3 is involved with APP processing and regulating Aβ levels. PLD3 may also interact with Akt and insulin in myoblasts in vitro. # Clinical significance ## Alzheimer's disease Mutations in PLD3 have been studied for their potential role in the pathogenesis of late-onset Alzheimer's disease (LOAD). In 2013, Cruchaga et al. found that a particular rare coding variant or missense mutation in PLD3 (Val232Met) doubled the risk for Alzheimer's disease among cases and controls of European and African-American descent. PLD3 mRNA and protein expression was reduced in AD brains compared with non-AD brains in regions that PLD3 is normally found with high expression, and another study also found that PLD3 accumulates on neuritic plaques in AD brains. A common PLD3 single nucleotide polymorphism (SNP) was also found to have an association with Aβ pathology among normal, healthy individuals, suggesting that common PLD3 variants may also be involved in the pathogenesis of AD. A meta-analysis conducted in 2015 concluded that the Val232Met PLD3 variant has a modest effect on increasing AD risk. However, the findings from Cruchaga et al. could not be replicated in follow-up studies on the role of PLD3 in both familial and non-familial, sporadic Alzheimer's disease in Western population samples. The Val232Met PLD3 mutant was also not identified in a sample of AD patients and healthy control subjects from mainland China, suggesting that this particular PLD3 mutant may not significantly affect AD risk in the mainland Chinese population. A study showed that while there is an excess of PLD3 variants in LOAD, none of the variants described by Cruchaga et al. drive the association between PLD3 and LOAD in a European cohort, including the Val232Met variant. This study along with an additional study also demonstrated that these rare coding variants of PLD3 were not observed in early-onset AD (EOAD) in a European cohort, suggesting that PLD3 may not have a role in EOAD. The underlying mechanisms on how mutations in PLD3 affects APP processing in AD remains unclear. Results from the study by Cruchaga et al. indicated that PLD3 loss-of-function increases risk for Alzheimer's disease by affecting APP processing. The involvement of PLD3 in APP processing was challenged in a recent study which showed that a PLD3 loss-of-function does not significantly affect the burden of amyloid plaques on AD development in mice. PLD3 loss-of-function in this study did, however, change the morphology of the lysosomal system in neurons, indicating that PLD3 loss-of-function may still be involved in the pathophysiology of AD through some other mechanism such as by contributing to the impairment of the endosomal-lysosomal system that occurs during AD. ## Spinocerebellar ataxia In 2017, the PLD3 gene was identified as one of the novel genes linked to spinocerebellar ataxia, another neurodegenerative genetic disease.

PLD3 Phospholipase D3, also known as PLD3, is a protein that in humans is encoded by the PLD3 gene.[1][2] PLD3 belongs to the phospholipase D superfamily because it contains the two HKD motifs common to members of the phospholipase D family, however, it has no known catalytic function similar to PLD1 or PLD2. PLD3 is highly expressed in the brain in both humans and mice, and is mainly localized in the endoplasmic reticulum (ER) and the lysosome. PLD3 may play a role in regulating the lysosomal system, myogenesis, late-stage neurogenesis, inhibiting insulin signal transduction, and amyloid precursor protein (APP) processing. The involvement in PLD3 in the lysosomal system and in APP processing and the loss-of-function mutations in PLD3 are thought to be linked to late-onset Alzheimer's disease (LOAD).[3][4] However, there are also studies that challenge the association between PLD3 and Alzheimer's disease (AD).[5][6][7][8][9] How APP processing is affected by PLD3 during AD still remains unclear, and its role in the pathogenesis of AD is ambiguous.[9][10] PLD3 may contribute to the onset of AD by a mechanism other than by influencing APP metabolism, with one proposed mechanism suggesting that PLD3 contributes to the onset of AD by impairing the endosomal-lysosomal system.[9] In 2017, PLD3 was shown to have an association with another neurodegenerative disease, spinocerebellar ataxia.[11] # Genetics PLD3 was first characterized as a human homolog of the HindIII K4L protein in the vaccinia virus, having a DNA sequence 48.1% similar to the viral gene.[12] The PLD3 gene in humans is located at chromosome 19q13.2, with a sequence comprising at least 15 exons and is alternatively spliced at the low GC 5' UTR into 25 predicted transcripts.[13][14] Translation of the 490 amino acid-long PLD3 protein is initiated around exons 5 to 7, and ends at the stop codon in exon 15.[13] # Structure PLD3 is a 490 amino acid-long type 2 transmembrane protein, unlike PLD1 and PLD2 which do not contain a transmembrane protein domain in their protein structure.[13] The cytosolic N-terminal of the protein faces towards the cytoplasm of the cell, and lacks consensus sites for N-glycosylation.[13] The N-terminus is also predicted to contain a transmembrane domain.[15] The bulk of the protein is located in the ER lumen, containing the C-terminal domain.[16] The C-terminal domain contains seven glycosylation sites along with a prenylation motif and two HXKXXXXD/E (HKD) motifs.[13] In PLD1 and PLD2, this is the catalytic domain or active site of the protein, which is why PLD3 was assigned to the phospholipase D superfamily.[13] However, PLD3 has no known catalytic activity and aside from presence of the HKD motifs, PLD3 has no structural commonalities with PLD1 or PLD2.[13] # Tissue and subcellular distribution Expression of PLD3 in tissues differs with the transcript size of its mRNA.[13] The longer 2200 base pair transcript is ubiquitously expressed in the body, exhibiting higher expression levels in the heart, skeletal muscle, and the brain.[13] Meanwhile, the shorter 1700 base pair transcript is found in abundance in the brain, but at low expression in non-nervous tissue.[13][17] PLD3 expression is especially pronounced in mature neurons in the mammalian forebrain.[17] High expression of PLD3 is specifically seen in the hippocampus and the frontal, temporal, and occipital lobes in the cerebral cortex.[3][17] The PLD3 gene is also found with high expression in the cerebellum.[11] Subcellular localization of PLD3 is thought to primarily be in the endoplasmic reticulum (ER), as it has been shown to co-localize with protein disulfide-isomerase, a protein known to be a marker for the ER.[13] PLD3 may also be localized in lysosomes, co-localizing with lysosomal markers LAMP1 and LAMP2 in lysosomes in separate studies.[9][18] PLD3 was identified as a protein in insulin secretory granules derived from pancreatic beta cells.[19] # Function PLD3 is a member of the phospholipase D protein family, however, it has no known catalytic activity like that of PLD1 and PLD2.[13] PLD3 may play some role in influencing protein processing through the lysosome as well as a regulatory role in lysosomal morphology.[9] Some studies suggest that PLD3 is involved in amyloid precursor protein (APP) processing and regulating amyloid beta (Aβ) levels.[3] Overexpression of wildtype PLD3 is linked to a decrease in intracellular APP and extracellular Aβ isoforms Aβ40 and Aβ42, while a knockdown of PLD3 is linked to an increase in extracellular Aβ40 and Aβ42.[3] PLD3 was implied to be involved in sensing oxidative stress, such that suppressing the PLD3 gene with short hairpin RNA increased the viability of cells exposed to oxidative stress.[20] Increased PLD3 expression was shown to increase myotube formation in differentiated mouse myoblasts in vitro, and ER stress which also increases myotube formation was also shown to increase PLD3 expression.[15] Decreasing PLD3 expression meanwhile decreases myotube formation.[15] These findings suggest a possible role of PLD3 in myogenesis, although its exact mechanism of action remains unknown.[15] Overexpression of PLD3 in mouse myoblasts in vitro may inhibit Akt phosphorylation and block signal transduction during insulin signalling.[21] PLD3 may be involved in the later stages of neurogenesis, contributing to processes associated with neurotransmission, target cell innervation, and neuronal survival.[17] Elevated expression of PLD3 was found to be one of the consistent factors that contribute to the self-renewal activity of hematopoietic stem cell populations, suggesting a possible role of PLD3 in the mechanism behind the maintenance of durable, long-term self-renewing cell populations.[22] # Interactions The human progranulin protein (PGRN), encoded by the human granulin gene (GRN), is co-expressed with and interacts with PLD3 accumulated on neuritic plaques in AD brains.[23] PLD3 may interact with APP and amyloid beta, as some studies indicate that PLD3 is involved with APP processing and regulating Aβ levels.[3] PLD3 may also interact with Akt and insulin in myoblasts in vitro.[21] # Clinical significance ## Alzheimer's disease Mutations in PLD3 have been studied for their potential role in the pathogenesis of late-onset Alzheimer's disease (LOAD).[3] In 2013, Cruchaga et al. found that a particular rare coding variant or missense mutation in PLD3 (Val232Met) doubled the risk for Alzheimer's disease among cases and controls of European and African-American descent.[3] PLD3 mRNA and protein expression was reduced in AD brains compared with non-AD brains in regions that PLD3 is normally found with high expression, and another study also found that PLD3 accumulates on neuritic plaques in AD brains.[3][23] A common PLD3 single nucleotide polymorphism (SNP) was also found to have an association with Aβ pathology among normal, healthy individuals, suggesting that common PLD3 variants may also be involved in the pathogenesis of AD.[24] A meta-analysis conducted in 2015 concluded that the Val232Met PLD3 variant has a modest effect on increasing AD risk.[4] However, the findings from Cruchaga et al. could not be replicated in follow-up studies on the role of PLD3 in both familial and non-familial, sporadic Alzheimer's disease in Western population samples.[5][6][7] The Val232Met PLD3 mutant was also not identified in a sample of AD patients and healthy control subjects from mainland China, suggesting that this particular PLD3 mutant may not significantly affect AD risk in the mainland Chinese population.[8] A study showed that while there is an excess of PLD3 variants in LOAD, none of the variants described by Cruchaga et al. drive the association between PLD3 and LOAD in a European cohort, including the Val232Met variant.[25] This study along with an additional study also demonstrated that these rare coding variants of PLD3 were not observed in early-onset AD (EOAD) in a European cohort, suggesting that PLD3 may not have a role in EOAD.[25][26] The underlying mechanisms on how mutations in PLD3 affects APP processing in AD remains unclear.[10] Results from the study by Cruchaga et al. indicated that PLD3 loss-of-function increases risk for Alzheimer's disease by affecting APP processing.[3] The involvement of PLD3 in APP processing was challenged in a recent study which showed that a PLD3 loss-of-function does not significantly affect the burden of amyloid plaques on AD development in mice.[9] PLD3 loss-of-function in this study did, however, change the morphology of the lysosomal system in neurons, indicating that PLD3 loss-of-function may still be involved in the pathophysiology of AD through some other mechanism such as by contributing to the impairment of the endosomal-lysosomal system that occurs during AD.[27][28] - - ## Spinocerebellar ataxia In 2017, the PLD3 gene was identified as one of the novel genes linked to spinocerebellar ataxia, another neurodegenerative genetic disease.[11]

https://www.wikidoc.org/index.php/PLD3

07781a541a0280bbc73b09eed9bcd69b65e90dc9

wikidoc

PLD5

PLD5 Phospholipase D family, member 5 is a protein that in humans is encoded by the PLD5 gene. # Model organisms Model organisms have been used in the study of PLD5 function. A conditional knockout mouse line, called Pld5tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on mutant mice but no significant abnormalities were observed.

PLD5 Phospholipase D family, member 5 is a protein that in humans is encoded by the PLD5 gene.[1] # Model organisms Model organisms have been used in the study of PLD5 function. A conditional knockout mouse line, called Pld5tm1a(KOMP)Wtsi[6][7] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[8][9][10] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[4][11] Twenty five tests were carried out on mutant mice but no significant abnormalities were observed.[4]

https://www.wikidoc.org/index.php/PLD5

a7102907f452082a98909c0f25b79079ddb74877

wikidoc

PLK1

PLK1 Serine/threonine-protein kinase PLK1, also known as polo-like kinase 1 (PLK-1) or serine/threonine-protein kinase 13 (STPK13), is an enzyme that in humans is encoded by the PLK1 (polo-like kinase 1) gene. # Structure PLK1 consists of 603 amino acids and is 66kDa. In addition to the N-terminus kinase domain, there are two conserved polo-box regions of 30 amino acids at the C-terminus. Kinase activity is regulated at least in part, by the polo-boxes that are functionally important for both auto-inhibition and subcellular localization. # Localization During interphase, PLK1 localizes to centrosomes. In early mitosis, it associates with mitotic spindle poles. A recombinant GFP-PLK1 protein localizes to centromere/kinetochore region, suggesting a possible role for chromosome separation. # Cell cycle regulation Plk1 is an early trigger for G2/M transition. Plk1 supports the functional maturation of the centrosome in late G2/early prophase and establishment of the bipolar spindle. Plk1 phosphorylates and activates cdc25C, a phosphatase that dephosphorylates and activates the cyclinB/cdc2 complex. Plk phosphorylates and activates components of the anaphase-promoting complex (APC). The APC, which is activated by Fizzy-Cdc20 family proteins, is a cell cycle ubiquitin-protein ligase (E3) that degrades mitotic cyclins, chromosomal proteins that maintain cohesion of sister chromatids, and anaphase inhibitors. Abnormal spindle (Asp), a Polo kinase substrate, is a microtubule-associated protein essential for correct behavior of spindle poles and M-phase microtubules. Plk1 localizes to the central region of the spindle in late mitosis and associates with kinesin-like protein CHO1/MKLP1. The homologous motor protein in Drosophila is the pavarotti gene product (PAR). Studies have shown that the loss of PLK1 expression can induce pro-apoptotic pathways and inhibit growth. Based on yeast and murine studies of meiosis, human PLK1 may also have a regulatory function in meiosis. S. cerevisiae polo kinase CDC5 is required to phosphorylate and remove meiotic cohesion during the first cell division. In CDC5 depleted cells, kinetochores are bioriented during meiosis I, and Mam1, a protein essential for coorientation, fails to associate with kinetochores. CDC5 is believed to have roles in sister-kinetochore coorientation and chromosome segregation during meiosis I. # Role in tumorigenesis Plk1 is considered a proto-oncogene, whose overexpression is often observed in tumor cells. Aneuploidy and tumorigenesis can also result from centrosome abnormality, particularly centrosome amplification defects. Centrosome duplication and maturation regulated by Plk1 occurs from late S phase to prophase. Abnormal centrosome amplification may lead to multipolar spindles and results in unequal segregation of chromosomes.Plk1 overexpression also increases the centrosome size and/or centrosome number, which will also lead to improper segregation of chromosomes, aneuploidy, and tumorigenesis. Oncogenic properties of PLK1 are believed to be due to its role in driving cell cycle progression. Supporting evidence comes from the overexpression studies of PLK1 in NIH3T3 cell line. These cells become capable of forming foci and growing in soft agar and more importantly, these cells can form tumors in nude mice due to PLK1 overexpression. PLK1 has also been linked to known pathways that are altered during the neoplastic transformation. Retinoblastoma tumor suppressor (RB) pathway activation results in the repression of PLK1 promoter in a SWI/SNF chromatin remodeling complex dependent manner. In case of RB inactivation, PLK1 expression seems to be deregulated. This new finding suggests that PLK1 may be a target of the retinoblastoma tumor suppressor (RB) pathway. Moreover, PLK1 seems to be involved in the tumor suppressor p53 related pathways. Evidence suggests that PLK1 can inhibit transactivation and pro-apoptotic functions of p53 function by physical interaction and phosphorylation. # Clinical significance PLK1 is being studied as a target for cancer drugs. Many colon and lung cancers are caused by K-RAS mutations. These cancers are dependent on PLK1. When PLK1 expression was silenced with RNA interference in cell culture, K-RAS cells were selectively killed, without harming normal cells. PLK1 inhibitor volasertib is being evaluated in clinical trials for use in acute myeloid leukemia (AML). A combination of PLK1 and EGFR inhibition overcomes T790M-mediated drug resistance in vitro and in vivo in non-small cell lung cancer (NSCLC). In HNSCC mutations of the AJUBA mediate sensitivity to treatment with cell-cycle inhibitors including Plk1 inhibitor volasertib. Rigosertib is an experimental RAS/PI3K/PLK1 inhibitor. # Interactions PLK1 has been shown to interact with: - CHEK2, - NUDC, - PIN1, - PSMA3, - PSMA5, - PSMA6, - PSMA7, - PSMB3, and - TSC1. Structural analysis has been used to explain the broad specificity of PLK1.

PLK1 Serine/threonine-protein kinase PLK1, also known as polo-like kinase 1 (PLK-1) or serine/threonine-protein kinase 13 (STPK13), is an enzyme that in humans is encoded by the PLK1 (polo-like kinase 1) gene.[1] # Structure PLK1 consists of 603 amino acids and is 66kDa. In addition to the N-terminus kinase domain, there are two conserved polo-box regions of 30 amino acids at the C-terminus. Kinase activity is regulated at least in part, by the polo-boxes that are functionally important for both auto-inhibition and subcellular localization.[2] # Localization During interphase, PLK1 localizes to centrosomes. In early mitosis, it associates with mitotic spindle poles. A recombinant GFP-PLK1 protein localizes to centromere/kinetochore region, suggesting a possible role for chromosome separation.[3] # Cell cycle regulation Plk1 is an early trigger for G2/M transition. Plk1 supports the functional maturation of the centrosome in late G2/early prophase and establishment of the bipolar spindle. Plk1 phosphorylates and activates cdc25C, a phosphatase that dephosphorylates and activates the cyclinB/cdc2 complex. Plk phosphorylates and activates components of the anaphase-promoting complex (APC). The APC, which is activated by Fizzy-Cdc20 family proteins, is a cell cycle ubiquitin-protein ligase (E3) that degrades mitotic cyclins, chromosomal proteins that maintain cohesion of sister chromatids, and anaphase inhibitors. Abnormal spindle (Asp), a Polo kinase substrate, is a microtubule-associated protein essential for correct behavior of spindle poles and M-phase microtubules. Plk1 localizes to the central region of the spindle in late mitosis and associates with kinesin-like protein CHO1/MKLP1. The homologous motor protein in Drosophila is the pavarotti gene product (PAR).[4] Studies have shown that the loss of PLK1 expression can induce pro-apoptotic pathways and inhibit growth. Based on yeast and murine studies of meiosis, human PLK1 may also have a regulatory function in meiosis. S. cerevisiae polo kinase CDC5 is required to phosphorylate and remove meiotic cohesion during the first cell division. In CDC5 depleted cells, kinetochores are bioriented during meiosis I, and Mam1, a protein essential for coorientation, fails to associate with kinetochores. CDC5 is believed to have roles in sister-kinetochore coorientation and chromosome segregation during meiosis I.[5] # Role in tumorigenesis Plk1 is considered a proto-oncogene, whose overexpression is often observed in tumor cells. Aneuploidy and tumorigenesis can also result from centrosome abnormality, particularly centrosome amplification defects. Centrosome duplication and maturation regulated by Plk1 occurs from late S phase to prophase. Abnormal centrosome amplification may lead to multipolar spindles and results in unequal segregation of chromosomes.Plk1 overexpression also increases the centrosome size and/or centrosome number, which will also lead to improper segregation of chromosomes, aneuploidy, and tumorigenesis. Oncogenic properties of PLK1 are believed to be due to its role in driving cell cycle progression. Supporting evidence comes from the overexpression studies of PLK1 in NIH3T3 cell line. These cells become capable of forming foci and growing in soft agar and more importantly, these cells can form tumors in nude mice due to PLK1 overexpression.[6] PLK1 has also been linked to known pathways that are altered during the neoplastic transformation. Retinoblastoma tumor suppressor (RB) pathway activation results in the repression of PLK1 promoter in a SWI/SNF chromatin remodeling complex dependent manner. In case of RB inactivation, PLK1 expression seems to be deregulated. This new finding suggests that PLK1 may be a target of the retinoblastoma tumor suppressor (RB) pathway. Moreover, PLK1 seems to be involved in the tumor suppressor p53 related pathways. Evidence suggests that PLK1 can inhibit transactivation and pro-apoptotic functions of p53 function by physical interaction and phosphorylation.[7] # Clinical significance PLK1 is being studied as a target for cancer drugs. Many colon and lung cancers are caused by K-RAS mutations. These cancers are dependent on PLK1. When PLK1 expression was silenced with RNA interference in cell culture, K-RAS cells were selectively killed, without harming normal cells.[8][9] PLK1 inhibitor volasertib is being evaluated in clinical trials for use in acute myeloid leukemia (AML).[10] A combination of PLK1 and EGFR inhibition overcomes T790M-mediated drug resistance in vitro and in vivo in non-small cell lung cancer (NSCLC).[11] In HNSCC mutations of the AJUBA mediate sensitivity to treatment with cell-cycle inhibitors including Plk1 inhibitor volasertib.[12] Rigosertib is an experimental RAS/PI3K/PLK1 inhibitor.[13] # Interactions PLK1 has been shown to interact with: - CHEK2,[14] - NUDC,[15] - PIN1,[16][17] - PSMA3,[18][19] - PSMA5,[20] - PSMA6,[20] - PSMA7,[20] - PSMB3,[20] and - TSC1.[21] Structural analysis has been used to explain the broad specificity of PLK1.[22]

https://www.wikidoc.org/index.php/PLK1

c8665c95c371e3fb5962011149226170e0604807

wikidoc

PLK4

PLK4 Serine/threonine-protein kinase PLK4 also known as polo-like kinase 4 is an enzyme that in humans is encoded by the PLK4 gene. The Drosophila homolog is SAK, the C elegans homolog is zyg-1, and the Xenopus homolog is Plx4. # Function PLK4 encodes a member of the polo family of serine/threonine protein kinases. The protein localizes to centrioles—complex microtubule-based structures found in centrosomes—and regulates centriole duplication during the cell cycle. Overexpression of PLK4 results in centrosome amplification, and knockdown of PLK4 results in loss of centrosomes. # Structure PLK4 contains an N-terminal kinase domain (residues 12-284) and a C-terminal localization domain (residues 596-898). Other polo-like kinase members contain 2 C-terminal polo box domains (PBD). PLK4 contains these 2 domains in addition to a third PBD, which facilitates oligomerization, targeting, and promotes trans-autophosphorylation, limiting centriole duplication to once per cell cycle. # As a cancer drug target Inhibitors of the enzymatic activity PLK4 have potential in the treatment of cancer. The PLK4 inhibitor R1530 down regulates the expression of mitotic checkpoint kinase BubR1 that in turn leads to polyploidy rendering cancer cells unstable and more sensitive to cancer chemotherapy. Furthermore, normal cells are resistant to the polyploidy inducing effects of R1530. Another PLK4 inhibitor, CFI-400945 has demonstrated efficacy in animal models of breast and ovarian cancer. Another PLK4 inhibitor, centrinone, has been reported to deplete centrioles in human and other vertebrate cell types, which resulted in a p53-dependent cell cycle arrest in G1. Inhibition of PLK4 using a chemical genetic strategy has validated this p53-dependent cell cycle arrest in G1. PLK4 was also identified as a potential therapeutic target for malignant rhabdoid tumors, medulloblastomas and possibly, other embryonal tumors of the brain. # Interactions and substrates Documented PLK4 substrates include STIL, GCP6, Hand1, Ect2, FBXW5, and itself (via autophosphorylation). Autophosphorylation of PLK4 results in ubiquitination and subsequent destruction by the proteasome. PLK4 has been shown to interact with Stratifin.

PLK4 Serine/threonine-protein kinase PLK4 also known as polo-like kinase 4 is an enzyme that in humans is encoded by the PLK4 gene.[1] The Drosophila homolog is SAK, the C elegans homolog is zyg-1, and the Xenopus homolog is Plx4.[2] # Function PLK4 encodes a member of the polo family of serine/threonine protein kinases. The protein localizes to centrioles—complex microtubule-based structures found in centrosomes—and regulates centriole duplication during the cell cycle.[1] Overexpression of PLK4 results in centrosome amplification, and knockdown of PLK4 results in loss of centrosomes.[3][4] # Structure PLK4 contains an N-terminal kinase domain (residues 12-284) and a C-terminal localization domain (residues 596-898).[5] Other polo-like kinase members contain 2 C-terminal polo box domains (PBD). PLK4 contains these 2 domains in addition to a third PBD, which facilitates oligomerization, targeting, and promotes trans-autophosphorylation, limiting centriole duplication to once per cell cycle.[5] # As a cancer drug target Inhibitors of the enzymatic activity PLK4 have potential in the treatment of cancer.[6] The PLK4 inhibitor R1530 down regulates the expression of mitotic checkpoint kinase BubR1 that in turn leads to polyploidy rendering cancer cells unstable and more sensitive to cancer chemotherapy. Furthermore, normal cells are resistant to the polyploidy inducing effects of R1530.[7] Another PLK4 inhibitor, CFI-400945 has demonstrated efficacy in animal models of breast and ovarian cancer.[8][9] Another PLK4 inhibitor, centrinone, has been reported to deplete centrioles in human and other vertebrate cell types, which resulted in a p53-dependent cell cycle arrest in G1.[10] Inhibition of PLK4 using a chemical genetic strategy has validated this p53-dependent cell cycle arrest in G1.[11] PLK4 was also identified as a potential therapeutic target for malignant rhabdoid tumors, medulloblastomas and possibly, other embryonal tumors of the brain.[12] [13] [14] # Interactions and substrates Documented PLK4 substrates include STIL, GCP6,[15] Hand1,[16][17] Ect2,[18] FBXW5,[19] and itself (via autophosphorylation). Autophosphorylation of PLK4 results in ubiquitination and subsequent destruction by the proteasome.[20][21] PLK4 has been shown to interact with Stratifin.[22]

https://www.wikidoc.org/index.php/PLK4

af41b0952495b7bdb81eb48105624852a4a4f4fb

wikidoc

PLS3

PLS3 Plastin-3 is a highly conserved protein that in humans is encoded by the PLS3 gene on the X chromosome. # Function Plastins are a family of actin-binding proteins that are conserved throughout eukaryote evolution and expressed in most tissues of higher eukaryotes. In humans, two ubiquitous plastin isoforms (L and T) have been identified. Plastin 1 (otherwise known as Fimbrin) is a third distinct plastin isoform which is specifically expressed at high levels in the small intestine. The L isoform is expressed only in hemopoietic cell lineages, while the T isoform has been found in all other normal cells of solid tissues that have replicative potential (fibroblasts, endothelial cells, epithelial cells, melanocytes, etc.). The C-terminal 570 amino acids of the T-plastin and L-plastin proteins are 83% identical. It contains a potential calcium-binding site near the N-terminus. # Clinical significance Defects in PLS3 are associated with osteoporosis and bone fracture in humans and in knockout zebrafish.

PLS3 Plastin-3 is a highly conserved protein that in humans is encoded by the PLS3 gene on the X chromosome.[1][2] # Function Plastins are a family of actin-binding proteins that are conserved throughout eukaryote evolution and expressed in most tissues of higher eukaryotes. In humans, two ubiquitous plastin isoforms (L and T) have been identified. Plastin 1 (otherwise known as Fimbrin) is a third distinct plastin isoform which is specifically expressed at high levels in the small intestine. The L isoform is expressed only in hemopoietic cell lineages, while the T isoform has been found in all other normal cells of solid tissues that have replicative potential (fibroblasts, endothelial cells, epithelial cells, melanocytes, etc.). The C-terminal 570 amino acids of the T-plastin and L-plastin proteins are 83% identical. It contains a potential calcium-binding site near the N-terminus.[2] # Clinical significance Defects in PLS3 are associated with osteoporosis and bone fracture in humans and in knockout zebrafish.[3]

https://www.wikidoc.org/index.php/PLS3

59a200447f0f10bca3af9de6d77fef77f715a199

wikidoc

PMM1

PMM1 Phosphomannomutase 1 is an enzyme that in humans is encoded by the PMM1 gene. Phosphomannomutase catalyzes the conversion between D-mannose 6-phosphate and D-mannose 1-phosphate which is a substrate for GDP-mannose synthesis. GDP-mannose is used for synthesis of dolichol-phosphate-mannose, which is essential for N-linked glycosylation and thus the secretion of several glycoproteins as well as for the synthesis of glycosyl-phosphatidyl-inositol (GPI) anchored proteins. This enzyme has been extracted from the venom of the wasp species Polistes major major.

PMM1 Phosphomannomutase 1 is an enzyme that in humans is encoded by the PMM1 gene.[1][2][3] Phosphomannomutase catalyzes the conversion between D-mannose 6-phosphate and D-mannose 1-phosphate which is a substrate for GDP-mannose synthesis. GDP-mannose is used for synthesis of dolichol-phosphate-mannose, which is essential for N-linked glycosylation and thus the secretion of several glycoproteins as well as for the synthesis of glycosyl-phosphatidyl-inositol (GPI) anchored proteins.[3] This enzyme has been extracted from the venom of the wasp species Polistes major major.[4]

https://www.wikidoc.org/index.php/PMM1

4fb812ddaddab04ef04dfda6b61f31c06b70d291

wikidoc

PMS2

PMS2 Mismatch repair endonuclease PMS2 is an enzyme that in humans is encoded by the PMS2 gene. # Function This gene is one of the PMS2 gene family members which are found in clusters on chromosome 7. Human PMS2 related genes are located at bands 7p12, 7p13, 7q11, and 7q22. Exons 1 through 5 of these homologues share high degree of identity to human PMS2 The product of this gene is involved in DNA mismatch repair. The protein forms a heterodimer with MLH1 and this complex interacts with MSH2 bound to mismatched bases. Defects in this gene are associated with hereditary nonpolyposis colorectal cancer, with Turcot syndrome, and are a cause of supratentorial primitive neuroectodermal tumors. Alternatively spliced transcript variants have been observed. ## Mismatch repair and endonuclease activity PMS2 is involved in mismatch repair and is known to have latent endonuclease activity that depends on the integrity of the meta-binding motif in MutL homologs. As an endonuclease, PMS2 introduces nicks into a discontinuous DNA strand. # Interactions PMS2 has been shown to interact with MLH1 by forming the heterodimer MutLα. There is competition between MLH3, PMS1, and PMS2 for the interacting domain on MLH1, which is located in residues 492-742. The interacting domains in PMS2 have heptad repeats that are characteristic of leucine zipper proteins. MLH1 interacts with PMS2 at residues 506-756. The MutS heterodimers, MutSα and MutSβ, associate with MutLα upon mismatch binding. MutLα is believed to join the mismatch recognition step to other processes, including: removal of mismatches from the new DNA strand, resynthesis of the degraded DNA, and repair of the nick in the DNA. MutLα is shown to have weak ATPase activity and also possesses endonuclease activity that introduces nicks into the discontinuous strand of DNA. This facilitates 5' to 3' degradation of the mismatched DNA strand by EXO1. The active site of MutLα is located on the PMS2 subunit. PMS1 and PMS2 compete for interaction with MLH1. Proteins in the interactome of PMS2 have been identified by tandem affinity purification. Human PMS2 is expressed at very low levels and is not believed to be strongly cell cycle regulated. ## Interactions involving p53 and p73 PMS2 has also been shown to interact with p53 and p73. In the absence of p53, PMS2-deficient and PMS2-proficient cells are still capable of arresting the cell cycle at the G2/M checkpoint when treated with cisplatin. Cells that are deficient in p53 and PMS2, exhibit increased sensitivity to anticancer agents. PMS2 is a protective mediator of cell survival in p53-deficient cells and modulates protective DNA damage response pathways independently of p53. PMS2 and MLH1 can protect cells from cell death by counteracting p73-mediated apoptosis in a mismatch repair dependent manner. PMS2 can interact with p73 to enhance cisplatin-induced apoptosis by stabilizing p73. Cisplatin stimulates the interaction between PMS2 and p73, which is dependent on c-Abl. The MutLα complex may function as an adapter to bring p73 to the site of damaged DNA and also act as an activator of p73, due to the presence of PMS2. It may also be possibly for overexpressed PMS2 to stimulate apoptosis in the absence of MLH1 and in the presence of p73 and cisplatin due to the stabilizing actions of PMS2 on p73. Upon DNA damage, p53 induces cell cycle arrest through the p21/WAF pathway and initiates repair by expression of MLH1 and PMS2. The MSH1/PMS2 complex acts as a sensor of the extent of the damage to the DNA, and initiates apoptosis by stabilizing p73 if the damage is beyond repair. Loss of PMS2 does not always lead to instability of MLH1 since it can also form complexes with MLH3 and PMS1. # Clinical significance ## Mutations PMS2 is a gene that encodes for DNA repair proteins involved in mismatch repair. The PMS2 gene is located on chromosome 7p22 and it consists of 15 exons. Exon 11 of the PMS2 gene has a coding repeat of eight adenosines. Comprehensive genomic profiling of 100,000 human cancer samples revealed that mutations in the promoter region of PMS2 are significantly associated with high tumor mutational burden (TMB), particularly in melanoma. TMB has been shown to be a reliable predictor of whether a patient may respond to cancer immunotherapy, where high TMB is associated with more favorable treatment outcomes. Heterozygous germline mutations in DNA mismatch repair genes like PMS2 lead to autosomal dominant Lynch syndrome. Only 2% of families that have Lynch syndrome have mutations in the PMS2 gene. The age of patients when they first presented with PMS2-associated Lynch syndrome varies greatly, with a reported range of 23 to 77 years. In rare cases, a homozygous defect may cause this syndrome. In such cases a child inherits the gene mutation from both parents and the condition is called Turcot syndrome or Constitutional MMR Deficiency (CMMR-D). Up until 2011, 36 patients with brain tumors due to biallelic PMS2 germline mutations have been reported. Inheritance of Turcot syndrome can be dominant or recessive. Recessive inheritance of Turcot syndrome is caused by compound heterozygous mutations in PMS2. 31 out of 57 families reported with CMMR-D have germline PMS2 mutations. 19 out of 60 PMS2 homozygous or compound heterozygous mutation carriers had gastrointestinal cancer or adenomas as the first manifestation of CMMR-D. Presence of pseudogenes can cause confusion when identifying mutations in PMS2, leading to false positive conclusions of the presence of mutated PMS2. ## Deficiency and overexpression Overexpression of PMS2 results in hypermutability and DNA damage tolerance. Deficiency of PMS2 also contributes to genetic instability by allowing for mutations to propagate due to reduced MMR function. It has been shown that PMS2-/- mice developed lymphomas and sarcomas. It was also shown that male mice that are PMS2-/- are sterile, indicating that PMS2 may have a role in spermatogenesis. ## Role in normal colon PMS2 is usually expressed at a high level in cell nuclei of enterocytes (absorptive cells) within the colonic crypts lining the inner surface of the colon (see image, panel A). DNA repair, involving high expression of PMS2, ERCC1 and ERCC4 (XPF) proteins, appears to be very active in colon crypts in normal, non-neoplastic colonic epithelium. In the case of PMS2, the expression level in normal colonic epithelium is high in 77% to 100% of crypts. Cells are produced at the crypt base and migrate upward along the crypt axis before being shed into the colonic lumen days later. There are 5 to 6 stem cells at the bases of the crypts. If the stem cells at the base of the crypt express PMS2, generally all several thousand cells of the crypt will also express PMS2. This is indicated by the brown color seen by immunostaining of PMS2 in most of the enterocytes in the crypt in panel A of the image in this section. Similar expression of ERCC4 (XPF) and ERCC1 occurs in the thousands of enterocytes in each colonic crypt of the normal colonic epithelium. The tissue section in the image shown here was also counterstained with hematoxylin to stain DNA in nuclei a blue-gray color. Nuclei of cells in the lamina propria (cells which are below and surround the epithelial crypts) largely show hematoxylin blue-gray color and have little expression of PMS2, ERCC1 or ERCC4 (XPF). ## Colon cancer About 88% of cells of epithelial origin in colon cancers, and about 50% of the colon crypts in the epithelium within 10 cm adjacent to cancers (in the field defects from which the cancers likely arose) have reduced or absent expression of PMS2. Deficiencies in PMS2 in colon epithelium appear to mostly be due to epigenetic repression. In tumors classified as mismatch repair deficient and lacking, in a majority PMS2 expression is deficient because of lack of its pairing partner MLH1. Pairing of PMS2 with MLH1 stabilizes. The loss of MLH1 in sporadic cancers was due to epigenetic silencing caused by promoter methylation in 65 out of 66 cases. In 16 cancers Pms2 was deficient even though MLH1 protein expression was present. Of these 16 cases, no cause was determined for 10, but 6 were found to have a heterozygous germline mutation in Pms2, followed by likely loss of heterozygosity in the tumor. Thus only 6 of 119 tumors lacking expression for Pms2 (5%) were due to mutation of PMS2. ## Coordination with ERCC1 and ERCC4 (XPF) When PMS2 is reduced in colonic crypts in a field defect, it is most often associated with reduced expression of DNA repair enzymes ERCC1 and ERCC4 (XPF) as well (see images in this section). A deficiency in ERCC1 and/or ERCC4 (XPF) would cause DNA damage accummulation. Such excess DNA damage often leads to apoptosis. However, an added defect in PMS2 can inhibit this apoptosis. Thus, an added deficiency in PMS2 likely would be selected for in the face of the increased DNA damages when ERCC1 and/or ERCC4 (XPF) are deficient. When ERCC1 deficient Chinese hamster ovary cells were repeatedly subjected to DNA damage, of five clones derived from the surviving cells, three were mutated in Pms2. ## Progression to colon cancer ERCC1, PMS2 double mutant Chinese hamster ovary cells, when exposed to Ultraviolet light (a DNA damaging agent), showed a 7,375-fold greater mutation frequency than wild type Chinese hamster ovary cells, and a 967-fold greater mutation frequency than the cells defective in ERCC1, alone. Thus colonic cell deficiency in both ERCC1 and PMS2 causes genome instability. A similar genetically unstable situation is expected for cells doubly defective for PMS2 and ERCC4 (XPF). This instability would likely enhance progression to colon cancer by causing a mutator phenotype, and account for the presence of the cells doubly deficient in PMS2 and ERCC1 in field defects associated with colon cancer. As indicated by Harper and Elledge, defects in the ability to properly respond to and repair DNA damage underlie many forms of cancer.

PMS2 Mismatch repair endonuclease PMS2 is an enzyme that in humans is encoded by the PMS2 gene.[1] # Function This gene is one of the PMS2 gene family members which are found in clusters on chromosome 7. Human PMS2 related genes are located at bands 7p12, 7p13, 7q11, and 7q22. Exons 1 through 5 of these homologues share high degree of identity to human PMS2 [2] The product of this gene is involved in DNA mismatch repair. The protein forms a heterodimer with MLH1 and this complex interacts with MSH2 bound to mismatched bases. Defects in this gene are associated with hereditary nonpolyposis colorectal cancer, with Turcot syndrome, and are a cause of supratentorial primitive neuroectodermal tumors. Alternatively spliced transcript variants have been observed.[3] ## Mismatch repair and endonuclease activity PMS2 is involved in mismatch repair and is known to have latent endonuclease activity that depends on the integrity of the meta-binding motif in MutL homologs. As an endonuclease, PMS2 introduces nicks into a discontinuous DNA strand.[4] # Interactions PMS2 has been shown to interact with MLH1 by forming the heterodimer MutLα.[5][6][7][8][9][10] There is competition between MLH3, PMS1, and PMS2 for the interacting domain on MLH1, which is located in residues 492-742.[6] The interacting domains in PMS2 have heptad repeats that are characteristic of leucine zipper proteins.[6] MLH1 interacts with PMS2 at residues 506-756.[7] The MutS heterodimers, MutSα and MutSβ, associate with MutLα upon mismatch binding. MutLα is believed to join the mismatch recognition step to other processes, including: removal of mismatches from the new DNA strand, resynthesis of the degraded DNA, and repair of the nick in the DNA.[10] MutLα is shown to have weak ATPase activity and also possesses endonuclease activity that introduces nicks into the discontinuous strand of DNA. This facilitates 5' to 3' degradation of the mismatched DNA strand by EXO1.[10] The active site of MutLα is located on the PMS2 subunit. PMS1 and PMS2 compete for interaction with MLH1.[10] Proteins in the interactome of PMS2 have been identified by tandem affinity purification.[10][11] Human PMS2 is expressed at very low levels and is not believed to be strongly cell cycle regulated.[12] ## Interactions involving p53 and p73 PMS2 has also been shown to interact with p53 and p73. In the absence of p53, PMS2-deficient and PMS2-proficient cells are still capable of arresting the cell cycle at the G2/M checkpoint when treated with cisplatin.[13] Cells that are deficient in p53 and PMS2, exhibit increased sensitivity to anticancer agents. PMS2 is a protective mediator of cell survival in p53-deficient cells and modulates protective DNA damage response pathways independently of p53.[13] PMS2 and MLH1 can protect cells from cell death by counteracting p73-mediated apoptosis in a mismatch repair dependent manner.[13] PMS2 can interact with p73 to enhance cisplatin-induced apoptosis by stabilizing p73. Cisplatin stimulates the interaction between PMS2 and p73, which is dependent on c-Abl.[9] The MutLα complex may function as an adapter to bring p73 to the site of damaged DNA and also act as an activator of p73, due to the presence of PMS2.[9] It may also be possibly for overexpressed PMS2 to stimulate apoptosis in the absence of MLH1 and in the presence of p73 and cisplatin due to the stabilizing actions of PMS2 on p73.[9] Upon DNA damage, p53 induces cell cycle arrest through the p21/WAF pathway and initiates repair by expression of MLH1 and PMS2.[8] The MSH1/PMS2 complex acts as a sensor of the extent of the damage to the DNA, and initiates apoptosis by stabilizing p73 if the damage is beyond repair.[8] Loss of PMS2 does not always lead to instability of MLH1 since it can also form complexes with MLH3 and PMS1.[14] # Clinical significance ## Mutations PMS2 is a gene that encodes for DNA repair proteins involved in mismatch repair. The PMS2 gene is located on chromosome 7p22 and it consists of 15 exons. Exon 11 of the PMS2 gene has a coding repeat of eight adenosines.[15] Comprehensive genomic profiling of 100,000 human cancer samples revealed that mutations in the promoter region of PMS2 are significantly associated with high tumor mutational burden (TMB), particularly in melanoma.[16] TMB has been shown to be a reliable predictor of whether a patient may respond to cancer immunotherapy, where high TMB is associated with more favorable treatment outcomes.[17] Heterozygous germline mutations in DNA mismatch repair genes like PMS2 lead to autosomal dominant Lynch syndrome. Only 2% of families that have Lynch syndrome have mutations in the PMS2 gene.[18] The age of patients when they first presented with PMS2-associated Lynch syndrome varies greatly, with a reported range of 23 to 77 years.[19] In rare cases, a homozygous defect may cause this syndrome. In such cases a child inherits the gene mutation from both parents and the condition is called Turcot syndrome or Constitutional MMR Deficiency (CMMR-D).[20] Up until 2011, 36 patients with brain tumors due to biallelic PMS2 germline mutations have been reported.[20] Inheritance of Turcot syndrome can be dominant or recessive. Recessive inheritance of Turcot syndrome is caused by compound heterozygous mutations in PMS2.[21] 31 out of 57 families reported with CMMR-D have germline PMS2 mutations.[22] 19 out of 60 PMS2 homozygous or compound heterozygous mutation carriers had gastrointestinal cancer or adenomas as the first manifestation of CMMR-D.[22] Presence of pseudogenes can cause confusion when identifying mutations in PMS2, leading to false positive conclusions of the presence of mutated PMS2.[15] ## Deficiency and overexpression Overexpression of PMS2 results in hypermutability and DNA damage tolerance.[23] Deficiency of PMS2 also contributes to genetic instability by allowing for mutations to propagate due to reduced MMR function.[23] It has been shown that PMS2-/- mice developed lymphomas and sarcomas. It was also shown that male mice that are PMS2-/- are sterile, indicating that PMS2 may have a role in spermatogenesis.[4] ## Role in normal colon PMS2 is usually expressed at a high level in cell nuclei of enterocytes (absorptive cells) within the colonic crypts lining the inner surface of the colon (see image, panel A). DNA repair, involving high expression of PMS2, ERCC1 and ERCC4 (XPF) proteins, appears to be very active in colon crypts in normal, non-neoplastic colonic epithelium. In the case of PMS2, the expression level in normal colonic epithelium is high in 77% to 100% of crypts.[24] Cells are produced at the crypt base and migrate upward along the crypt axis before being shed into the colonic lumen days later.[25] There are 5 to 6 stem cells at the bases of the crypts.[25] If the stem cells at the base of the crypt express PMS2, generally all several thousand cells of the crypt[26] will also express PMS2. This is indicated by the brown color seen by immunostaining of PMS2 in most of the enterocytes in the crypt in panel A of the image in this section. Similar expression of ERCC4 (XPF) and ERCC1 occurs in the thousands of enterocytes in each colonic crypt of the normal colonic epithelium. The tissue section in the image shown here was also counterstained with hematoxylin to stain DNA in nuclei a blue-gray color. Nuclei of cells in the lamina propria (cells which are below and surround the epithelial crypts) largely show hematoxylin blue-gray color and have little expression of PMS2, ERCC1 or ERCC4 (XPF). ## Colon cancer About 88% of cells of epithelial origin in colon cancers, and about 50% of the colon crypts in the epithelium within 10 cm adjacent to cancers (in the field defects from which the cancers likely arose) have reduced or absent expression of PMS2.[24] Deficiencies in PMS2 in colon epithelium appear to mostly be due to epigenetic repression. In tumors classified as mismatch repair deficient and lacking, in a majority PMS2 expression is deficient because of lack of its pairing partner MLH1.[27] Pairing of PMS2 with MLH1 stabilizes.[28] The loss of MLH1 in sporadic cancers was due to epigenetic silencing caused by promoter methylation in 65 out of 66 cases. In 16 cancers Pms2 was deficient even though MLH1 protein expression was present. Of these 16 cases, no cause was determined for 10, but 6 were found to have a heterozygous germline mutation in Pms2, followed by likely loss of heterozygosity in the tumor. Thus only 6 of 119 tumors lacking expression for Pms2 (5%) were due to mutation of PMS2. ## Coordination with ERCC1 and ERCC4 (XPF) When PMS2 is reduced in colonic crypts in a field defect, it is most often associated with reduced expression of DNA repair enzymes ERCC1 and ERCC4 (XPF) as well (see images in this section). A deficiency in ERCC1 and/or ERCC4 (XPF) would cause DNA damage accummulation. Such excess DNA damage often leads to apoptosis.[29] However, an added defect in PMS2 can inhibit this apoptosis.[30][31] Thus, an added deficiency in PMS2 likely would be selected for in the face of the increased DNA damages when ERCC1 and/or ERCC4 (XPF) are deficient. When ERCC1 deficient Chinese hamster ovary cells were repeatedly subjected to DNA damage, of five clones derived from the surviving cells, three were mutated in Pms2.[32] ## Progression to colon cancer ERCC1, PMS2 double mutant Chinese hamster ovary cells, when exposed to Ultraviolet light (a DNA damaging agent), showed a 7,375-fold greater mutation frequency than wild type Chinese hamster ovary cells, and a 967-fold greater mutation frequency than the cells defective in ERCC1, alone.[32] Thus colonic cell deficiency in both ERCC1 and PMS2 causes genome instability. A similar genetically unstable situation is expected for cells doubly defective for PMS2 and ERCC4 (XPF). This instability would likely enhance progression to colon cancer by causing a mutator phenotype,[33] and account for the presence of the cells doubly deficient in PMS2 and ERCC1 [or PMS2 and ERCC4 (XPF)] in field defects associated with colon cancer. As indicated by Harper and Elledge,[34] defects in the ability to properly respond to and repair DNA damage underlie many forms of cancer.

https://www.wikidoc.org/index.php/PMS2

63d10a7763fe0acce007995142a27f698bfff3d0

wikidoc

PNKD

PNKD PNKD is the abbreviation for a human neurological movement disorder paroxysmal nonkinesiogenic dyskinesia. Like many other human genetics disorders, PNKD also refers to the disease, the disease gene and the encoded protein. (PNKD) is a protein that in humans is encoded by the PNKD gene. Alternative splicing results in the transcription of three isoforms. The mouse ortholog is called brain protein 17 (Brp17). # Structure This gene is located on chromosome 2 at the band 2q35 and contains 12 exons. At least three isoforms of varying lengths (long, medium, and short) can be produced by alternative splicing of this gene. While the gene products of the long (PNKD-L) and medium (PNKD-M) isoforms contain the C-terminal β-lactamase domain, the short (PNKD-S) isoform, commonly referred to as myofibrillogenesis regulator-1 (MR-1), contains only three exons and lacks homology to any known protein. These isoforms also differ in their tissue-specific expression and subcellular localization. Specifically, PNKD-L is only expressed in the central nervous system whereas PNKD-M and PNKD-S are ubiquitously expressed across tissues. Moreover, PNKD-L localizes to the cell membrane, PNKD-S to the cytoplasm and nucleus, and PNKD-M to the mitochondrion. # Function The function of PNKD proteins are unknown but the long and medium isoforms of PNKD contain a conserved β-lactamase domain which suggest it may function as an enzyme. The closest mammalian homolog to PNKD is HAGH, an enzyme involves in a two-step reaction to hydrolyze SLG and produce D-lactic acid and reduced GSH. However, the hydrolytic activity of PNKD is minimal. The long form of PNKD is neuronal specific and encodes a synaptic protein that localizes dominantly to the pre-synaptic membrane. Post-synaptic area and vesicular structure also occasionally has PNKD long form. PNKD long form interacts with pre-synaptic protein RIM and inhibits synaptic exocytosis. PNKD with disease mutations is less effective in inhibition thus the synaptic release is increased. This would cause excessive neurotransmitter release in the brain and maybe the root cause for triggering epilepsy in PNKD patients. # Clinical significance Point mutations in PNKD exon 1 cause an inherited neurological movement disorder in human, paroxysmal non-kinesigenic dyskinesia. Overexpression of PNKD has also been associated with multiple cancers, including pancreatic ductal adenocarcinoma, gastric cancer, ovarian cancer, and breast cancer and may serve as a therapeutic target for treating these cancers or a biomarker for assessing patient outcome. The signaling pathways involved may vary depending on the cancer. For instance, in human breast cancer (MCF7) cells, PNKD may promote tumor cell proliferation by activating the MEK/ERK signaling pathway, while in human hepatoma (HepG2) cells, PNKD may operate through the MLC2/FAK/AKT pathway. # Interactions PNKD has been shown to interact with: - Rab3-interacting molecule (RIM)1 - RIM2

PNKD PNKD is the abbreviation for a human neurological movement disorder paroxysmal nonkinesiogenic dyskinesia. Like many other human genetics disorders, PNKD also refers to the disease, the disease gene and the encoded protein. (PNKD) is a protein that in humans is encoded by the PNKD gene.[1][2] Alternative splicing results in the transcription of three isoforms. The mouse ortholog is called brain protein 17 (Brp17). # Structure This gene is located on chromosome 2 at the band 2q35 and contains 12 exons.[2] At least three isoforms of varying lengths (long, medium, and short) can be produced by alternative splicing of this gene. While the gene products of the long (PNKD-L) and medium (PNKD-M) isoforms contain the C-terminal β-lactamase domain, the short (PNKD-S) isoform, commonly referred to as myofibrillogenesis regulator-1 (MR-1), contains only three exons and lacks homology to any known protein.[3][4] These isoforms also differ in their tissue-specific expression and subcellular localization. Specifically, PNKD-L is only expressed in the central nervous system whereas PNKD-M and PNKD-S are ubiquitously expressed across tissues.[3] Moreover, PNKD-L localizes to the cell membrane, PNKD-S to the cytoplasm and nucleus, and PNKD-M to the mitochondrion.[5] # Function The function of PNKD proteins are unknown but the long and medium isoforms of PNKD contain a conserved β-lactamase domain which suggest it may function as an enzyme. The closest mammalian homolog to PNKD is HAGH, an enzyme involves in a two-step reaction to hydrolyze SLG and produce D-lactic acid and reduced GSH. However, the hydrolytic activity of PNKD is minimal.[3] The long form of PNKD is neuronal specific and encodes a synaptic protein that localizes dominantly to the pre-synaptic membrane. Post-synaptic area and vesicular structure also occasionally has PNKD long form. PNKD long form interacts with pre-synaptic protein RIM and inhibits synaptic exocytosis. PNKD with disease mutations is less effective in inhibition thus the synaptic release is increased. This would cause excessive neurotransmitter release in the brain and maybe the root cause for triggering epilepsy in PNKD patients.[6] # Clinical significance Point mutations in PNKD exon 1 cause an inherited neurological movement disorder in human, paroxysmal non-kinesigenic dyskinesia.[2] Overexpression of PNKD has also been associated with multiple cancers, including pancreatic ductal adenocarcinoma,[7] gastric cancer,[8] ovarian cancer,[9] and breast cancer[4] and may serve as a therapeutic target for treating these cancers or a biomarker for assessing patient outcome. The signaling pathways involved may vary depending on the cancer. For instance, in human breast cancer (MCF7) cells, PNKD may promote tumor cell proliferation by activating the MEK/ERK signaling pathway, while in human hepatoma (HepG2) cells, PNKD may operate through the MLC2/FAK/AKT pathway.[4] # Interactions PNKD has been shown to interact with: - Rab3-interacting molecule (RIM)1[6] - RIM2[6]

https://www.wikidoc.org/index.php/PNKD

9c1dac095dabe7e37208b27ff8291f7157fe6dea

wikidoc

PNPO

PNPO Pyridoxine-5'-phosphate oxidase is an enzyme that in humans is encoded by the PNPO gene. Vitamin B6, or pyridoxal 5-prime-phosphate (PLP), is critical for normal cellular function, and some cancer cells have notable differences in vitamin B6 metabolism compared to their normal counterparts. The rate-limiting enzyme in vitamin B6 synthesis is pyridoxine-5-prime-phosphate (PNP) oxidase (PNPO; EC 1.4.3.5). # Model organisms Model organisms have been used in the study of PNPO function. A conditional knockout mouse line, called Pnpotm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on mutant mice and two significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.

PNPO Pyridoxine-5'-phosphate oxidase is an enzyme that in humans is encoded by the PNPO gene.[1][2][3] Vitamin B6, or pyridoxal 5-prime-phosphate (PLP), is critical for normal cellular function, and some cancer cells have notable differences in vitamin B6 metabolism compared to their normal counterparts. The rate-limiting enzyme in vitamin B6 synthesis is pyridoxine-5-prime-phosphate (PNP) oxidase (PNPO; EC 1.4.3.5).[supplied by OMIM][3] # Model organisms Model organisms have been used in the study of PNPO function. A conditional knockout mouse line, called Pnpotm1a(KOMP)Wtsi[8][9] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[10][11][12] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[6][13] Twenty four tests were carried out on mutant mice and two significant abnormalities were observed.[6] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.[6]

https://www.wikidoc.org/index.php/PNPO

f49d3f26d5a0633708e053b70640168e229b68c8

wikidoc

POLG

POLG DNA polymerase subunit gamma (POLG or POLG1) is an enzyme that in humans is encoded by the POLG gene. Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). # Structure POLG is located on the q arm of chromosome 15 in position 26.1 and has 23 exons. The POLG gene produces a 140 kDa protein composed of 1239 amino acids. POLG, the protein encoded by this gene, is a member of the DNA polymerase type-A family. It is a mitochondrion nucleiod with an Mg2+ cofactor and 15 turns, 52 beta strands, and 39 alpha helixes. POLG contains a polyglutamine tract near its N-terminus that may be polymorphic. Two transcript variants encoding the same protein have been found for this gene. # Function POLG is a gene that codes for the catalytic subunit of the mitochondrial DNA polymerase, called DNA polymerase gamma. The human POLG cDNA and gene were cloned and mapped to chromosome band 15q25. In eukaryotic cells, the mitochondrial DNA is replicated by DNA polymerase gamma, a trimeric protein complex composed of a catalytic subunit, POLG, and a dimeric accessory subunit of 55 kDa encoded by the POLG2 gene. The catalytic subunit contains three enzymatic activities, a DNA polymerase activity, a 3’-5’ exonuclease activity that proofreads misincorporated nucleotides, and a 5’-dRP lyase activity required for base excision repair. ## Catalytic activity Deoxynucleoside triphosphate + DNA(n) = diphosphate + DNA(n+1). # Clinical significance Mutations in the POLG gene are associated with several mitochondrial diseases, progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Pathogenic variants have also been linked with fatal congenital myopathy and gastrointestinal pseudo-obstruction and fatal infantile hepatic failure. A list of all published mutations in the POLG coding region and their associated disease can be found at the Human DNA Polymerase Gamma Mutation Database. # Interactions POLG has been shown to have 50 binary protein-protein interactions including 32 co-complex interactions. POLG appears to interact with POLG2, Dlg4, Tp53, and Sod2.

POLG DNA polymerase subunit gamma (POLG or POLG1) is an enzyme that in humans is encoded by the POLG gene.[1] Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE).[2] # Structure POLG is located on the q arm of chromosome 15 in position 26.1 and has 23 exons. The POLG gene produces a 140 kDa protein composed of 1239 amino acids.[3][4] POLG, the protein encoded by this gene, is a member of the DNA polymerase type-A family. It is a mitochondrion nucleiod with an Mg2+ cofactor and 15 turns, 52 beta strands, and 39 alpha helixes.[5][6] POLG contains a polyglutamine tract near its N-terminus that may be polymorphic. Two transcript variants encoding the same protein have been found for this gene. [2] # Function POLG is a gene that codes for the catalytic subunit of the mitochondrial DNA polymerase, called DNA polymerase gamma.[2] The human POLG cDNA and gene were cloned and mapped to chromosome band 15q25.[7] In eukaryotic cells, the mitochondrial DNA is replicated by DNA polymerase gamma, a trimeric protein complex composed of a catalytic subunit, POLG, and a dimeric accessory subunit of 55 kDa encoded by the POLG2 gene.[8] The catalytic subunit contains three enzymatic activities, a DNA polymerase activity, a 3’-5’ exonuclease activity that proofreads misincorporated nucleotides, and a 5’-dRP lyase activity required for base excision repair. ## Catalytic activity Deoxynucleoside triphosphate + DNA(n) = diphosphate + DNA(n+1).[5][6] # Clinical significance Mutations in the POLG gene are associated with several mitochondrial diseases, progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE).[2] Pathogenic variants have also been linked with fatal congenital myopathy and gastrointestinal pseudo-obstruction and fatal infantile hepatic failure.[9][10] A list of all published mutations in the POLG coding region and their associated disease can be found at the Human DNA Polymerase Gamma Mutation Database. # Interactions POLG has been shown to have 50 binary protein-protein interactions including 32 co-complex interactions. POLG appears to interact with POLG2, Dlg4, Tp53, and Sod2.[11]

https://www.wikidoc.org/index.php/POLG

45fc168580f59d4686351c147daf8d18805a95b3

wikidoc

POLH

POLH Polymerase (DNA directed), eta, also known as POLH, is a protein which in humans is encoded by the POLH gene. # Function This gene encodes a member of the Y family of specialized DNA polymerases. It copies undamaged DNA with a lower fidelity than other DNA-directed polymerases. However, it accurately replicates UV-damaged DNA; when thymine dimers are present, this polymerase inserts the complementary nucleotides in the newly synthesized DNA, thereby bypassing the lesion and suppressing the mutagenic effect of UV-induced DNA damage. This polymerase is thought to be involved in hypermutation during immunoglobulin class switch recombination. Mutations in this gene result in XPV, a variant type of xeroderma pigmentosum. # Clinical significance Xeroderma pigmentosum (XP) is an autosomal recessive human disease characterized by sunlight sensitivity, cutaneous and ocular deterioration, and premature malignant skin neoplasms after exposure to sunlight. XP has been classified into eight complementation groups, XP-A to XP-G and XP-V. Cells from XP-A to XP-G patients have defects in the process of nucleotide excision repair (NER), which eliminates a wide variety of structurally unrelated lesions, including ultraviolet light (UV)-induced cyclobutane pyrimidine dimers (CPD) and (6-4) photoproducts, as well as certain chemical adducts. The genes and proteins of XP groups A, B, C, D, F and G have been isolated and found to represent some of the subunits of the core NER machinery. In contrast, cells belonging to the eighth group, XP variant (XP-V), are NER-proficient but display abnormal DNA replication, including reduced ability to elongate nascent DNA strands on UV-irradiated DNA. Thus, the XP-V gene product is likely to be involved in the process of DNA replication on damaged DNA known as post-replication repair, but not in NER

POLH Template:PBB Polymerase (DNA directed), eta, also known as POLH, is a protein which in humans is encoded by the POLH gene.[1][2][3] # Function This gene encodes a member of the Y family of specialized DNA polymerases. It copies undamaged DNA with a lower fidelity than other DNA-directed polymerases. However, it accurately replicates UV-damaged DNA; when thymine dimers are present, this polymerase inserts the complementary nucleotides in the newly synthesized DNA, thereby bypassing the lesion and suppressing the mutagenic effect of UV-induced DNA damage. This polymerase is thought to be involved in hypermutation during immunoglobulin class switch recombination.[1] Mutations in this gene result in XPV, a variant type of xeroderma pigmentosum.[4] # Clinical significance Xeroderma pigmentosum (XP) is an autosomal recessive human disease characterized by sunlight sensitivity, cutaneous and ocular deterioration, and premature malignant skin neoplasms after exposure to sunlight. XP has been classified into eight complementation groups, XP-A to XP-G and XP-V. Cells from XP-A to XP-G patients have defects in the process of nucleotide excision repair (NER), which eliminates a wide variety of structurally unrelated lesions, including ultraviolet light (UV)-induced cyclobutane pyrimidine dimers (CPD) and (6-4) photoproducts, as well as certain chemical adducts. The genes and proteins of XP groups A, B, C, D, F and G have been isolated and found to represent some of the subunits of the core NER machinery. In contrast, cells belonging to the eighth group, XP variant (XP-V), are NER-proficient but display abnormal DNA replication, including reduced ability to elongate nascent DNA strands on UV-irradiated DNA. Thus, the XP-V gene product is likely to be involved in the process of DNA replication on damaged DNA known as post-replication repair, but not in NER

https://www.wikidoc.org/index.php/POLH

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PON1

PON1 Serum paraoxonase/arylesterase 1 (PON1) also known as A esterase , homocysteine thiolactonase or serum aryldialkylphosphatase 1 is an enzyme that in humans is encoded by the PON1 gene. Paraoxonase 1 has esterase and more specifically paraoxonase activity. Serum PON1 is found in all mammalian species studied so far but is not present in the serum of birds, fish and reptiles or in insects. PON1 is the first discovered member of a multigene family also containing PON2 and PON3, the genes for which are located adjacent to each other on chromosome 7. # Structure Human PON1 is a glycoprotein composed of 354 amino acids and has a molecular weight of 43000 Daltons which associates with high-density lipoprotein (HDL, "good cholesterol") in the circulation. Serum PON1 is secreted mainly by the liver, although local synthesis occurs in several tissues and PON1 protein is found in almost all tissues. X-ray crystallography has revealed the structure of PON1 to be a 6 bladed propeller with a unique lid structure covering the active site passage which allows association with HDL. # Function PON1 is responsible for hydrolysing organophosphate pesticides and nerve gasses. Polymorphisms in the PON1 gene significantly affect the catalytic ability of the enzyme. PON1 (paraoxonase 1) is also a major anti-atherosclerotic component of high-density lipoprotein (HDL). The PON1 gene is activated by PPAR-γ, which increases synthesis and release of paraoxonase 1 enzyme from the liver, reducing atherosclerosis. The "natural" substrates for PON1 appear to be lactones. However, PON1 has evolved to be a highly promiscuous enzyme capable of hydrolysing a wide variety of substrates such as lactones (including a number of important pharmaceutical agents such as statins), glucuronide drugs, thiolactones, arylesters, cyclic carbonates, organophosphorus pesticides and nerve gases such as sarin, soman and VX, oestrogen esters and lipid peroxides (oxidised lipids). # Genetics PON1 in humans is encoded by the PON1 gene which is located on the long arm of chromosome 7. Although many nutritional, life-style and pharmaceutical modulators of PON1 are known., by far the biggest effect on PON1 activity levels, which can vary by over 40 fold between individuals, is through PON1 genetic polymorphisms. The coding region PON1-Q192R polymorphism determines a substrate dependent effect on activity. Some substrates e.g. paraoxon are hydrolysed faster by the R- isoform while others such as diazoxon and lipid-peroxides are hydrolysed more rapidly by the Q- isoform. Both the coding region PON1-L55M and the promoter region PON1-T-108C polymorphisms are associated with different serum concentrations and therefore activities. The 55L allele results in significantly higher PON1 mRNA and serum protein levels and therefore activity compared to the 55M allele. The -108C allele has greater promoter activity than the -108T allele which results in different serum activities. The distribution of the PON1 polymorphisms varies with ethnicity. The frequency of the PON1-192R allele increases the further from Europe a population originates, the frequency in Caucasians of 15-30% increases to 70-90% in Far Eastern Oriental and Sub-Saharan African populations. In the southern US African-Americans are five times more likely to be RR than Caucasians. In contrast the PON1-55M allele is much less frequent in Oriental and black African populations compared to Caucasians and are extremely rare or absent in some populations e.g. Thais. These ethnic differences in SNP distribution can lead to large activity differences between populations. # Clinical significance PON1 was first discovered through its ability to hydrolyse and therefore detoxify organophosphorus compounds which are widely used as pesticides and nerve gases. Despite decades of research it is only now becoming clear that PON1 protects humans from the acute and chronic harmful effects of these compounds Low PON1 activity found in children may increase their susceptibility to organophosphates. Oxidised-lipids are the major cause of inflammation and are responsible for the initiation and/or propagation of several inflammatory diseases including atherosclerosis (heart disease and stroke), diabetes, liver and kidney diseases, rheumatic diseases, eye diseases (macular degeneration), cancer and HIV infection. Because of its ability to destroy oxidised-lipids PON1 appears to play some role in all these diseases. However, the greatest research interest has been the role of PON1 in atherosclerosis, where, because of its ability to remove harmful oxidised-lipids, PON1 protects against the development of atherosclerosis Oxidized polyunsaturated fatty acids (notably in oxidized low-density lipoprotein) form lactone-like structures that are PON substrates. PON1 also protects against bacterial infection by destroying the bacterial signalling molecules that cause gram negative bacteria to invade human tissue and form colonies, thus PON1 contributes to the bodies innate immunity Recently it has been suggested that PON1 has a role in healthy aging, however, the mechanism is currently unknown PON1 activity is low in infants compared to adults. A study of Mexican-American children showed that PON1 activity increased 3.5 times between birth and age seven. An association between PON1 gene polymorphism and susceptibility to Parkinson's disease was not found in a Chinese population. # Notes

PON1 Serum paraoxonase/arylesterase 1 (PON1) also known as A esterase , homocysteine thiolactonase or serum aryldialkylphosphatase 1 is an enzyme that in humans is encoded by the PON1 gene.[1] Paraoxonase 1 has esterase and more specifically paraoxonase activity.[2] Serum PON1 is found in all mammalian species studied so far but is not present in the serum of birds, fish and reptiles or in insects. PON1 is the first discovered member of a multigene family also containing PON2 and PON3, the genes for which are located adjacent to each other on chromosome 7. # Structure Human PON1 is a glycoprotein composed of 354 amino acids and has a molecular weight of 43000 Daltons which associates with high-density lipoprotein (HDL, "good cholesterol") in the circulation. Serum PON1 is secreted mainly by the liver, although local synthesis occurs in several tissues and PON1 protein is found in almost all tissues. X-ray crystallography has revealed the structure of PON1 to be a 6 bladed propeller with a unique lid structure covering the active site passage which allows association with HDL.[3][4][5] # Function PON1 is responsible for hydrolysing organophosphate pesticides and nerve gasses. Polymorphisms in the PON1 gene significantly affect the catalytic ability of the enzyme.[6] PON1 (paraoxonase 1) is also a major anti-atherosclerotic component of high-density lipoprotein (HDL).[7][8] The PON1 gene is activated by PPAR-γ, which increases synthesis and release of paraoxonase 1 enzyme from the liver, reducing atherosclerosis.[9] The "natural" substrates for PON1 appear to be lactones.[10] However, PON1 has evolved to be a highly promiscuous enzyme capable of hydrolysing a wide variety of substrates such as lactones (including a number of important pharmaceutical agents such as statins), glucuronide drugs, thiolactones, arylesters, cyclic carbonates, organophosphorus pesticides and nerve gases such as sarin, soman and VX, oestrogen esters and lipid peroxides (oxidised lipids). # Genetics PON1 in humans is encoded by the PON1 gene which is located on the long arm of chromosome 7.[11] Although many nutritional, life-style and pharmaceutical modulators of PON1 are known.,[12][13] by far the biggest effect on PON1 activity levels, which can vary by over 40 fold between individuals, is through PON1 genetic polymorphisms.[4] The coding region PON1-Q192R polymorphism determines a substrate dependent effect on activity. Some substrates e.g. paraoxon are hydrolysed faster by the R- isoform while others such as diazoxon and lipid-peroxides are hydrolysed more rapidly by the Q- isoform.[4] Both the coding region PON1-L55M and the promoter region PON1-T-108C polymorphisms are associated with different serum concentrations and therefore activities. The 55L allele results in significantly higher PON1 mRNA and serum protein levels and therefore activity compared to the 55M allele.[12][13] The -108C allele has greater promoter activity than the -108T allele which results in different serum activities.[12][13] The distribution of the PON1 polymorphisms varies with ethnicity. The frequency of the PON1-192R allele increases the further from Europe a population originates, the frequency in Caucasians of 15-30% increases to 70-90% in Far Eastern Oriental and Sub-Saharan African populations.[14] In the southern US African-Americans are five times more likely to be RR than Caucasians.[15] In contrast the PON1-55M allele is much less frequent in Oriental and black African populations compared to Caucasians and are extremely rare or absent in some populations e.g. Thais. These ethnic differences in SNP distribution can lead to large activity differences between populations.[14] # Clinical significance PON1 was first discovered through its ability to hydrolyse and therefore detoxify organophosphorus compounds which are widely used as pesticides and nerve gases. Despite decades of research it is only now becoming clear that PON1 protects humans from the acute and chronic harmful effects of these compounds[16][17] Low PON1 activity found in children may increase their susceptibility to organophosphates. Oxidised-lipids are the major cause of inflammation and are responsible for the initiation and/or propagation of several inflammatory diseases including atherosclerosis (heart disease and stroke), diabetes, liver and kidney diseases, rheumatic diseases, eye diseases (macular degeneration), cancer and HIV infection[citation needed]. Because of its ability to destroy oxidised-lipids PON1 appears to play some role in all these diseases. However, the greatest research interest has been the role of PON1 in atherosclerosis, where, because of its ability to remove harmful oxidised-lipids, PON1 protects against the development of atherosclerosis[18] Oxidized polyunsaturated fatty acids (notably in oxidized low-density lipoprotein) form lactone-like structures that are PON substrates.[19] PON1 also protects against bacterial infection by destroying the bacterial signalling molecules that cause gram negative bacteria to invade human tissue and form colonies, thus PON1 contributes to the bodies innate immunity[20] Recently it has been suggested that PON1 has a role in healthy aging, however, the mechanism is currently unknown[21] PON1 activity is low in infants compared to adults. A study of Mexican-American children showed that PON1 activity increased 3.5 times between birth and age seven.[22] An association between PON1 gene polymorphism and susceptibility to Parkinson's disease was not found in a Chinese population.[23] # Notes

https://www.wikidoc.org/index.php/PON1

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POT1

POT1 Protection of telomeres protein 1 is a protein that in humans is encoded by the POT1 gene. # Function This gene is a member of the telombin family and encodes a nuclear protein involved in telomere maintenance. Specifically, this protein functions as a member of a multi-protein complex known as shelterin, that binds to the TTAGGG repeats of telomeres, regulating telomere length and protecting chromosome ends from illegitimate recombination, catastrophic chromosome instability, and abnormal chromosome segregation. Alternatively spliced transcript variants have been described. The absence of POT1 in mouse embryonic fibroblasts and chicken cells leads to a detrimental DNA damage response on telomeres resulting in telomere dysfunction-induced foci (TIFs). POT1 is required for telomere protection because it allows for telomere inhibition of DNA damage response factors. The protein also serves a role in the regulation of telomerase activity on telomeres. In vitro experiments utilizing human POT1 have shown that reduction in POT1 levels result in the elongation of telomeres. # Interactions POT1 has been shown to interact with ACD and TINF2. # Pathology - Increased transcriptional expression of this gene is associated with stomach carcinogenesis and its progression. - Mutations in this gene have also been associated to the acquisition of the malignant features of chronic lymphocytic leukemia. - POT1 loss-of-function variants predispose to familial melanoma and glioma.

POT1 Protection of telomeres protein 1 is a protein that in humans is encoded by the POT1 gene.[1][2][3] # Function This gene is a member of the telombin family and encodes a nuclear protein involved in telomere maintenance. Specifically, this protein functions as a member of a multi-protein complex known as shelterin, that binds to the TTAGGG repeats of telomeres, regulating telomere length and protecting chromosome ends from illegitimate recombination, catastrophic chromosome instability, and abnormal chromosome segregation. Alternatively spliced transcript variants have been described.[3] The absence of POT1 in mouse embryonic fibroblasts and chicken cells leads to a detrimental DNA damage response on telomeres resulting in telomere dysfunction-induced foci (TIFs). POT1 is required for telomere protection because it allows for telomere inhibition of DNA damage response factors. The protein also serves a role in the regulation of telomerase activity on telomeres. In vitro experiments utilizing human POT1 have shown that reduction in POT1 levels result in the elongation of telomeres.[4] # Interactions POT1 has been shown to interact with ACD[5][6][7] and TINF2.[6][7][8] # Pathology - Increased transcriptional expression of this gene is associated with stomach carcinogenesis and its progression. - Mutations in this gene have also been associated to the acquisition of the malignant features of chronic lymphocytic leukemia.[9] - POT1 loss-of-function variants predispose to familial melanoma[10] and glioma.[11]

https://www.wikidoc.org/index.php/POT1

4d754dd784a0a94614a03c9ce45c7920395588f2

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PPAN

PPAN Suppressor of SWI4 1 homolog is a protein that in humans is encoded by the PPAN gene. The protein encoded by this gene is an evolutionarily conserved protein similar to yeast SSF1 as well as to the gene product of the Drosophila gene peter pan (PPAN). SSF1 is known to be involved in the second step of mRNA splicing. Both SSF1 and PPAN are essential for cell growth and proliferation. This gene was found to cotranscript with P2RY11/P2Y(11), an immediate downstream gene on the chromosome that encodes an ATP receptor. The chimeric transcripts of this gene and P2RY11 were found to be ubiquitously present and regulated during granulocytic differentiation. Exogenous expression of this gene was reported to reduce the anchorage-independent growth of some tumor cells. One of the introns of PPAN encodes the Small nucleolar RNA SNORD105.

PPAN Suppressor of SWI4 1 homolog is a protein that in humans is encoded by the PPAN gene.[1][2] The protein encoded by this gene is an evolutionarily conserved protein similar to yeast SSF1 as well as to the gene product of the Drosophila gene peter pan (PPAN). SSF1 is known to be involved in the second step of mRNA splicing. Both SSF1 and PPAN are essential for cell growth and proliferation. This gene was found to cotranscript with P2RY11/P2Y(11), an immediate downstream gene on the chromosome that encodes an ATP receptor. The chimeric transcripts of this gene and P2RY11 were found to be ubiquitously present and regulated during granulocytic differentiation. Exogenous expression of this gene was reported to reduce the anchorage-independent growth of some tumor cells.[2] One of the introns of PPAN encodes the Small nucleolar RNA SNORD105.[3]

https://www.wikidoc.org/index.php/PPAN

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PPIB

PPIB Peptidyl-prolyl cis-trans isomerase B is an enzyme that is encoded by the PPIB gene. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to regulate protein folding of type I collagen. Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved. # Structure Like other cyclophilins, PPIB forms a β-barrel structure with a hydrophobic core. This β-barrel is composed of eight anti-parallel β-strands and capped by two α-helices at the top and bottom. In addition, the β-turns and loops in the strands contribute to the flexibility of the barrel. In particular, PPIB is a 21 kDa protein which contains a C-terminal ER retention motif that directs the protein to the ER organelle, while its N-terminal extension attaches it to its substrates. # Function PPIB is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds and regulate protein folding and maturation. Proline is the only amino acid known to exist in both the cis and trans isomerization rate in vivo, and is often the rate-limiting step in protein refolding. The PPIase family is further divided into three structurally distinct subfamilies: cyclophilin (CyP), FK506-binding protein (FKBP), and parvulin (Pvn). While each family demonstrates PPIase activity, the families have no sequence of structural similarities. As a cyclophilin, PPIB binds cyclosporin A (CsA) and can be found within in the cell or secreted by the cell. # Human PPIB PPIB is the second of 18 cyclophilins to be identified in humans, after CypA. PPIB localizes to the endoplasmic reticulum (ER) and participates in many biological processes, including mitochondrial metabolism, apoptosis, redox, and inflammation, as well as in related diseases and conditions, such as ischemic reperfusion injury, AIDS, and cancer. It is also associated with viral infections.In eukaryotes, cyclophilins localize ubiquitously to many cell and tissue types. In addition to PPIase and protein chaperone activities, cyclophilins function in mitochondrial metabolism, apoptosis, immunological response, inflammation, and cell growth and proliferation. Along with PPIC, PPIB localizes to the endoplasmic reticulum (ER), where it maintains redox homeostasis. Depletion of these two cyclophilins leads to hyperoxidation of the ER. In the ER, PPIB interacts with proteins such as P3H1, CRTAP, BiP, GRP94, PDI, and calreticulin to form foldase and chaperone complexes and facilitate protein folding, especially for type I collagen. This protein is the major PPIase for type I collagen, since the collagen contains an abundance of prolines that require cis-trans isomerization for proper folding. Thus, PPIB is essential for collagen biosynthesis and post-translational modification and affects fibril assembly, matrix cross-linking, and bone mineralization. In addition, it is associated with the secretory pathway and released in biological fluids. This protein can bind to cells derived from T- and B-lymphocytes, and may regulate cyclosporine A-mediated immunosuppression. In one experiment, the addition of PPIB into cell cultures in vitro induced chemotaxis and integrin-mediated adhesion of T cells to the extracellular matrix (ECM), suggesting that it might function in innate immunity by recruing T cells into infected tissue in vivo. # Clinical significance As a cyclophilin, PPIB binds the immunosuppressive drug CsA to form a CsA-cyclophilin complex, which then targets calcineurin to inhibit the signaling pathway for T-cell activation. In cardiac myogenic cells, cyclophilins have been observed to be activated by heat shock and hypoxia-reoxygenation as well as complex with heat shock proteins. Thus, cyclophilins may function in cardioprotection during ischemia-reperfusion injury. PPIB contributes to the replication and infection of viruses causing diseases such as AIDS, hepatitis C, measles, and influenza A. Thus, therapeutic targeting of PPIB with selective inhibitors may prove effective in combating viral infections and inflammation. Currently, PPIB is employed as a biomarker for various types of cancer. Moreover, there are two antigenic epitopes (CypB84-92 and CypB91-99) recognized by HLA-A24-restricted and tumor-specific cytotoxic T lymphocytes which could be used as cancer vaccines, and in fact, were used to treat lung cancer in a clinical trial. # Bacterial PPIB PPIB has been identified in both Gram-negative bacteria and Gram-positive bacteria as an intracellular protein. In Escherichia coli, PPIB has been shown to have both PPIase activity and Chaperone (protein) activity. In Staphylococcus aureus, PPIB has been shown to have PPIase activity, and to directly assist in the refolding of Staphylococcal nuclease. Aside from these bacteria, PPIB has been identified in Brucella abortus, Mycobacterium tuberculosis, Bacillus subtilis and other bacteria. # Interactions PPIB has been shown to interact with: - Apolipoprotein B. - P3H1, - CRTAP, - BiP, - GRP94, - PDI, and - calreticulin.

PPIB Peptidyl-prolyl cis-trans isomerase B is an enzyme that is encoded by the PPIB gene.[1] As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to regulate protein folding of type I collagen.[2][3] Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved. # Structure Like other cyclophilins, PPIB forms a β-barrel structure with a hydrophobic core. This β-barrel is composed of eight anti-parallel β-strands and capped by two α-helices at the top and bottom. In addition, the β-turns and loops in the strands contribute to the flexibility of the barrel.[4] In particular, PPIB is a 21 kDa protein which contains a C-terminal ER retention motif that directs the protein to the ER organelle, while its N-terminal extension attaches it to its substrates.[3][5] # Function PPIB is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds and regulate protein folding and maturation. Proline is the only amino acid known to exist in both the cis and trans isomerization rate in vivo, and is often the rate-limiting step in protein refolding.[6] The PPIase family is further divided into three structurally distinct subfamilies: cyclophilin (CyP), FK506-binding protein (FKBP), and parvulin (Pvn).[7][8] While each family demonstrates PPIase activity, the families have no sequence of structural similarities. As a cyclophilin, PPIB binds cyclosporin A (CsA) and can be found within in the cell or secreted by the cell.[5][9] # Human PPIB PPIB is the second of 18 cyclophilins to be identified in humans, after CypA.[7][9] PPIB localizes to the endoplasmic reticulum (ER) and participates in many biological processes, including mitochondrial metabolism, apoptosis, redox, and inflammation, as well as in related diseases and conditions, such as ischemic reperfusion injury, AIDS, and cancer.[5][10] It is also associated with viral infections.In eukaryotes, cyclophilins localize ubiquitously to many cell and tissue types.[5][4] In addition to PPIase and protein chaperone activities, cyclophilins function in mitochondrial metabolism, apoptosis, immunological response, inflammation, and cell growth and proliferation.[2][5][4] Along with PPIC, PPIB localizes to the endoplasmic reticulum (ER), where it maintains redox homeostasis. Depletion of these two cyclophilins leads to hyperoxidation of the ER.[11] In the ER, PPIB interacts with proteins such as P3H1, CRTAP, BiP, GRP94, PDI, and calreticulin to form foldase and chaperone complexes and facilitate protein folding, especially for type I collagen.[12][13] This protein is the major PPIase for type I collagen, since the collagen contains an abundance of prolines that require cis-trans isomerization for proper folding. Thus, PPIB is essential for collagen biosynthesis and post-translational modification and affects fibril assembly, matrix cross-linking, and bone mineralization.[12] In addition, it is associated with the secretory pathway and released in biological fluids. This protein can bind to cells derived from T- and B-lymphocytes, and may regulate cyclosporine A-mediated immunosuppression.[14] In one experiment, the addition of PPIB into cell cultures in vitro induced chemotaxis and integrin-mediated adhesion of T cells to the extracellular matrix (ECM), suggesting that it might function in innate immunity by recruing T cells into infected tissue in vivo.[5] # Clinical significance As a cyclophilin, PPIB binds the immunosuppressive drug CsA to form a CsA-cyclophilin complex, which then targets calcineurin to inhibit the signaling pathway for T-cell activation. In cardiac myogenic cells, cyclophilins have been observed to be activated by heat shock and hypoxia-reoxygenation as well as complex with heat shock proteins. Thus, cyclophilins may function in cardioprotection during ischemia-reperfusion injury.[5] PPIB contributes to the replication and infection of viruses causing diseases such as AIDS, hepatitis C, measles, and influenza A. Thus, therapeutic targeting of PPIB with selective inhibitors may prove effective in combating viral infections and inflammation.[3] Currently, PPIB is employed as a biomarker for various types of cancer.[10] Moreover, there are two antigenic epitopes (CypB84-92 and CypB91-99) recognized by HLA-A24-restricted and tumor-specific cytotoxic T lymphocytes which could be used as cancer vaccines, and in fact, were used to treat lung cancer in a clinical trial.[5] # Bacterial PPIB PPIB has been identified in both Gram-negative bacteria and Gram-positive bacteria as an intracellular protein. In Escherichia coli, PPIB has been shown to have both PPIase activity and Chaperone (protein) activity.[15] In Staphylococcus aureus, PPIB has been shown to have PPIase activity, and to directly assist in the refolding of Staphylococcal nuclease.[16] Aside from these bacteria, PPIB has been identified in Brucella abortus, Mycobacterium tuberculosis, Bacillus subtilis and other bacteria.[17][18][19] # Interactions PPIB has been shown to interact with: - Apolipoprotein B.[20] - P3H1,[13] - CRTAP,[13] - BiP,[12] - GRP94,[12] - PDI,[12] and - calreticulin.[12]

https://www.wikidoc.org/index.php/PPIB

fb1473dee938ff8d160a748534c067587bec78a2

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PPIC

PPIC Peptidyl-prolyl cis-trans isomerase C (PPIC) is an enzyme that in humans is encoded by the PPIC gene on chromosome 5. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to facilitate folding or repair of proteins. In addition, PPIC participates in many biological processes, including mitochondrial metabolism, apoptosis, redox, and inflammation, as well as in related diseases and conditions, such as ischemic reperfusion injury, AIDS, and cancer. # Structure Like other cyclophilins, PPIC forms a β-barrel structure with a hydrophobic core. This β-barrel is composed of eight anti-parallel β-strands and capped by two α-helices at the top and bottom. In addition, the β-turns and loops in the strands contribute to the flexibility of the barrel. PPIC in particular is composed of 212 residues and contains a hydrophobic, ER-targeting sequence at the N-terminal. The PPIase domain is homologous to PPIA and can be bound and inhibited by CsA. # Function The protein encoded by this gene is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins. Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved. The PPIase family is further divided into three structurally distinct subfamilies: cyclophilin (CyP), FK506-binding protein (FKBP), and parvulin (Pvn). As a cyclophilin, PPI binds cyclosporin A (CsA) and can be found within in the cell or secreted by the cell. In eukaryotes, cyclophilins localize ubiquitously to many cell and tissue types, though PPIC especially is highly expressed in kidney. In addition to PPIase and protein chaperone activities, cyclophilins function in mitochondrial metabolism, apoptosis, immunological response, inflammation, and cell growth and proliferation. Along with PPIB, PPIC localizes to the endoplasmic reticulum (ER), where it maintains redox homeostasis. Depletion of these two cyclophilins lead to hyperoxidation of the ER. In the brain, PPIC complexes with cyclophilin C-associated protein (CyCAP) to activate microglia and macrophage function via the calcineurin/NFAT pathway. # Clinical Significance As a cyclophilin, PPIC binds the immunosuppressive drug CsA to form a CsA-cyclophilin complex, which then targets calcineurin to inhibit the signaling pathway for T-cell activation. In cardiac myogenic cells, cyclophilins have been observed to be activated by heat shock and hypoxia-reoxygenation as well as complex with heat shock proteins. Thus, cyclophilins may function in cardioprotection during ischemia-reperfusion injury. Similarly, PPIC may confer neuroprotection by forming a complex with CyCAP to activate survival mechanisms and mitigate ischemic damage in the brain. Currently, cyclophilin expression is highly correlated with cancer pathogenesis, but the specific mechanisms remain to be elucidated. For instance, studies identify PPIC as a reliable indicator of circulating tumor cells in epithelial ovarian cancer (EOC) and, thus, may serve as a biomarker for detection and treatment of the cancer. # Interactions PPIC has been shown to interact with: - CsA, - CyCAP, - calcineurin, and - NFATc1.

PPIC Peptidyl-prolyl cis-trans isomerase C (PPIC) is an enzyme that in humans is encoded by the PPIC gene on chromosome 5. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to facilitate folding or repair of proteins.[1][2][3] In addition, PPIC participates in many biological processes, including mitochondrial metabolism, apoptosis, redox, and inflammation, as well as in related diseases and conditions, such as ischemic reperfusion injury, AIDS, and cancer.[4][5][6][7] # Structure Like other cyclophilins, PPIC forms a β-barrel structure with a hydrophobic core. This β-barrel is composed of eight anti-parallel β-strands and capped by two α-helices at the top and bottom. In addition, the β-turns and loops in the strands contribute to the flexibility of the barrel.[6] PPIC in particular is composed of 212 residues and contains a hydrophobic, ER-targeting sequence at the N-terminal. The PPIase domain is homologous to PPIA and can be bound and inhibited by CsA.[2] # Function The protein encoded by this gene is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins.[3] Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved.[4][8] The PPIase family is further divided into three structurally distinct subfamilies: cyclophilin (CyP), FK506-binding protein (FKBP), and parvulin (Pvn).[4][6] As a cyclophilin, PPI binds cyclosporin A (CsA) and can be found within in the cell or secreted by the cell.[5] In eukaryotes, cyclophilins localize ubiquitously to many cell and tissue types, though PPIC especially is highly expressed in kidney.[5][6][9] In addition to PPIase and protein chaperone activities, cyclophilins function in mitochondrial metabolism, apoptosis, immunological response, inflammation, and cell growth and proliferation.[4][5][6] Along with PPIB, PPIC localizes to the endoplasmic reticulum (ER), where it maintains redox homeostasis. Depletion of these two cyclophilins lead to hyperoxidation of the ER.[7] In the brain, PPIC complexes with cyclophilin C-associated protein (CyCAP) to activate microglia and macrophage function via the calcineurin/NFAT pathway.[9] # Clinical Significance As a cyclophilin, PPIC binds the immunosuppressive drug CsA to form a CsA-cyclophilin complex, which then targets calcineurin to inhibit the signaling pathway for T-cell activation.[5] In cardiac myogenic cells, cyclophilins have been observed to be activated by heat shock and hypoxia-reoxygenation as well as complex with heat shock proteins. Thus, cyclophilins may function in cardioprotection during ischemia-reperfusion injury.[5] Similarly, PPIC may confer neuroprotection by forming a complex with CyCAP to activate survival mechanisms and mitigate ischemic damage in the brain.[9] Currently, cyclophilin expression is highly correlated with cancer pathogenesis, but the specific mechanisms remain to be elucidated.[5] For instance, studies identify PPIC as a reliable indicator of circulating tumor cells in epithelial ovarian cancer (EOC) and, thus, may serve as a biomarker for detection and treatment of the cancer.[10] # Interactions PPIC has been shown to interact with: - CsA,[9][11] - CyCAP,[9][11] - calcineurin,[9] and - NFATc1.[9]

https://www.wikidoc.org/index.php/PPIC

79364b224e7497664f5d62046605a57380217fab

wikidoc

PPID

PPID PPID may also refer to Private Personal Identifier, a standard SAML assertion. Peptidylprolyl isomerase D (cyclophilin D), also known as PPID, is a human gene. The protein encoded by this gene is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins. This protein has been shown to possess PPIase activity and, similar to other family members, can bind to the immunosuppressant cyclosporin A.

PPID PPID may also refer to Private Personal Identifier, a standard SAML assertion. Peptidylprolyl isomerase D (cyclophilin D), also known as PPID, is a human gene.[1] The protein encoded by this gene is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins. This protein has been shown to possess PPIase activity and, similar to other family members, can bind to the immunosuppressant cyclosporin A.[1]

https://www.wikidoc.org/index.php/PPID

e8fe7fab3b49a80bdb1e83488dd55e498f7c7150

wikidoc

PPIF

PPIF Peptidyl-prolyl cis-trans isomerase, mitochondrial (PPIF) is an enzyme that in humans is encoded by the PPIF gene. It has also been referred to as, but should not be confused with, cyclophilin D (CypD), which is encoded by the PPID gene. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to facilitate folding or repair of proteins. PPIF is a major component of the mitochondrial permeability transition pore (MPTP) and, thus, highly involved in mitochondrial metabolism and apoptosis, as well as in mitochondrial diseases and related conditions, including cardiac diseases, neurodegenerative diseases, and muscular dystrophy. In addition, PPIF participates in inflammation, as well as in ischemic reperfusion injury, AIDS, and cancer. # Structure Like other cyclophilins, PPIF forms a β-barrel structure with a hydrophobic core. This β-barrel is composed of eight anti-parallel β-strands and capped by two α-helices at the top and bottom. In addition, the β-turns and loops in the strands contribute to the flexibility of the barrel. PPIF weighs 17.5 kDa and forms part of the MPTP in the inner mitochondrial membrane (IMM). # Function The protein encoded by this gene is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins. Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved. The PPIase family is further divided into three structurally distinct subfamilies: cyclophilin (CyP), FK506-binding protein (FKBP), and parvulin (Pvn). As a cyclophilin, PPI binds cyclosporin A (CsA) and can be found within in the cell or secreted by the cell. In eukaryotes, cyclophilins localize ubiquitously to many cell and tissue types, though studies on PPIF focus primarily on heart, liver, and brain tissue. In addition to PPIase and protein chaperone activities, cyclophilins also function in mitochondrial metabolism, apoptosis, immunological response, inflammation, and cell growth and proliferation. PPIF is especially involved in mitochondrial apoptosis as a major component of the MPTP. Through its PPIase ability, the protein interacts with and induces a conformational change in adenine nucleotide translocase (ANT), the other MPTP component. This activation, along with high calcium ion levels, induces the opening the MPTP, resulting in mitochondrial swelling, increasing reactive oxygen species (ROS) levels, membrane depolarization, failing ATP production, caspase cascade activation, and ultimately, apoptosis. # Clinical significance As a cyclophilin, PPIF binds the immunosuppressive drug CsA to form a CsA-cyclophilin complex, which then targets calcineurin to inhibit the signaling pathway for T-cell activation. Due to its association with the MPTP, PPIF is also involved in neurodegenerative diseases, including glaucoma, diabetic retinopathy, Parkinson’s disease, and Alzheimer’s disease. For neurodegenerative diseases, treatment of reperfusion events with CsA, a PPID inhibitor, prevents cytochrome C release and significantly reduces cell death in neurons. As such, PPID proves to be an effective therapeutic target for patients suffering neurodegenerative diseases. In addition, PPIF, as part of the MPTP, is involved in ischemia/reperfusion injury, traumatic brain injury (TBI), muscular dystrophy, and drug toxicity. Though PPIF was identified as a candidate for dilated cardiomyopathy (DCM) for one afflicted family, further study revealed no mutations in the gene to implicate it in the disease. Nonetheless, in cardiac myogenic cells, cyclophilins have been observed to be activated by heat shock and hypoxia-reoxygenation as well as complex with heat shock proteins. Thus, cyclophilins may function in cardioprotection during ischemia-reperfusion injury. Currently, cyclophilin expression is highly correlated with cancer pathogenesis, but the specific mechanisms remain to be elucidated. # Interactions PPIF has been shown to interact with: - CsA - ANT

PPIF Peptidyl-prolyl cis-trans isomerase, mitochondrial (PPIF) is an enzyme that in humans is encoded by the PPIF gene. It has also been referred to as, but should not be confused with, cyclophilin D (CypD), which is encoded by the PPID gene.[1][2] As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to facilitate folding or repair of proteins.[2] PPIF is a major component of the mitochondrial permeability transition pore (MPTP) and, thus, highly involved in mitochondrial metabolism and apoptosis, as well as in mitochondrial diseases and related conditions, including cardiac diseases, neurodegenerative diseases, and muscular dystrophy.[3] In addition, PPIF participates in inflammation, as well as in ischemic reperfusion injury, AIDS, and cancer.[4][5][6][7] # Structure Like other cyclophilins, PPIF forms a β-barrel structure with a hydrophobic core. This β-barrel is composed of eight anti-parallel β-strands and capped by two α-helices at the top and bottom. In addition, the β-turns and loops in the strands contribute to the flexibility of the barrel.[6] PPIF weighs 17.5 kDa and forms part of the MPTP in the inner mitochondrial membrane (IMM).[2][8] # Function The protein encoded by this gene is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins.[2] Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved.[4][9] The PPIase family is further divided into three structurally distinct subfamilies: cyclophilin (CyP), FK506-binding protein (FKBP), and parvulin (Pvn).[4][6] As a cyclophilin, PPI binds cyclosporin A (CsA) and can be found within in the cell or secreted by the cell.[5] In eukaryotes, cyclophilins localize ubiquitously to many cell and tissue types, though studies on PPIF focus primarily on heart, liver, and brain tissue.[3][5][6] In addition to PPIase and protein chaperone activities, cyclophilins also function in mitochondrial metabolism, apoptosis, immunological response, inflammation, and cell growth and proliferation.[4][5][6] PPIF is especially involved in mitochondrial apoptosis as a major component of the MPTP. Through its PPIase ability, the protein interacts with and induces a conformational change in adenine nucleotide translocase (ANT), the other MPTP component. This activation, along with high calcium ion levels, induces the opening the MPTP, resulting in mitochondrial swelling, increasing reactive oxygen species (ROS) levels, membrane depolarization, failing ATP production, caspase cascade activation, and ultimately, apoptosis.[10][11][12] # Clinical significance As a cyclophilin, PPIF binds the immunosuppressive drug CsA to form a CsA-cyclophilin complex, which then targets calcineurin to inhibit the signaling pathway for T-cell activation.[5] Due to its association with the MPTP, PPIF is also involved in neurodegenerative diseases, including glaucoma, diabetic retinopathy, Parkinson’s disease, and Alzheimer’s disease.[12] For neurodegenerative diseases, treatment of reperfusion events with CsA, a PPID inhibitor, prevents cytochrome C release and significantly reduces cell death in neurons. As such, PPID proves to be an effective therapeutic target for patients suffering neurodegenerative diseases. In addition, PPIF, as part of the MPTP, is involved in ischemia/reperfusion injury, traumatic brain injury (TBI), muscular dystrophy, and drug toxicity.[3] Though PPIF was identified as a candidate for dilated cardiomyopathy (DCM) for one afflicted family, further study revealed no mutations in the gene to implicate it in the disease.[11] Nonetheless, in cardiac myogenic cells, cyclophilins have been observed to be activated by heat shock and hypoxia-reoxygenation as well as complex with heat shock proteins. Thus, cyclophilins may function in cardioprotection during ischemia-reperfusion injury. Currently, cyclophilin expression is highly correlated with cancer pathogenesis, but the specific mechanisms remain to be elucidated.[5] # Interactions PPIF has been shown to interact with: - CsA[10] - ANT[10]

https://www.wikidoc.org/index.php/PPIF

05aaf5a2f74c3885ab11debb5400dc97b3f66272

wikidoc

PPT1

PPT1 Palmitoyl-protein thioesterase 1 (PPT-1), also known as palmitoyl-protein hydrolase 1, is an enzyme that in humans is encoded by the PPT1 gene. # Function PPT-1 a member of the palmitoyl protein thioesterase family. PPT-1 is a small glycoprotein involved in the catabolism of lipid-modified proteins during lysosomal degradation. This enzyme removes thioester-linked fatty acyl groups such as palmitate from cysteine residues. # Clinical significance Defects in this gene are a cause of neuronal ceroid lipofuscinosis type 1 (CLN1). <ref Genetic basis and phenotypic correlations of the neuronal ceroid lipofusinoses. Warrier V; Vieira M; Mole SE. Biochimica et Biophysica Acta. 1832(11):1827-30, 2013>

PPT1 Palmitoyl-protein thioesterase 1 (PPT-1), also known as palmitoyl-protein hydrolase 1, is an enzyme that in humans is encoded by the PPT1 gene.[1][2][3] # Function PPT-1 a member of the palmitoyl protein thioesterase family. PPT-1 is a small glycoprotein involved in the catabolism of lipid-modified proteins during lysosomal degradation. This enzyme removes thioester-linked fatty acyl groups such as palmitate from cysteine residues.[1] # Clinical significance Defects in this gene are a cause of neuronal ceroid lipofuscinosis type 1 (CLN1). <ref Genetic basis and phenotypic correlations of the neuronal ceroid lipofusinoses. [Review] Warrier V; Vieira M; Mole SE. Biochimica et Biophysica Acta. 1832(11):1827-30, 2013>

https://www.wikidoc.org/index.php/PPT1

37e50f8e9950394dec00c5ca698a0b13229fe06e

wikidoc

PRC1

PRC1 Protein Regulator of cytokinesis 1 (PRC1) is a protein that in humans is encoded by the PRC1 gene and is involved in cytokinesis. # Function PRC1 protein is expressed at relatively high levels during S and G2/M phases of the cell cycle before dropping dramatically after mitotic exit and entrance into G1 phase. PRC1 is located in the nucleus during interphase, becomes associated with the mitotic spindle in a highly dynamic manner during anaphase, and localizes to the cell midbody during cytokinesis. PRC1 was first identified in 1998 using and ''in vitro'' phosphorylation screening method and shown to be a substrate of several cyclin-dependent kinases (CDKs). Correspondingly, ablation of PRC1 has been shown to disrupt spindle midzone assembly in mammalian systems. At least three alternatively spliced transcript variants encoding distinct isoforms of PRC1 have been observed. Additionally, PRC1 has sequence homology with Ase1 in yeasts, SPD-1 (spindle defective 1) in C. elegans, Feo in D. melanogaster, and MAP65 in plants, all of which fall in a conserved family of nonmotor microtubule-associated proteins (MAPs). # Structure The crystal structure of PRC1 has only recently been characterized in vitro. In 2013, PRC1 was illustrated as a lengthy molecule consisting of a C-terminal spectrin microtubule-binding domain, an extended rod domain, and an N-terminal dimerization domain. Consisting of an intricate arrangement of α-helices, the rod domain, together with the dimerization-conducting N terminus cooperate to facilitate binding of other proteins, such as Kinesin-4, to PRC1. PRC1’s rod domain adopts multiple conformations, all affected by its C-terminal spectrin domain. A model has been suggested in which PRC1 is likely to be a flexible molecule both in solution and on single microtubules but becomes more rigid when the microtubule-binding domains are restricted with antiparallel microtubule filament crosslinking, seen at the spindle midzone. The overall structure of the PRC1 homodimer is reminiscent of actin-bundling proteins, and this process of microtubule filament crosslinking is similar to that of actin. # Role in cytokinesis PRC1’s role in midzone microtubule formation, essential to the cytokinetic machinery of mammals, is made possible through its collaboration with Kinesin-4 in setting up a controlled zone of overlapping, antiparallel microtubules at the spindle midzone. PRC1 is normally inhibited until anaphase onset by CDK1 mediated phosphorylation, preventing its dimerization. Upon anaphase onset and removal of inhibitory CDK1 phosphorylation, PRC1 dimers form. These homodimers specifically recognize antiparallel microtubule overlaps, found at the spindle midzone, and bind, allowing microtubule sliding, cross-linking of microtubule filaments, and assembly of central-spindle-mediating proteins, including but not limited to Kinesin-4. PRC1 dimers, required for the high-affinity interaction with Kinesin-4, recruit Kinesin-4 to regions of antiparallel microtubule overlap, where Kinesin-4, a plus-end directed motor protein that inhibits microtubule dynamics, helps to form length-dependent end tags that help stabilize and regulate spindle microtubule assembly within cytokinesis. This PRC1-Kinesin-4 complex differentially identifies and regulates the spindle midzone microtubules during cell division. This regulation is crucial in order for cytokinesis to progress properly. # Interactions - PRC1 is a non-motor microtubule-associated protein (MAP) whose C-terminal spectrin domain (aa 341-640) binds microtubules with micromolar affinity (0.6 +/- 0.3uM) - PRC1 has been shown to interact with TRIM37. - PRC1 interacts with Kinesin-4 that plays an important role in crossing spindle microtubules and setting midzone length in mammalian cytokinesis. - PRC1 is negatively modulated by CDKs, particularly CDK1. - PLK1 negatively regulates PRC1 through phosphorylation at Thr-602, near the C-terminus of PRC1, only after dephosphorylation of PRC1 at an inhibitory CDK1 site. - PRC1 binds directly to CYK-4 subunit of the centralspindlin complex to stabilise the central spindle.

PRC1 Protein Regulator of cytokinesis 1 (PRC1) is a protein that in humans is encoded by the PRC1 gene and is involved in cytokinesis.[1][2] # Function PRC1 protein is expressed at relatively high levels during S and G2/M phases of the cell cycle before dropping dramatically after mitotic exit and entrance into G1 phase. PRC1 is located in the nucleus during interphase, becomes associated with the mitotic spindle in a highly dynamic manner during anaphase, and localizes to the cell midbody during cytokinesis. PRC1 was first identified in 1998 using and ''in vitro'' phosphorylation screening method and shown to be a substrate of several cyclin-dependent kinases (CDKs).[1] Correspondingly, ablation of PRC1 has been shown to disrupt spindle midzone assembly in mammalian systems.[3] At least three alternatively spliced transcript variants encoding distinct isoforms of PRC1 have been observed.[2] Additionally, PRC1 has sequence homology with Ase1 in yeasts, SPD-1 (spindle defective 1) in C. elegans, Feo in D. melanogaster, and MAP65 in plants, all of which fall in a conserved family of nonmotor microtubule-associated proteins (MAPs).[4][5][6] # Structure The crystal structure of PRC1 has only recently been characterized in vitro. In 2013, PRC1 was illustrated as a lengthy molecule consisting of a C-terminal spectrin microtubule-binding domain, an extended rod domain, and an N-terminal dimerization domain.[5][7] Consisting of an intricate arrangement of α-helices, the rod domain, together with the dimerization-conducting N terminus cooperate to facilitate binding of other proteins, such as Kinesin-4, to PRC1. PRC1’s rod domain adopts multiple conformations, all affected by its C-terminal spectrin domain. A model has been suggested in which PRC1 is likely to be a flexible molecule both in solution and on single microtubules but becomes more rigid when the microtubule-binding domains are restricted with antiparallel microtubule filament crosslinking, seen at the spindle midzone. The overall structure of the PRC1 homodimer is reminiscent of actin-bundling proteins, and this process of microtubule filament crosslinking is similar to that of actin.[5] # Role in cytokinesis PRC1’s role in midzone microtubule formation, essential to the cytokinetic machinery of mammals, is made possible through its collaboration with Kinesin-4 in setting up a controlled zone of overlapping, antiparallel microtubules at the spindle midzone.[8] PRC1 is normally inhibited until anaphase onset by CDK1 mediated phosphorylation, preventing its dimerization. Upon anaphase onset and removal of inhibitory CDK1 phosphorylation, PRC1 dimers form. These homodimers specifically recognize antiparallel microtubule overlaps, found at the spindle midzone, and bind, allowing microtubule sliding, cross-linking of microtubule filaments, and assembly of central-spindle-mediating proteins, including but not limited to Kinesin-4.[8][9] PRC1 dimers, required for the high-affinity interaction with Kinesin-4, recruit Kinesin-4 to regions of antiparallel microtubule overlap, where Kinesin-4, a plus-end directed motor protein that inhibits microtubule dynamics, helps to form length-dependent end tags that help stabilize and regulate spindle microtubule assembly within cytokinesis.[5][8] This PRC1-Kinesin-4 complex differentially identifies and regulates the spindle midzone microtubules during cell division.[8] This regulation is crucial in order for cytokinesis to progress properly. # Interactions - PRC1 is a non-motor microtubule-associated protein (MAP) whose C-terminal spectrin domain (aa 341-640) binds microtubules with micromolar affinity (0.6 +/- 0.3uM) [10] - PRC1 has been shown to interact with TRIM37.[11] - PRC1 interacts with Kinesin-4 that plays an important role in crossing spindle microtubules and setting midzone length in mammalian cytokinesis.[5] - PRC1 is negatively modulated by CDKs, particularly CDK1.[9] - PLK1 negatively regulates PRC1 through phosphorylation at Thr-602, near the C-terminus of PRC1, only after dephosphorylation of PRC1 at an inhibitory CDK1 site.[8][12] - PRC1 binds directly to CYK-4 subunit of the centralspindlin complex to stabilise the central spindle.[13]

https://www.wikidoc.org/index.php/PRC1

68edc7bf6b5b5e3501b36268795f8855841ea14c

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PRNP

PRNP PRNP (PRioN Protein) is the human gene encoding for the major prion protein PrP (for prion protein), also known as CD230 (cluster of differentiation 230). Expression of the protein is most predominant in the nervous system but occurs in many other tissues throughout the body. The protein can exist in multiple isoforms, the normal PrPC, and as Protease resistant PrPRes like the disease-causing PrPSc(scrapie) and an isoform located in mitochondria. The misfolded version PrPSc is associated with a variety of cognitive disorders and neurodegenerative diseases such as bovine spongiform encephalopathy, chronic wasting disease, Creutzfeldt–Jakob disease, fatal familial insomnia, feline spongiform encephalopathy, Gerstmann–Sträussler–Scheinker syndrome, kuru, scrapie, transmissible mink encephalopathy, ungulate spongiform encephalopathy, and variant Creutzfeldt–Jakob disease. # Gene The human PRNP gene is located on the short (p) arm of chromosome 20 between the end (terminus) of the arm and position 12, from base pair 4,615,068 to base pair 4,630,233. # Structure PrP is highly conserved through mammals, lending credence to application of conclusions from test animals such as mice. Comparison between primates is especially similar, ranging from 92.9-99.6% similarity in amino acid sequences. The human protein structure consists of a globular domain with three α-helices and a two-strand antiparallel β-sheet, an NH2-terminal tail, and a short COOH-terminal tail. A glycophosphatidylinositol (GPI) membrane anchor at the COOH-terminal tethers PrP to cell membranes, and this proves to be integral to the transmission of conformational change; secreted PrP lacking the anchor component is unaffected by the infectious isoform. The primary sequence of PrP is 253 amino acids long before post-translational modification. Signal sequences in the amino- and carboxy- terminal ends are removed posttranslationally, resulting in a mature length of 208 amino acids. For human and golden hamster PrP, two glycosylated sites exist on helices 2 and 3 at Asn181 and Asn197. Murine PrP has glycosylation sites as Asn180 and Asn196. A disulfide bond exists between Cys179 of the second helix and Cys214 of the third helix (human PrPC numbering). PrP messenger RNA contains a pseudoknot structure (prion pseudoknot), which is thought to be involved in regulation of PrP protein translation. ## Ligand-binding The mechanism for conformational conversion to the scrapie isoform is speculated to be an elusive ligand-protein, but, so far, no such compound has been identified. However, a large body of research has developed on candidates and their interaction with the PrPC. Copper, zinc, manganese, and nickel are confirmed PrP ligands that bind to its octarepeat region. Ligand binding causes a conformational change with unknown effect. Heavy metal binding at PrP has been linked to resistance to oxidative stress arising from heavy metal toxicity. ## PrPC (normal cellular) isoform Although the precise function of PrP is not yet known, it is possibly involved in the transport of ionic copper to cells from the surrounding environment. Researchers have also proposed roles for PrP in cell signaling or in the formation of synapses. PrPC attaches to the outer surface of the cell membrane by a glycosylphosphatidylinositol anchor at its C-terminal Ser231. Prion protein contains 5 amino-terminal octapeptide repeats with sequence PHGGGWGQ. This is thought to generate a copper-binding domain via nitrogen atoms in the histidine imidazole side-chains and deprotonated amide nitrogens from the 2nd and 3rd glycines in the repeat. The ability to bind copper is, therefore, pH-dependent. NMR shows copper binding results in a conformational change at the N-terminus. ## PrPSc (scrapie) isoform PrPSc is a conformational isoform of PrPC, but this orientation tends to accumulate in compact, protease-resistant aggregates within neural tissue. The abnormal PrPSc isoform has a different secondary and tertiary structure from PrPC, but identical primary sequence. Circular dichroism shows that normal PrPC has 43% alpha helical and 3% beta sheet content, whereas PrPSc is only 30% alpha helix and 43% beta sheet. This refolding renders the PrPSc isoform extremely resistant to proteolysis. The propagation of PrPSc is a topic of great interest, as its accumulation is a pathological cause of neurodegeneration. Based on the progressive nature of spongiform encephalopathies, the predominant hypothesis posits that the change from normal PrPC is caused by the presence and interaction with PrPSc. Strong support for this is taken from studies in which PRNP-knockout mice are resistant to the introduction of PrPSc. Despite widespread acceptance of the conformation conversion hypothesis, some studies mitigate claims for a direct link between PrPSc and cytotoxicity. Polymorphisms at sites 136, 154, and 171 are associated with varying susceptibility to scrapie. Polymorphisms of the PrP-VRQ form and PrP-ARQ form are associated with increased susceptibility, whereas PrP-ARR is associated with resistance. The National Scrapie Plan aims to breed out these scrapie polymorphisms by increasing the frequency of the resistant allele. However, PrP-ARR polymorphisms are susceptible to atypical scrapie, so this may prove unfruitful. # Function ## Nervous system The strong association to neurodegenerative diseases raises many questions of the function of PrP in the brain. A common approach is using PrP-knockout and transgenic mice to investigate deficiencies and differences. Initial attempts produced two strains of PrP-null mice that shows no physiological or developmental differences when subjected to an array of tests. However, more recent strains have shown significant cognitive abnormalities. As the null mice age, a marked loss of Purkinje cells in the cerebellum results in decreased motor coordination. However, this effect is not a direct result of PrP’s absence, and rather arises from increased Doppel gene expression. Other observed differences include reduced stress response and increased exploration of novel environments. Circadian rhythm is altered in null mice. Fatal familial insomnia is thought to be the result of a point mutation in PRNP at codon 178, which corroborates PrP’s involvement in sleep-wake cycles. In addition, circadian regulation has been demonstrated in PrP mRNA, which cycles regularly with day-night. ### Memory While null mice exhibit normal learning ability and short-term memory, long-term memory consolidation deficits have been demonstrated. As with ataxia, however, this is attributable to Doppel gene expression. However, spatial learning, a predominantly hippocampal-function, is decreased in the null mice and can be recovered with the reinstatement of PrP in neurons; this indicates that loss of PrP function is the cause. The interaction of hippocampal PrP with laminin (LN) is pivotal in memory processing and is likely modulated by the kinases PKA and ERK1/2. Further support for PrP’s role in memory formation is derived from several population studies. A test of healthy young humans showed increased long-term memory ability associated with an MM or MV genotype when compared to VV. Down syndrome patients with a single valine substitution have been linked to earlier cognitive decline. Several polymorphisms in PRNP have been linked with cognitive impairment in the elderly as well as earlier cognitive decline. All of these studies investigated differences in codon 129, indicating its importance in the overall functionality of PrP, in particular with regard to memory. ### Neurons and synapses PrP is present in both the pre- and post-synaptic compartments, with the greatest concentration in the pre-synaptic portion. Considering this and PrP’s suite of behavioral influences, the neural cell functions and interactions are of particular interest. Based on the copper ligand, one proposed function casts PrP as a copper buffer for the synaptic cleft. In this role, the protein could serve as either a copper homeostasis mechanism, a calcium modulator, or a sensor for copper or oxidative stress. Loss of PrP function has been linked to long-term potentiation (LTP). This effect can be positive or negative and is due to changes in neuronal excitability and synaptic transmission in the hippocampus. Some research indicates PrP involvement in neuronal development, differentiation, and neurite outgrowth. The PrP-activated signal transduction pathway is associated with axon and dendritic outgrowth with a series of kinases. ## Immune system Though most attention is focused on PrP’s presence in the nervous system, it is also abundant in immune system tissue. PrP immune cells include haematopoietic stem cells, mature lymphoid and myeloid compartments, and certain lymphocytes; also, it has been detected in natural killer cells, platelets, and monocytes. T cell activation is accompanied by a strong up-regulation of PrP, though it is not requisite. The lack of immuno-response to transmissible spongiform encephalopathies (TSE), neurodegenerative diseases caused by prions, could stem from the tolerance for PrPSc. ## Muscles, liver, and pituitary PrP-null mice provide clues to a role in muscular physiology when subjected to a forced swimming test, which showed reduced locomotor activity. Ageing mice with an overexpression of PRNP showed significant degradation of muscle tissue. Though present, very low levels of PrP exist in the liver and could be associated with liver fibrosis. Presence in the pituitary has been shown to affect neuroendrocrine function in amphibians, but little is known concerning mammalian pituitary PrP. ## Cellular Varying expression of PrP through the cell cycle has led to speculation on involvement in development. A wide range of studies has been conducted investigating the role in cell proliferation, differentiation, death, and survival. Engagement of PrP has been linked to activation of signal transduction. Modulation of signal transduction pathways has been demonstrated in cross-linking with antibodies and ligand-binding (hop/STI1 or copper). Given the diversity of interactions, effects, and distribution, PrP has been proposed as dynamic surface protein functioning in signaling pathways. Specific sites along the protein bind other proteins, biomolecules, and metals. These interfaces allow specific sets of cells to communicate based on level of expression and the surrounding microenvironment. The anchoring on a GPI raft in the lipid bilayer supports claims of an extracellular scaffolding function. # Diseases caused by PrP misfolding More than 20 mutations in the PRNP gene have been identified in people with inherited prion diseases, which include the following: - Creutzfeldt–Jakob disease - glutamic acid-200 is replaced by lysine while valine is present at amino acid 129 - Gerstmann-Sträussler-Scheinker syndrome - usually a change in codon 102 from proline to leucine - fatal familial insomnia - aspartic acid-178 is replaced by asparagine while methionine is present at amino acid 129 The conversion of PrPC to PrPSc conformation is the mechanism of transmission of fatal, neurodegenerative transmissible spongiform encephalopathies (TSE). This can arise from genetic factors, infection from external source, or spontaneously for reasons unknown. Accumulation of PrPSc corresponds with progression of neurodegeneration and is the proposed cause. Some PRNP mutations lead to a change in single amino acids (the building-blocks of proteins) in the prion protein. Others insert additional amino acids into the protein or cause an abnormally short protein to be made. These mutations cause the cell to make prion proteins with an abnormal structure. The abnormal protein PrPSc accumulates in the brain and destroys nerve cells, which leads to the mental and behavioral features of prion diseases. Several other changes in the PRNP gene (called polymorphisms) do not cause prion diseases but may affect a person's risk of developing these diseases or alter the course of the disorders. An allele that codes for a PRNP variant, G127V, provides resistance to Kuru. In addition, some prion diseases can be transmitted from external sources of PrPSc. - Scrapie - fatal neurodegenerative disease in sheep, not transmissible to humans - Bovine spongiform encephalopathy (mad-cow disease) - fatal neurodegenerative disease in cows, which can be transmitted to humans by ingestion of brain, spinal, or digestive tract tissue of an infected cow - Kuru - TSE in humans, transmitted via funerary cannibalism. Generally, affected family members were given, by tradition, parts of the central nervous system according to ritual when consuming deceased family members. ## Alzheimer’s disease PrPC protein is one of several cellular receptors of soluble amyloid beta (Aβ) oligomers, which are canonically implicated in causing Alzheimer’s disease. These oligomers are composed smaller Aβ plaques, and are the most damaging to the integrity of a neuron. The precise mechanism of soluble Aβ oligomers directly inducing neurotoxicity is unknown, and experimental deletion of PRNP in animals has yielded several conflicting findings. When Aβ oligomers were injected into the cerebral ventricles of a mouse model of Alzheimer’s, PRNP deletion did not offer protection, only anti-PrPC antibodies prevented long-term memory and spatial learning deficits. This would suggest either an unequal relation between PRNP and Aβ oligomer-mediated neurodegeneration or a site-specific relational significance. In the case of direct injection of Aβ oligomers into the hippocampus, PRNP-knockout mice were found to be indistinguishable from control with respect to both neuronal death rates and measurements of synaptic plasticity. It was further found that Aβ-oligomers bind to PrPC at the postsynaptic density, indirectly overactivating the NMDA receptor via the Fyn enzyme, resulting in excitotoxicity. Soluble Aβ oligomers also bind to PrPC at the dendritic spines, forming a complex with Fyn and excessively activating tau, another protein implicated in Alzheimer’s. As the gene FYN codes for the enzyme Fyn, FYN-knockout mice display neither excitotoxic events nor dendritic spine shrinkage when injected with Aβ oligomers. In mammals, the full functional significance of PRNP remains unclear, as PRNP deletion has been prophylactically implemented by the cattle industry without apparent harm. In mice, this same deletion phenotypically varies between Alzheimer’s mouse lines, as hAPPJ20 mice and TgCRND8 mice show a slight increase in epileptic activity, contributing to conflicting results when examining Alzheimer’s survival rates. Of note, the deletion of PRNP in both APPswe and SEN1dE9, two other transgenic models of Alzheimer’s, attenuated the epilepsy-induced death phenotype seen in a subset of these animals. Taken collectively, recent evidence suggests PRNP may be important for conducing the neurotoxic effects of soluble Aβ-oligomers and the emergent disease state of Alzheimer’s. In humans, the Methionine/Valine polymorphism at codon 129 of PRNP (rs1799990) is most closely associated with Alzheimer’s disease. Variant V allele carriers (VV and MV) show a 13% decreased risk with respect to developing Alzheimer’s compared to the methionine homozygote (MM). However, the protective effects of variant V carriers have been found exclusively in Caucasians. The decreased risk in V allele carriers is further limited to late-onset Alzheimer’s disease only (≥ 65 years). PRNP can also functionally interact with polymorphisms in two other genes implicated in Alzheimer’s, PSEN1 and APOE, to compound risk for both Alzheimer’s and sporadic Creutzfeldt–Jakob disease. A point mutation on codon 102 of PRNP at least in part contributed to three separate patients’ atypical frontotemporal dementia within the same family, suggesting a new phenotype for Gerstmann-Straussler-Scheinker syndrome. The same study proposed sequencing PRNP in cases of ambiguously diagnosed dementia, as the various forms of dementia can prove challenging to differentially diagnose. # Interactions A strong interaction exists between PrP and cochaperone Hsp70/Hsp90 organizing protein/Stress-induced protein 1 (hop (protein)/STI1).

PRNP PRNP (PRioN Protein) is the human gene encoding for the major prion protein PrP (for prion protein), also known as CD230 (cluster of differentiation 230).[1][2][3][4] Expression of the protein is most predominant in the nervous system but occurs in many other tissues throughout the body.[5][6][7] The protein can exist in multiple isoforms, the normal PrPC, and as Protease resistant PrPRes like the disease-causing PrPSc(scrapie) and an isoform located in mitochondria. The misfolded version PrPSc is associated with a variety of cognitive disorders and neurodegenerative diseases such as bovine spongiform encephalopathy, chronic wasting disease, Creutzfeldt–Jakob disease, fatal familial insomnia, feline spongiform encephalopathy, Gerstmann–Sträussler–Scheinker syndrome, kuru, scrapie, transmissible mink encephalopathy, ungulate spongiform encephalopathy, and variant Creutzfeldt–Jakob disease. # Gene The human PRNP gene is located on the short (p) arm of chromosome 20 between the end (terminus) of the arm and position 12, from base pair 4,615,068 to base pair 4,630,233. # Structure PrP is highly conserved through mammals, lending credence to application of conclusions from test animals such as mice.[8] Comparison between primates is especially similar, ranging from 92.9-99.6% similarity in amino acid sequences. The human protein structure consists of a globular domain with three α-helices and a two-strand antiparallel β-sheet, an NH2-terminal tail, and a short COOH-terminal tail.[9] A glycophosphatidylinositol (GPI) membrane anchor at the COOH-terminal tethers PrP to cell membranes, and this proves to be integral to the transmission of conformational change; secreted PrP lacking the anchor component is unaffected by the infectious isoform.[10] The primary sequence of PrP is 253 amino acids long before post-translational modification. Signal sequences in the amino- and carboxy- terminal ends are removed posttranslationally, resulting in a mature length of 208 amino acids. For human and golden hamster PrP, two glycosylated sites exist on helices 2 and 3 at Asn181 and Asn197. Murine PrP has glycosylation sites as Asn180 and Asn196. A disulfide bond exists between Cys179 of the second helix and Cys214 of the third helix (human PrPC numbering). PrP messenger RNA contains a pseudoknot structure (prion pseudoknot), which is thought to be involved in regulation of PrP protein translation.[11] ## Ligand-binding The mechanism for conformational conversion to the scrapie isoform is speculated to be an elusive ligand-protein, but, so far, no such compound has been identified. However, a large body of research has developed on candidates and their interaction with the PrPC.[12] Copper, zinc, manganese, and nickel are confirmed PrP ligands that bind to its octarepeat region.[13] Ligand binding causes a conformational change with unknown effect. Heavy metal binding at PrP has been linked to resistance to oxidative stress arising from heavy metal toxicity.[13][14] ## PrPC (normal cellular) isoform Although the precise function of PrP is not yet known, it is possibly involved in the transport of ionic copper to cells from the surrounding environment. Researchers have also proposed roles for PrP in cell signaling or in the formation of synapses.[15] PrPC attaches to the outer surface of the cell membrane by a glycosylphosphatidylinositol anchor at its C-terminal Ser231. Prion protein contains 5 amino-terminal octapeptide repeats with sequence PHGGGWGQ. This is thought to generate a copper-binding domain via nitrogen atoms in the histidine imidazole side-chains and deprotonated amide nitrogens from the 2nd and 3rd glycines in the repeat. The ability to bind copper is, therefore, pH-dependent. NMR shows copper binding results in a conformational change at the N-terminus. ## PrPSc (scrapie) isoform PrPSc is a conformational isoform of PrPC, but this orientation tends to accumulate in compact, protease-resistant aggregates within neural tissue.[16] The abnormal PrPSc isoform has a different secondary and tertiary structure from PrPC, but identical primary sequence. Circular dichroism shows that normal PrPC has 43% alpha helical and 3% beta sheet content, whereas PrPSc is only 30% alpha helix and 43% beta sheet.[17] This refolding renders the PrPSc isoform extremely resistant to proteolysis. The propagation of PrPSc is a topic of great interest, as its accumulation is a pathological cause of neurodegeneration. Based on the progressive nature of spongiform encephalopathies, the predominant hypothesis posits that the change from normal PrPC is caused by the presence and interaction with PrPSc.[18] Strong support for this is taken from studies in which PRNP-knockout mice are resistant to the introduction of PrPSc.[19] Despite widespread acceptance of the conformation conversion hypothesis, some studies mitigate claims for a direct link between PrPSc and cytotoxicity.[20] Polymorphisms at sites 136, 154, and 171 are associated with varying susceptibility to scrapie. Polymorphisms of the PrP-VRQ form and PrP-ARQ form are associated with increased susceptibility, whereas PrP-ARR is associated with resistance. The National Scrapie Plan aims to breed out these scrapie polymorphisms by increasing the frequency of the resistant allele. However, PrP-ARR polymorphisms are susceptible to atypical scrapie, so this may prove unfruitful. # Function ## Nervous system The strong association to neurodegenerative diseases raises many questions of the function of PrP in the brain. A common approach is using PrP-knockout and transgenic mice to investigate deficiencies and differences.[21] Initial attempts produced two strains of PrP-null mice that shows no physiological or developmental differences when subjected to an array of tests. However, more recent strains have shown significant cognitive abnormalities.[12] As the null mice age, a marked loss of Purkinje cells in the cerebellum results in decreased motor coordination. However, this effect is not a direct result of PrP’s absence, and rather arises from increased Doppel gene expression.[22] Other observed differences include reduced stress response and increased exploration of novel environments.[23][24] Circadian rhythm is altered in null mice.[7] Fatal familial insomnia is thought to be the result of a point mutation in PRNP at codon 178, which corroborates PrP’s involvement in sleep-wake cycles.[25] In addition, circadian regulation has been demonstrated in PrP mRNA, which cycles regularly with day-night.[26] ### Memory While null mice exhibit normal learning ability and short-term memory, long-term memory consolidation deficits have been demonstrated. As with ataxia, however, this is attributable to Doppel gene expression. However, spatial learning, a predominantly hippocampal-function, is decreased in the null mice and can be recovered with the reinstatement of PrP in neurons; this indicates that loss of PrP function is the cause.[27][28] The interaction of hippocampal PrP with laminin (LN) is pivotal in memory processing and is likely modulated by the kinases PKA and ERK1/2.[29][30] Further support for PrP’s role in memory formation is derived from several population studies. A test of healthy young humans showed increased long-term memory ability associated with an MM or MV genotype when compared to VV.[31] Down syndrome patients with a single valine substitution have been linked to earlier cognitive decline.[32] Several polymorphisms in PRNP have been linked with cognitive impairment in the elderly as well as earlier cognitive decline.[33][34][35] All of these studies investigated differences in codon 129, indicating its importance in the overall functionality of PrP, in particular with regard to memory. ### Neurons and synapses PrP is present in both the pre- and post-synaptic compartments, with the greatest concentration in the pre-synaptic portion.[36] Considering this and PrP’s suite of behavioral influences, the neural cell functions and interactions are of particular interest. Based on the copper ligand, one proposed function casts PrP as a copper buffer for the synaptic cleft. In this role, the protein could serve as either a copper homeostasis mechanism, a calcium modulator, or a sensor for copper or oxidative stress.[37] Loss of PrP function has been linked to long-term potentiation (LTP). This effect can be positive or negative and is due to changes in neuronal excitability and synaptic transmission in the hippocampus.[38][39] Some research indicates PrP involvement in neuronal development, differentiation, and neurite outgrowth. The PrP-activated signal transduction pathway is associated with axon and dendritic outgrowth with a series of kinases.[20][40] ## Immune system Though most attention is focused on PrP’s presence in the nervous system, it is also abundant in immune system tissue. PrP immune cells include haematopoietic stem cells, mature lymphoid and myeloid compartments, and certain lymphocytes; also, it has been detected in natural killer cells, platelets, and monocytes. T cell activation is accompanied by a strong up-regulation of PrP, though it is not requisite. The lack of immuno-response to transmissible spongiform encephalopathies (TSE), neurodegenerative diseases caused by prions, could stem from the tolerance for PrPSc.[41] ## Muscles, liver, and pituitary PrP-null mice provide clues to a role in muscular physiology when subjected to a forced swimming test, which showed reduced locomotor activity. Ageing mice with an overexpression of PRNP showed significant degradation of muscle tissue. Though present, very low levels of PrP exist in the liver and could be associated with liver fibrosis. Presence in the pituitary has been shown to affect neuroendrocrine function in amphibians, but little is known concerning mammalian pituitary PrP.[12] ## Cellular Varying expression of PrP through the cell cycle has led to speculation on involvement in development. A wide range of studies has been conducted investigating the role in cell proliferation, differentiation, death, and survival.[12] Engagement of PrP has been linked to activation of signal transduction. Modulation of signal transduction pathways has been demonstrated in cross-linking with antibodies and ligand-binding (hop/STI1 or copper).[12] Given the diversity of interactions, effects, and distribution, PrP has been proposed as dynamic surface protein functioning in signaling pathways. Specific sites along the protein bind other proteins, biomolecules, and metals. These interfaces allow specific sets of cells to communicate based on level of expression and the surrounding microenvironment. The anchoring on a GPI raft in the lipid bilayer supports claims of an extracellular scaffolding function.[12] # Diseases caused by PrP misfolding More than 20 mutations in the PRNP gene have been identified in people with inherited prion diseases, which include the following:[42][43] - Creutzfeldt–Jakob disease - glutamic acid-200 is replaced by lysine while valine is present at amino acid 129 - Gerstmann-Sträussler-Scheinker syndrome - usually a change in codon 102 from proline to leucine[44] - fatal familial insomnia - aspartic acid-178 is replaced by asparagine while methionine is present at amino acid 129[45] The conversion of PrPC to PrPSc conformation is the mechanism of transmission of fatal, neurodegenerative transmissible spongiform encephalopathies (TSE). This can arise from genetic factors, infection from external source, or spontaneously for reasons unknown. Accumulation of PrPSc corresponds with progression of neurodegeneration and is the proposed cause. Some PRNP mutations lead to a change in single amino acids (the building-blocks of proteins) in the prion protein. Others insert additional amino acids into the protein or cause an abnormally short protein to be made. These mutations cause the cell to make prion proteins with an abnormal structure. The abnormal protein PrPSc accumulates in the brain and destroys nerve cells, which leads to the mental and behavioral features of prion diseases. Several other changes in the PRNP gene (called polymorphisms) do not cause prion diseases but may affect a person's risk of developing these diseases or alter the course of the disorders. An allele that codes for a PRNP variant, G127V, provides resistance to Kuru.[46][47] In addition, some prion diseases can be transmitted from external sources of PrPSc.[48] - Scrapie - fatal neurodegenerative disease in sheep, not transmissible to humans - Bovine spongiform encephalopathy (mad-cow disease) - fatal neurodegenerative disease in cows, which can be transmitted to humans by ingestion of brain, spinal, or digestive tract tissue of an infected cow - Kuru - TSE in humans, transmitted via funerary cannibalism. Generally, affected family members were given, by tradition, parts of the central nervous system according to ritual when consuming deceased family members. ## Alzheimer’s disease PrPC protein is one of several cellular receptors of soluble amyloid beta (Aβ) oligomers, which are canonically implicated in causing Alzheimer’s disease.[49] These oligomers are composed smaller Aβ plaques, and are the most damaging to the integrity of a neuron.[49] The precise mechanism of soluble Aβ oligomers directly inducing neurotoxicity is unknown, and experimental deletion of PRNP in animals has yielded several conflicting findings. When Aβ oligomers were injected into the cerebral ventricles of a mouse model of Alzheimer’s, PRNP deletion did not offer protection, only anti-PrPC antibodies prevented long-term memory and spatial learning deficits.[50][51] This would suggest either an unequal relation between PRNP and Aβ oligomer-mediated neurodegeneration or a site-specific relational significance. In the case of direct injection of Aβ oligomers into the hippocampus, PRNP-knockout mice were found to be indistinguishable from control with respect to both neuronal death rates and measurements of synaptic plasticity.[49][51] It was further found that Aβ-oligomers bind to PrPC at the postsynaptic density, indirectly overactivating the NMDA receptor via the Fyn enzyme, resulting in excitotoxicity.[50] Soluble Aβ oligomers also bind to PrPC at the dendritic spines, forming a complex with Fyn and excessively activating tau, another protein implicated in Alzheimer’s.[50] As the gene FYN codes for the enzyme Fyn, FYN-knockout mice display neither excitotoxic events nor dendritic spine shrinkage when injected with Aβ oligomers.[50] In mammals, the full functional significance of PRNP remains unclear, as PRNP deletion has been prophylactically implemented by the cattle industry without apparent harm.[49] In mice, this same deletion phenotypically varies between Alzheimer’s mouse lines, as hAPPJ20 mice and TgCRND8 mice show a slight increase in epileptic activity, contributing to conflicting results when examining Alzheimer’s survival rates.[49] Of note, the deletion of PRNP in both APPswe and SEN1dE9, two other transgenic models of Alzheimer’s, attenuated the epilepsy-induced death phenotype seen in a subset of these animals.[49] Taken collectively, recent evidence suggests PRNP may be important for conducing the neurotoxic effects of soluble Aβ-oligomers and the emergent disease state of Alzheimer’s.[49][50][51] In humans, the Methionine/Valine polymorphism at codon 129 of PRNP (rs1799990) is most closely associated with Alzheimer’s disease.[52] Variant V allele carriers (VV and MV) show a 13% decreased risk with respect to developing Alzheimer’s compared to the methionine homozygote (MM). However, the protective effects of variant V carriers have been found exclusively in Caucasians. The decreased risk in V allele carriers is further limited to late-onset Alzheimer’s disease only (≥ 65 years).[52] PRNP can also functionally interact with polymorphisms in two other genes implicated in Alzheimer’s, PSEN1 and APOE, to compound risk for both Alzheimer’s and sporadic Creutzfeldt–Jakob disease.[49] A point mutation on codon 102 of PRNP at least in part contributed to three separate patients’ atypical frontotemporal dementia within the same family, suggesting a new phenotype for Gerstmann-Straussler-Scheinker syndrome.[49][53] The same study proposed sequencing PRNP in cases of ambiguously diagnosed dementia, as the various forms of dementia can prove challenging to differentially diagnose.[53] # Interactions A strong interaction exists between PrP and cochaperone Hsp70/Hsp90 organizing protein/Stress-induced protein 1 (hop (protein)/STI1).[54][55]

https://www.wikidoc.org/index.php/PRNP

b1016f4a1f9cbebb05e50e5673e16c585afd8879

wikidoc

PSPH

PSPH Phosphoserine phosphatase is an enzyme that in humans is encoded by the PSPH gene. # Function The protein encoded by this gene belongs to a subfamily of the phosphotransferases. This encoded enzyme is responsible for the third and last step in L-serine formation. It catalyzes magnesium-dependent hydrolysis of L-phosphoserine and is also involved in an exchange reaction between L-serine and L-phosphoserine. Deficiency of this protein is thought to be linked to Williams syndrome. # Clinical significance Homozygous or compound heterozygous mutations in PSPH cause Neu-Laxova syndrome and Phosphoserine phosphatase deficiency. # Model organisms Model organisms have been used in the study of PSPH function. A conditional knockout mouse line called Psphtm1a(EUCOMM)Hmgu was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping

PSPH Phosphoserine phosphatase is an enzyme that in humans is encoded by the PSPH gene.[1][2][3] # Function The protein encoded by this gene belongs to a subfamily of the phosphotransferases. This encoded enzyme is responsible for the third and last step in L-serine formation. It catalyzes magnesium-dependent hydrolysis of L-phosphoserine and is also involved in an exchange reaction between L-serine and L-phosphoserine. Deficiency of this protein is thought to be linked to Williams syndrome.[3] # Clinical significance Homozygous or compound heterozygous mutations in PSPH cause Neu-Laxova syndrome[4] and Phosphoserine phosphatase deficiency.[5][6] # Model organisms Model organisms have been used in the study of PSPH function. A conditional knockout mouse line called Psphtm1a(EUCOMM)Hmgu was generated at the Wellcome Trust Sanger Institute.[7] Male and female animals underwent a standardized phenotypic screen[8] to determine the effects of deletion.[9][10][11][12] Additional screens performed: - In-depth immunological phenotyping[13]

https://www.wikidoc.org/index.php/PSPH

7a45405406697aadd07102561481578dbb386f4a

wikidoc

PTK6

PTK6 Tyrosine-protein kinase 6 is an enzyme that in humans is encoded by the PTK6 gene. # Function Tyrosine-protein kinase 6 (also known as Breast Tumor Kinase, Brk) is a cytoplasmic non-receptor protein kinase which may function as an intracellular signal transducer in epithelial tissues. The encoded protein has been shown to undergo autophosphorylation. # Clinical significance Overexpression of this gene in mammary epithelial cells leads to sensitization of the cells to epidermal growth factor and results in a partially transformed phenotype. Expression of this gene has been detected at low levels in some breast tumors but not in normal breast tissue. # Interactions PTK6 has been shown to interact with STAP2 and KHDRBS1.

PTK6 Tyrosine-protein kinase 6 is an enzyme that in humans is encoded by the PTK6 gene.[1][2][3] # Function Tyrosine-protein kinase 6 (also known as Breast Tumor Kinase, Brk) is a cytoplasmic non-receptor protein kinase which may function as an intracellular signal transducer in epithelial tissues. The encoded protein has been shown to undergo autophosphorylation.[3] # Clinical significance Overexpression of this gene in mammary epithelial cells leads to sensitization of the cells to epidermal growth factor and results in a partially transformed phenotype. Expression of this gene has been detected at low levels in some breast tumors but not in normal breast tissue.[3] # Interactions PTK6 has been shown to interact with STAP2[4] and KHDRBS1.[5]

https://www.wikidoc.org/index.php/PTK6

1c5f1151d5a2b59bb18998284b3aff59e784eeb1

wikidoc

PTK7

PTK7 Tyrosine-protein kinase-like 7 also known as colon carcinoma kinase 4 (CCK4) is a receptor tyrosine kinase that in humans is encoded by the PTK7 gene. # Function Receptor protein tyrosine kinases transduce extracellular signals across the cell membrane. A subgroup of these kinases lack detectable catalytic tyrosine kinase activity but retain roles in signal transduction. The protein encoded by this gene an intracellular domain with tyrosine kinase homology and may function as a cell adhesion molecule. This gene is thought to be expressed in colon carcinomas but not in normal colon, and therefore may be a marker for or may be involved in tumor progression. Four transcript variants encoding four different isoforms have been found for this gene. PTK7 serves as a context-dependent signalling switch for the Wnt pathways (particularly in planar cell polarity related functions such as convergent extension and neural crest cell migration) and appears to have similar functions for plexin and Flt-1 pathways. PTK7 was identified to be highly expressed in colon cancer by Saha et al. using serial analysis of gene expression (LongSAGE). Pfizer is targeting PTK7 for cancer by generating an antibody-drug conjugate against the PTK7 receptor.

PTK7 Tyrosine-protein kinase-like 7 also known as colon carcinoma kinase 4 (CCK4) is a receptor tyrosine kinase that in humans is encoded by the PTK7 gene.[1][2] # Function Receptor protein tyrosine kinases transduce extracellular signals across the cell membrane. A subgroup of these kinases lack detectable catalytic tyrosine kinase activity but retain roles in signal transduction. The protein encoded by this gene an intracellular domain with tyrosine kinase homology and may function as a cell adhesion molecule. This gene is thought to be expressed in colon carcinomas but not in normal colon, and therefore may be a marker for or may be involved in tumor progression. Four transcript variants encoding four different isoforms have been found for this gene.[2] PTK7 serves as a context-dependent signalling switch for the Wnt pathways (particularly in planar cell polarity related functions such as convergent extension and neural crest cell migration) and appears to have similar functions for plexin and Flt-1 pathways.[3] PTK7 was identified to be highly expressed in colon cancer by Saha et al. using serial analysis of gene expression (LongSAGE).[4] Pfizer is targeting PTK7 for cancer by generating an antibody-drug conjugate against the PTK7 receptor.

https://www.wikidoc.org/index.php/PTK7

aec1c4f07aad61d6781795bbbc80c2c7b67d6c27

wikidoc

PTRF

PTRF Polymerase I and transcript release factor, also known as Cavin1, Cavin-1 or PTRF, is a protein which in humans is encoded by the PTRF gene. # Function PTRF (Cavin1) has been shown to be crucial for caveola formation and function. Termination of RNA polymerase I catalyzed transcription is a 2-step process that involves pausing of transcription elongation and release of both the pre-ribosomal RNA and Pol I from the DNA template. The pausing is mediated by TTF1 and PTRF. PTRF is a soluble protein containing putative leucine zipper, nuclear localization signal, and PEST domains. # Interactions PTRF (Cavin1) forms trimers with Cavin2 and Cavin3 in caveola formation and has been shown to interact with other membrane associating proteins such as EHD2 and caveolins. PTRF has been shown to interact with ZNF148.

PTRF Polymerase I and transcript release factor, also known as Cavin1, Cavin-1 or PTRF, is a protein which in humans is encoded by the PTRF gene.[1][2] # Function PTRF (Cavin1) has been shown to be crucial for caveola formation and function. [3] Termination of RNA polymerase I catalyzed transcription is a 2-step process that involves pausing of transcription elongation and release of both the pre-ribosomal RNA and Pol I from the DNA template. The pausing is mediated by TTF1 and PTRF.[4][5] PTRF is a soluble protein containing putative leucine zipper, nuclear localization signal, and PEST domains.[6] # Interactions PTRF (Cavin1) forms trimers with Cavin2 and Cavin3 in caveola formation and has been shown to interact with other membrane associating proteins such as EHD2 and caveolins. [7] PTRF has been shown to interact with ZNF148.[8]

https://www.wikidoc.org/index.php/PTRF

2f1f72a92ce05a2939e2834e2021809b2a3de183

wikidoc

PTX3

PTX3 Pentraxin-related protein PTX3 also known as TNF-inducible gene 14 protein (TSG-14) is a protein that in humans is encoded by the PTX3 gene. Pentraxin 3 (ptx3) is a member of the pentraxin superfamily. This super family characterized by cyclic multimeric structure. PTX3 is rapidly produced and released by several cell types, in particular by mononuclear phagocytes, dendritic cells (DCs), fibroblasts and endothelial cells in response to primary inflammatory signals . PTX3 binds with high affinity to the complement component C1q, the extracellular matrix component TNFα induced protein 6 (TNFAIP6; also called TNF-stimulated gene 6, TSG-6) and selected microorganisms, including Aspergillus fumigatus and Pseudomonas aeruginosa. PTX3 activates the classical pathway of complement activation and facilitates pathogen recognition by macrophages and DCs. # Structure Human and murine PTX3, localized in the syntenic region of chromosome 3 (q24-28), are highly conserved, sharing 82% identical and 92% conserved amino acids. The human PTX3 gene is organized into three exons coding for the leader peptide (which is cleaved from the mature protein), the amino-terminal domain and the pentraxin domain of the protein. The transcribed PTX3 protein is 381 amino acids long, has a predicted molecular weight of 40,165 Da and consists of a carboxy-terminal 203 amino acid long pentraxin domain coupled with an amino-terminal 178 amino acid long domain unrelated to other known proteins. The PTX3 carboxy-terminal domain contains a canonical pentraxin signature (HxCxS/TWxS) and two conserved cysteines (Cys-210 and Cys-271), and shares 57% conserved and 17% identical amino acids with short pentraxins. The presence of an amino-linked glycosylation site in the carboxy-terminal domain at Asn-220 accounts for the higher molecular weight observed in SDS–PAGE under reducing conditions (45 kDa as opposed to the predicted 40 kDa). Under native conditions PTX3 protomers are assembled to form multimers. The crystal structure of PTX3 has not been determined yet, however according to modeling, the PTX3 pentraxin domain well-accommodates on the tertiary fold of SAP, with almost all of the β-strands and the α-helical segments conserved. # PTX3 in blood PTX3 behaves as an acute phase response protein, as the blood levels of PTX3, low in normal conditions (about 25 ng/mL in the mouse, < 2 ng/mL in humans), increase rapidly (peaking at 6–8 h after induction) and dramatically (200–800 ng/mL) during endotoxic shock, sepsis and other inflammatory and infectious conditions, correlating with the severity of the disease. Under these conditions, PTX3 is a rapid marker for primary local activation of innate immunity and inflammation. # Pathogen versus apoptotic self recognition Similar to other members of the pentraxin family PTX3 binds apoptotic cells, thereby inhibiting their recognition by DCs. Binding occurs late in the apoptotic process and enhances cytokine production by DCs. In addition, preincubation of apoptotic cells with PTX3 enhances C1q binding and C3 deposition on the cell surface, suggesting a role for PTX3 in the complement-mediated clearance of apoptotic cells. Moreover, in the presence of dying cells, PTX3 restricts the cross presentation of antigens derived from dying cells. These results suggest that PTX3 has a dual role: protection against pathogens and control of autoimmunity.

PTX3 Pentraxin-related protein PTX3 also known as TNF-inducible gene 14 protein (TSG-14) is a protein that in humans is encoded by the PTX3 gene.[1][2] Pentraxin 3 (ptx3) is a member of the pentraxin superfamily. This super family characterized by cyclic multimeric structure.[3] PTX3 is rapidly produced and released by several cell types, in particular by mononuclear phagocytes, dendritic cells (DCs), fibroblasts and endothelial cells in response to primary inflammatory signals [e.g., toll-like receptor (TLR) engagement, TNFα, IL-1β].[4] PTX3 binds with high affinity to the complement component C1q, the extracellular matrix component TNFα induced protein 6 (TNFAIP6; also called TNF-stimulated gene 6, TSG-6) and selected microorganisms, including Aspergillus fumigatus and Pseudomonas aeruginosa.[5][6][7][8][9] PTX3 activates the classical pathway of complement activation and facilitates pathogen recognition by macrophages and DCs.[4][5][7] # Structure Human and murine PTX3, localized in the syntenic region of chromosome 3 (q24-28), are highly conserved, sharing 82% identical and 92% conserved amino acids. The human PTX3 gene is organized into three exons coding for the leader peptide (which is cleaved from the mature protein), the amino-terminal domain and the pentraxin domain of the protein. The transcribed PTX3 protein is 381 amino acids long, has a predicted molecular weight of 40,165 Da and consists of a carboxy-terminal 203 amino acid long pentraxin domain coupled with an amino-terminal 178 amino acid long domain unrelated to other known proteins. The PTX3 carboxy-terminal domain contains a canonical pentraxin signature (HxCxS/TWxS) and two conserved cysteines (Cys-210 and Cys-271), and shares 57% conserved and 17% identical amino acids with short pentraxins. The presence of an amino-linked glycosylation site in the carboxy-terminal domain at Asn-220 accounts for the higher molecular weight observed in SDS–PAGE under reducing conditions (45 kDa as opposed to the predicted 40 kDa). Under native conditions PTX3 protomers are assembled to form multimers.[6] The crystal structure of PTX3 has not been determined yet, however according to modeling, the PTX3 pentraxin domain well-accommodates on the tertiary fold of SAP, with almost all of the β-strands and the α-helical segments conserved.[10] # PTX3 in blood PTX3 behaves as an acute phase response protein, as the blood levels of PTX3, low in normal conditions (about 25 ng/mL in the mouse, < 2 ng/mL in humans), increase rapidly (peaking at 6–8 h after induction) and dramatically (200–800 ng/mL) during endotoxic shock, sepsis and other inflammatory and infectious conditions, correlating with the severity of the disease. Under these conditions, PTX3 is a rapid marker for primary local activation of innate immunity and inflammation.[11][12][13][14][11][15] # Pathogen versus apoptotic self recognition Similar to other members of the pentraxin family PTX3 binds apoptotic cells, thereby inhibiting their recognition by DCs. Binding occurs late in the apoptotic process and enhances cytokine production by DCs. In addition, preincubation of apoptotic cells with PTX3 enhances C1q binding and C3 deposition on the cell surface, suggesting a role for PTX3 in the complement-mediated clearance of apoptotic cells.[16][17][18] Moreover, in the presence of dying cells, PTX3 restricts the cross presentation of antigens derived from dying cells. These results suggest that PTX3 has a dual role: protection against pathogens and control of autoimmunity.[18][19]

https://www.wikidoc.org/index.php/PTX3

167e729d2013ff70b5bec82bf7067a6fecd31e01

wikidoc

PURA

PURA Pur-alpha is a protein that in humans is encoded by the PURA gene located at chromosome 5, band q31. Pur-alpha an ancient, multi-functional DNA- and RNA-binding protein. PURA is expressed in every human tissue. Human Pur-alpha is a protein of 322 amino acids. According to convention, PURA, the gene, is written italicized in all upper case letters. Pur-alpha, the protein, is written with the first letter capitalized and can be found listed as Pur-alpha, Pur-α, Pura, Puralpha, Pur alpha and Pur1. # Evolutionary conservation and function Pur-alpha was the first sequence-specific single-stranded DNA-binding protein to be discovered in higher organisms (GenBank M96684.1; GI:190749). It binds to both single-stranded and double-stranded DNA, making contact with G residues in the purine-rich strand of its binding site. Cumulative data shows that Pur-alpha preferentially binds to the sequence (G2-4N1-3)n, where N is not G. N denotes a nucleotide, and n denotes the number of repeats of this small sequence. N may be repeated up to three times in this sequence. Following the identification of a Pur factor, which specifically bound a purine-rich sequence in the control region of the c-MYC gene, the gene, PURA, encoding the protein, Pur-alpha, was cloned and sequenced for both human and mouse (GenBank U02098.1). Pur-alpha belongs to the four-member Pur protein family, which also includes Pur-beta (GenBank AY039216.1; GI:14906267) and two forms of Pur–gamma (Variant A, GenBank AF195513.2; Variant B, GenBank AY077841). Pur protein sequences from bacteria through humans contain an amino acid segment that is strongly conserved (see NCBI smart00712). Human Pur-alpha contains three repeats of this Pur domain and bacterial Pur-alpha contains one. This evolutionary conservation means that the specific sequence of this domain is important for the survival of most species throughout the spectrum of living organisms. This essential nature of the Pur domain piques interest because the functions of Pur-alpha in lower organisms and in humans differ greatly. For example, Pur-alpha is essential for brain and blood cell development in mammals, but bacteria have no brain and no blood. In humans Pur-alpha functions to activate transcription in the nucleus, to facilitate RNA transport in the cytoplasm and to regulate DNA replication in the cell cycle. In certain functions Pur-alpha interacts with family member Pur-beta. Several cell cycle regulatory functions may be mediated by Pur-alpha binding to Cyclin/Cdk protein kinases, which phosphorylate proteins regulating cell cycle transition points. Requirements for Pur-alpha in all organisms are united by Pur-alpha’s ability to bind nucleic acids coupled to its ability to interact with regulatory and transport proteins. # Relevance in human diseases ## Genetic perturbation in leukemia and anti-proliferative effect PURA, located at chromosome 5 band q31, is frequently deleted in myelodysplastic syndrome (MDS), a disorder of white blood cells, that may progress to acute myelogenous leukemia (AML). Loss of one copy of chromosome 7 is also frequent in MDS. PURB, the gene encoding Pur-beta, is located at 7p13. A visual fluorescence analysis of chromosomes from MDS patients shows that deletions of PURA at 5q31 are more strongly linked to progression of MDS to AML when combined with deletions of the PURB gene, including complete loss of chromosome 7. All of the PURA deletions noted, involve only one of the two paired, parentally-derived chromosomes. The implication is that Pur-alpha and -beta are each codominantly expressed, and that haploid levels are insufficient for a protective effect against cancer. All known PURA deletions in people occur in only one of the two copies of chromosome 5. Inducing increased levels of Pur-alpha in several different cultured cancer cell lines blocks cell proliferation. It also blocks anchorage-independent colony formation, a hallmark of cancer. This is true whether Pur-alpha is microinjected or expressed after introducing a cloned PURA cDNA into cells. The Pur-alpha inhibition of cancer cell proliferation occurs at specific points in the cell division cycle, primarily at checkpoints for transition to DNA replication or mitosis. These cell cycle effects are consistent with an interaction between Pur-alpha and CDK, cell cycle-dependent protein kinases. They are also consistent with documented interaction between Pur-alpha and the tumor suppressor protein, Rb. ## Role in mammalian brain development and neurological diseases Studies of genetic inactivation of PURA in the mouse provided evidence leading to that for PURA gene disorders in brain disease. Homozygous PURA knockouts die shortly after birth with severe defects in brain layer development, tissue wasting and movement disorders. Defects in blood cell development are also prominent, and it is not known how these may affect the brain. Heterozygous knockouts do not die early but exhibit seizure-like disorders. In rat hippocampal neurons, Pur-alpha is found in the cytoplasm together with mRNA transcripts, in a complex including non-coding RNAs, Pur-beta, fragile X mental retardation proteins and microtubule-associated proteins. This complex is transported by a kinesin motor to sites of translation at junctions of nerve cell dendrites. Recently PURA mutations have been found in multiple patients with brain disorders of a similar phenotype including hypotonia, developmental delay, movement disorders, and seizure or seizure-like movements. This spectrum of brain disorders is similar to the phenotype of a central nervous system syndrome termed the 5q31.3 microdeletion syndrome, and is the basis for a proposed PURA Syndrome based on PURA mutations rather than just deletions. ## Influence on HIV-1 replication In the brain Pur-alpha plays a role in diseases involving glial cells, cells that support nerve cells, as well as diseases involving nerve cells. These diseases include neuro-AIDS. Pur-alpha binds to a regulatory RNA element, called TAR, in the HIV-1 genome. This activates the expression of Tat, a transcriptional activator of its own gene. Pur-alpha binds TAR, allowing Tat to bind an adjacent TAR site to stimulate transcription. Pur-alpha then binds to the Tat protein itself. Pur-alpha also binds Cyclin T1, a regulatory partner of Cdk9 protein kinase, necessary for Tat activity. Cyclin T1/Cdk9 phosphorylates a region of RNA polymerase II. Such phosphorylation of the polymerase enhances its ability to complete RNA synthesis and stimulates replication of the HIV-1 RNA genome. ## Cooperative effect with HIV-1 on JC polyomavirus replication and expression Pur-alpha participates in development of progressive multifocal leukoencephalopathy (PML), a loss of the nerve sheath formed by oligodendroglial cells. Although HIV-1 is not usually found in these glial cells, HIV-1 proteins can pass through cell membranes to enter them. JCV is considered the causative agent of PML. JCV is activated in the glial cells by certain states of immune system suppression, including HIV-1 infection. There is a documented interaction between Pur-alpha, the HIV-1 protein, Tat, and a Pur-alpha-binding regulatory sequence in JCV DNA. Pur-alpha acts by altering both replication and gene expression of JCV. ## Role in amyotrophic lateral sclerosis (ALS) Pur-alpha plays a role in ALS, otherwise known as Lou Gehrig’s disease. ALS is a motor neuron disease involving both the brain and spinal cord, resulting in progressive loss of muscle control. ALS has several contributing causes, but the most common familial form is due to an expanded repeat of the hexanucleotide GGGGCC at the chromosomal locus C9ORF72. The C9ORF72 hexanucleotide repeat expansion (HRE) is capable of binding Pur-alpha very tightly. Pur-alpha may act in ALS directly by binding this DNA repeat expansion or its single-stranded RNA transcript. One potential consequence of this binding would be to influence an unconventional translation of this transcript repeat that results in long dipeptide repeats. This is termed RAN (Repeat Associated Non-ATG) translation initiation. Aberrant Pur-alpha association with its RNA sequence segment may also be a feature of ALS types that do not involve C9ORF72 expansion. Addition of Pur-alpha suppresses neurodegeneration in mouse neuronal cells and in Drosophila expressing the C9ORF72 HRE. Pur-alpha also reverses neuronal changes caused by defects in the gene, FUS, which can lead to ALS. The mechanism of action of Pur-alpha in ALS is not known. There is presently no evidence that the PURA sequence itself is mutated in the C9ORF72 form of ALS. Rather, it is a regulatory nucleic acid sequence to which Pur-alpha binds that is altered. # Notes

PURA Pur-alpha is a protein that in humans is encoded by the PURA gene[1] located at chromosome 5, band q31.[2][3] Pur-alpha an ancient, multi-functional DNA- and RNA-binding protein.[1][4] PURA is expressed in every human tissue. Human Pur-alpha is a protein of 322 amino acids. According to convention, PURA, the gene, is written italicized in all upper case letters. Pur-alpha, the protein, is written with the first letter capitalized and can be found listed as Pur-alpha, Pur-α, Pura, Puralpha, Pur alpha and Pur1. # Evolutionary conservation and function Pur-alpha was the first sequence-specific single-stranded DNA-binding protein to be discovered in higher organisms (GenBank M96684.1; GI:190749).[1] It binds to both single-stranded and double-stranded DNA, making contact with G residues in the purine-rich strand of its binding site. Cumulative data shows that Pur-alpha preferentially binds to the sequence (G2-4N1-3)n, where N is not G. N denotes a nucleotide, and n denotes the number of repeats of this small sequence. N may be repeated up to three times in this sequence.[1][5] Following the identification of a Pur factor, which specifically bound a purine-rich sequence in the control region of the c-MYC gene,[6] the gene, PURA, encoding the protein, Pur-alpha, was cloned and sequenced for both human[1] and mouse (GenBank U02098.1).[4] Pur-alpha belongs to the four-member Pur protein family, which also includes Pur-beta (GenBank AY039216.1; GI:14906267)[1] and two forms of Pur–gamma (Variant A, GenBank AF195513.2; Variant B, GenBank AY077841).[7] Pur protein sequences from bacteria through humans contain an amino acid segment that is strongly conserved (see NCBI smart00712).[1][8] Human Pur-alpha contains three repeats of this Pur domain and bacterial Pur-alpha contains one.[1][9] This evolutionary conservation means that the specific sequence of this domain is important for the survival of most species throughout the spectrum of living organisms. This essential nature of the Pur domain piques interest because the functions of Pur-alpha in lower organisms and in humans differ greatly. For example, Pur-alpha is essential for brain and blood cell development in mammals,[10] but bacteria have no brain and no blood. In humans Pur-alpha functions to activate transcription in the nucleus, to facilitate RNA transport in the cytoplasm and to regulate DNA replication in the cell cycle.[8] In certain functions Pur-alpha interacts with family member Pur-beta.[11][12] Several cell cycle regulatory functions may be mediated by Pur-alpha binding to Cyclin/Cdk protein kinases, which phosphorylate proteins regulating cell cycle transition points.[13][14] Requirements for Pur-alpha in all organisms are united by Pur-alpha’s ability to bind nucleic acids coupled to its ability to interact with regulatory and transport proteins. # Relevance in human diseases ## Genetic perturbation in leukemia and anti-proliferative effect PURA, located at chromosome 5 band q31, is frequently deleted in myelodysplastic syndrome (MDS),[15] a disorder of white blood cells, that may progress to acute myelogenous leukemia (AML).[2] Loss of one copy of chromosome 7 is also frequent in MDS. PURB, the gene encoding Pur-beta, is located at 7p13. A visual fluorescence analysis of chromosomes from MDS patients shows that deletions of PURA at 5q31 are more strongly linked to progression of MDS to AML when combined with deletions of the PURB gene, including complete loss of chromosome 7.[2] All of the PURA deletions noted, involve only one of the two paired, parentally-derived chromosomes. The implication is that Pur-alpha and -beta are each codominantly expressed, and that haploid levels are insufficient for a protective effect against cancer. All known PURA deletions in people occur in only one of the two copies of chromosome 5.[16] Inducing increased levels of Pur-alpha in several different cultured cancer cell lines blocks cell proliferation. It also blocks anchorage-independent colony formation, a hallmark of cancer.[13][17] This is true whether Pur-alpha is microinjected or expressed after introducing a cloned PURA cDNA into cells.[18] The Pur-alpha inhibition of cancer cell proliferation occurs at specific points in the cell division cycle, primarily at checkpoints for transition to DNA replication or mitosis.[18] These cell cycle effects are consistent with an interaction between Pur-alpha and CDK, cell cycle-dependent protein kinases.[13] They are also consistent with documented interaction between Pur-alpha and the tumor suppressor protein, Rb.[19] ## Role in mammalian brain development and neurological diseases Studies of genetic inactivation of PURA in the mouse provided evidence leading to that for PURA gene disorders in brain disease. Homozygous PURA knockouts die shortly after birth with severe defects in brain layer development, tissue wasting and movement disorders. Defects in blood cell development are also prominent, and it is not known how these may affect the brain. Heterozygous knockouts do not die early but exhibit seizure-like disorders.[10] In rat hippocampal neurons, Pur-alpha is found in the cytoplasm together with mRNA transcripts, in a complex including non-coding RNAs, Pur-beta, fragile X mental retardation proteins and microtubule-associated proteins. This complex is transported by a kinesin motor[20][21] to sites of translation at junctions of nerve cell dendrites.[22] Recently PURA mutations have been found in multiple patients with brain disorders of a similar phenotype including hypotonia, developmental delay, movement disorders, and seizure or seizure-like movements.[23][24][25] This spectrum of brain disorders is similar to the phenotype of a central nervous system syndrome termed the 5q31.3 microdeletion syndrome,[23] and is the basis for a proposed PURA Syndrome[26] based on PURA mutations rather than just deletions. ## Influence on HIV-1 replication In the brain Pur-alpha plays a role in diseases involving glial cells, cells that support nerve cells, as well as diseases involving nerve cells. These diseases include neuro-AIDS. Pur-alpha binds to a regulatory RNA element, called TAR, in the HIV-1 genome.[27] This activates the expression of Tat, a transcriptional activator of its own gene. Pur-alpha binds TAR, allowing Tat to bind an adjacent TAR site to stimulate transcription. Pur-alpha then binds to the Tat protein itself. Pur-alpha also binds Cyclin T1, a regulatory partner of Cdk9 protein kinase, necessary for Tat activity. Cyclin T1/Cdk9 phosphorylates a region of RNA polymerase II. Such phosphorylation of the polymerase enhances its ability to complete RNA synthesis and stimulates replication of the HIV-1 RNA genome.[28][29] ## Cooperative effect with HIV-1 on JC polyomavirus replication and expression Pur-alpha participates in development of progressive multifocal leukoencephalopathy (PML), a loss of the nerve sheath formed by oligodendroglial cells.[30][31][28] Although HIV-1 is not usually found in these glial cells, HIV-1 proteins can pass through cell membranes to enter them. JCV is considered the causative agent of PML. JCV is activated in the glial cells by certain states of immune system suppression, including HIV-1 infection.[32] There is a documented interaction between Pur-alpha, the HIV-1 protein, Tat, and a Pur-alpha-binding regulatory sequence in JCV DNA.[31] Pur-alpha acts by altering both replication and gene expression of JCV.[30][33][34][31][35] ## Role in amyotrophic lateral sclerosis (ALS) Pur-alpha plays a role in ALS, otherwise known as Lou Gehrig’s disease. ALS is a motor neuron disease involving both the brain and spinal cord, resulting in progressive loss of muscle control. ALS has several contributing causes, but the most common familial form is due to an expanded repeat of the hexanucleotide GGGGCC at the chromosomal locus C9ORF72.[36][37] The C9ORF72 hexanucleotide repeat expansion (HRE) is capable of binding Pur-alpha very tightly. Pur-alpha may act in ALS directly by binding this DNA repeat expansion or its single-stranded RNA transcript.[38][37] One potential consequence of this binding would be to influence an unconventional translation of this transcript repeat that results in long dipeptide repeats. This is termed RAN (Repeat Associated Non-ATG) translation initiation.[39] Aberrant Pur-alpha association with its RNA sequence segment may also be a feature of ALS types that do not involve C9ORF72 expansion.[40] Addition of Pur-alpha suppresses neurodegeneration in mouse neuronal cells and in Drosophila expressing the C9ORF72 HRE.[37] Pur-alpha also reverses neuronal changes caused by defects in the gene, FUS, which can lead to ALS.[40][41] The mechanism of action of Pur-alpha in ALS is not known. There is presently no evidence that the PURA sequence itself is mutated in the C9ORF72 form of ALS. Rather, it is a regulatory nucleic acid sequence to which Pur-alpha binds that is altered. # Notes

https://www.wikidoc.org/index.php/PURA

01c19d1c708c5d27a9cf175569245d0499369874

wikidoc

PUVA

PUVA # Overview PUVA is a psoralen + UVA treatment for eczema, psoriasis, graft-versus-host disease, vitiligo, mycosis fungoides, large-plaque parapsoriasis and cutaneous T-cell lymphoma. The psoralen is applied or taken orally to sensitize the skin, then the skin is exposed to UVA. Photodynamic therapy is the general use of nontoxic light-sensitive compounds that are exposed selectively to light, whereupon they become toxic to targeted malignant and other diseased cells. Still, PUVA therapy is often classified as a separate technique from photodynamic therapy. # Procedure Psoralens are photosensitizing agents found in plants. Psoralens are taken systemically or can be applied directly to the skin. The psoralens allow a relatively lower dose of UVA to be used. When they are combined with exposure to UVA in PUVA, they are highly effective at clearing psoriasis and vitiligo. Like UVB light treatments, the reason remains unclear, though investigators speculate there may be similar effects on cell turnover and the skin's immune response. Choosing the proper dose for PUVA is similar to the procedure followed with UVB. The physician can choose a dose based on the patient's skin type. The dose will increase in every treatment until the skin starts to respond. Some clinics test the skin before the treatments, by exposing a small area of the patient's skin to UVA, after ingestion of psoralen. The dose of UVA that produces uniform redness 72 hours later, called the minimum phototoxic dose (MPD), becomes the starting dose for treatment. At the very least for vitiligo, narrowband ultraviolet B (UVB) phototherapy is now used more commonly than PUVA since it does not require the use of the Psoralen. As with PUVA, treatment is carried out twice weekly in a clinic or every day at home, and there is no need to use psoralen. Narrowband UVB does not cure the legs and hands, compared to the face and neck. To the hands and legs PUVA may be more effective. The reason can be because UVA penetrates deeper in the skin, and the melanocytes in the skin of the hands and legs is deeper in the skin. The Narrowband UVB does not reach the melanocytes. # Side effects and complications Some patients experience nausea and itching after ingesting the psoralen compound. For these patients PUVA bath therapy may be a good option. Long term use of PUVA therapy has been associated with higher rates of skin cancer. The most significant complication of PUVA therapy for psoriasis is squamous cell skin cancer. Two carcinogenic components of the therapy include the nonionizing radiation of UVA light as well as the psoralen intercalation with DNA. Both processes negatively impact overall genome instability. # History Psoralens have been known since ancient Egypt but have only been available in a chemically synthesized form since the 1970s.

PUVA Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview PUVA is a psoralen + UVA treatment for eczema, psoriasis, graft-versus-host disease, vitiligo, mycosis fungoides, large-plaque parapsoriasis and cutaneous T-cell lymphoma.[1] The psoralen is applied or taken orally to sensitize the skin, then the skin is exposed to UVA. Photodynamic therapy is the general use of nontoxic light-sensitive compounds that are exposed selectively to light, whereupon they become toxic to targeted malignant and other diseased cells. Still, PUVA therapy is often classified as a separate technique from photodynamic therapy. # Procedure Psoralens are photosensitizing agents found in plants. Psoralens are taken systemically or can be applied directly to the skin. The psoralens allow a relatively lower dose of UVA to be used. When they are combined with exposure to UVA in PUVA, they are highly effective at clearing psoriasis and vitiligo. Like UVB light treatments, the reason remains unclear, though investigators speculate there may be similar effects on cell turnover and the skin's immune response. Choosing the proper dose for PUVA is similar to the procedure followed with UVB. The physician can choose a dose based on the patient's skin type. The dose will increase in every treatment until the skin starts to respond. Some clinics test the skin before the treatments, by exposing a small area of the patient's skin to UVA, after ingestion of psoralen. The dose of UVA that produces uniform redness 72 hours later, called the minimum phototoxic dose (MPD), becomes the starting dose for treatment. At the very least for vitiligo, narrowband ultraviolet B (UVB) phototherapy is now used more commonly than PUVA since it does not require the use of the Psoralen. As with PUVA, treatment is carried out twice weekly in a clinic or every day at home, and there is no need to use psoralen.[2] Narrowband UVB does not cure the legs and hands, compared to the face and neck. To the hands and legs PUVA may be more effective. The reason can be because UVA penetrates deeper in the skin, and the melanocytes in the skin of the hands and legs is deeper in the skin. The Narrowband UVB does not reach the melanocytes. # Side effects and complications Some patients experience nausea and itching after ingesting the psoralen compound. For these patients PUVA bath therapy may be a good option. Long term use of PUVA therapy has been associated with higher rates of skin cancer.[3] The most significant complication of PUVA therapy for psoriasis is squamous cell skin cancer. Two carcinogenic components of the therapy include the nonionizing radiation of UVA light as well as the psoralen intercalation with DNA. Both processes negatively impact overall genome instability. # History Psoralens have been known since ancient Egypt but have only been available in a chemically synthesized form since the 1970s.

https://www.wikidoc.org/index.php/PUVA

9b1da5d45d0f3aadf3b12c8b515d1f5a99153e1d

wikidoc

PXDN

PXDN Peroxidasin homolog is a protein that in humans is encoded by the PXDN gene. Peroxidasin requires ionic bromine as a co-factor, making bromine an essential element for human life. # Clinical significance Mutations in PXDN are associated with microphthalmia .

PXDN Peroxidasin homolog is a protein that in humans is encoded by the PXDN gene.[1][2][3] Peroxidasin requires ionic bromine as a co-factor, making bromine an essential element for human life.[4] # Clinical significance Mutations in PXDN are associated with microphthalmia .[5]

https://www.wikidoc.org/index.php/PXDN

154451e254b3a7b5fdc29e8efe370abaad9f5b32

wikidoc

Vein

Vein # Overview In the circulatory system, a vein is a blood vessel that carries blood toward the heart. The majority of veins in the body carry low-oxygen blood from the tissues back to the heart; the exceptions being the pulmonary and umbilical veins which both carry oxygenated blood. # Anatomy Veins function to return deoxygenated blood to the heart, and are essentially tubes that collapse when their lumens are not filled with blood. The thick, outer-most layer of a vein is comprised of collagen, wrapped in bands of smooth muscle while the interior is lined with endothelial cells. Most veins have one-way flaps called venous valves that prevent blood from backflowing and pooling in the lower extremities due to the effects of gravity. The precise location of veins is much more variable from person to person than that of arteries. ## Venous tone The total capacity of the veins is more than sufficient to hold the entire blood volume of the body; this capacity is reduced through the venous tone of the smooth muscles, minimizing the cross-sectional area (and hence volume) of the individual veins and therefore total venous system. The helical bands of smooth muscles which wrap around veins help maintain blood flow to the right atrium. In cases of vasovagal syncope, the smooth muscles relax and the veins of the extremities below the heart fill up with blood, failing to return sufficient volume to maintain cardiac output and blood flow to the brain. # Function Veins serve to return blood from organs to the heart. In systemic circulation oxygenated blood is pumped by the left ventricle through the arteries to the muscles and organs of the body, where its nutrients and gases are exchanged at capillaries, entering the veins filled with cellular waste and carbon dioxide. The de-oxygenated blood is taken by veins to the right atrium of the heart, which transfers the blood to the right ventricle, where it is then pumped to the pulmonary arteries and eventually the lungs. In pulmonary circulation the pulmonary veins return oxygenated blood from the lungs to the left atrium, which empties into the left ventricle, completing the cycle of blood circulation. The return of blood to the heart is assisted by the action of the skeletal-muscle pump which helps maintain the extremely low blood pressure of the venous system. Fainting can be caused by failure of the skeletal-muscular pump. Long periods of standing can result in blood pooling in the legs, with blood pressure too low to return blood to the heart. Neurogenic and hypovolaemic shock can also cause fainting. In these cases the smooth muscles surrounding the veins become slack and the veins fill with blood, absorbing a large portion of the total blood volume, keeping blood away from the brain and causing unconsciousness. Often the generalization is made that arteries carry oxygenated blood to the tissues, the tissues consume the oxygen, and the remaining deoxygenated blood is carried back to the heart for reoxygenation. This is an oversimplification: all veins carry oxygenated blood, although the blood carried by the veins is usually considerably less oxygenated than the blood carried by most arteries. # Medical interest Veins are used medically as points of access to the blood stream, permitting the withdrawal of blood specimens (venipuncture) for testing purposes, and enabling the infusion of fluid, electrolytes, nutrition, and medications. The latter is called intravenous delivery. It can be done by an injection with a syringe, or by inserting a catheter (a flexible tube). In contrast to arterial blood which is uniform throughout the body, the blood removed from veins for testing can vary in its contents depending on the part of the body the vein drains. In example, blood drained from a working muscle will contain significantly less oxygen and glucose than blood drained from the liver. However the more blood from different veins mixes as it returns to the heart, the more homogeneous it becomes. If an intravenous catheter has to be inserted, for most purposes this is done into a peripheral vein (a vein near the surface of the skin in the hand or arm, or less desirably, the leg). Some highly concentrated fluids or irritating medications must flow into the large central veins, which are sometimes used when peripheral access cannot be obtained. Catheters can be threaded into the superior vena cava for these uses: if long term use is thought to be needed, a more permanent access point can be inserted surgically. # Common diseases The most common vein disorder is venous insufficiency, usually manifested by spider veins or varicose veins. A variety of treatments are used depending on the patient's particular type and pattern of veins and on the physician's preferences. Treatment can include radio-frequency ablation, vein stripping, ambulatory phlebectomy, foam sclerotherapy, sclerotherapy, lasers or compression. # Deep vein thrombosis Deep vein thrombosis is a condition where a blood clot forms in a deep vein, which can lead to pulmonary embolism and chronic venous insufficiency. # Phlebology Phlebology is the medical discipline that involves the diagnosis and treatment of disorders of venous origin. Diagnostic techniques used include the history and physical examination, venous imaging techniques and laboratory evaluation related to venous thromboembolism. The American Medical Association has added Phlebology to their list of Self-Designated Practice Specialties. # Notable veins and vein systems The pulmonary veins carry relatively oxygenated blood from the lungs to the heart. The superior and inferior venae cavae carry relatively deoxygenated blood from the upper and lower systemic circulations, respectively. A portal venous system is a series of veins or venules that directly connect two capillary beds. Examples of such systems include the hepatic portal vein and hypophyseal portal system. # Color The blood carried by veins is dark red due to its high percentage of CO2 as it returns to the heart (in contrast to the high levels of O2 in arterial blood, which is bright red). Veins appear blue because the subcutaneous fat in the skin absorbs lower-frequency light, permitting only the highly energetic blue wavelengths to penetrate through to the dark vein and reflect off. This physical effect can also be seen in the iris of blue eyes (pigmentless iris in the front, dark retina in the back) and is called Rayleigh scattering. # Types of veins Veins can be classified into: - portal vein vs. non-portal (most common) - superficial veins vs. deep veins - pulmonary veins vs. systemic veins List of important named veins - Jugular veins - Pulmonary veins - Portal vein - Superior vena cava - Inferior vena cava - Iliac vein - Femoral vein - Popliteal vein - Great saphenous vein - Small saphenous vein Names of important venule systems - Portal venous system - Systemic venous system

Vein Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview In the circulatory system, a vein is a blood vessel that carries blood toward the heart. The majority of veins in the body carry low-oxygen blood from the tissues back to the heart; the exceptions being the pulmonary and umbilical veins which both carry oxygenated blood. # Anatomy Veins function to return deoxygenated blood to the heart, and are essentially tubes that collapse when their lumens are not filled with blood. The thick, outer-most layer of a vein is comprised of collagen, wrapped in bands of smooth muscle while the interior is lined with endothelial cells. Most veins have one-way flaps called venous valves that prevent blood from backflowing and pooling in the lower extremities due to the effects of gravity. The precise location of veins is much more variable from person to person than that of arteries. ## Venous tone The total capacity of the veins is more than sufficient to hold the entire blood volume of the body; this capacity is reduced through the venous tone of the smooth muscles, minimizing the cross-sectional area (and hence volume) of the individual veins and therefore total venous system. The helical bands of smooth muscles which wrap around veins help maintain blood flow to the right atrium. In cases of vasovagal syncope, the smooth muscles relax and the veins of the extremities below the heart fill up with blood, failing to return sufficient volume to maintain cardiac output and blood flow to the brain. # Function Veins serve to return blood from organs to the heart. In systemic circulation oxygenated blood is pumped by the left ventricle through the arteries to the muscles and organs of the body, where its nutrients and gases are exchanged at capillaries, entering the veins filled with cellular waste and carbon dioxide. The de-oxygenated blood is taken by veins to the right atrium of the heart, which transfers the blood to the right ventricle, where it is then pumped to the pulmonary arteries and eventually the lungs. In pulmonary circulation the pulmonary veins return oxygenated blood from the lungs to the left atrium, which empties into the left ventricle, completing the cycle of blood circulation. The return of blood to the heart is assisted by the action of the skeletal-muscle pump which helps maintain the extremely low blood pressure of the venous system. Fainting can be caused by failure of the skeletal-muscular pump. Long periods of standing can result in blood pooling in the legs, with blood pressure too low to return blood to the heart. Neurogenic and hypovolaemic shock can also cause fainting. In these cases the smooth muscles surrounding the veins become slack and the veins fill with blood, absorbing a large portion of the total blood volume, keeping blood away from the brain and causing unconsciousness. Often the generalization is made that arteries carry oxygenated blood to the tissues, the tissues consume the oxygen, and the remaining deoxygenated blood is carried back to the heart for reoxygenation. This is an oversimplification: all veins carry oxygenated blood,[1] although the blood carried by the veins is usually considerably less oxygenated than the blood carried by most arteries. # Medical interest Veins are used medically as points of access to the blood stream, permitting the withdrawal of blood specimens (venipuncture) for testing purposes, and enabling the infusion of fluid, electrolytes, nutrition, and medications. The latter is called intravenous delivery. It can be done by an injection with a syringe, or by inserting a catheter (a flexible tube). In contrast to arterial blood which is uniform throughout the body, the blood removed from veins for testing can vary in its contents depending on the part of the body the vein drains. In example, blood drained from a working muscle will contain significantly less oxygen and glucose than blood drained from the liver. However the more blood from different veins mixes as it returns to the heart, the more homogeneous it becomes. If an intravenous catheter has to be inserted, for most purposes this is done into a peripheral vein (a vein near the surface of the skin in the hand or arm, or less desirably, the leg). Some highly concentrated fluids or irritating medications must flow into the large central veins, which are sometimes used when peripheral access cannot be obtained. Catheters can be threaded into the superior vena cava for these uses: if long term use is thought to be needed, a more permanent access point can be inserted surgically. # Common diseases The most common vein disorder is venous insufficiency, usually manifested by spider veins or varicose veins. A variety of treatments are used depending on the patient's particular type and pattern of veins and on the physician's preferences. Treatment can include radio-frequency ablation, vein stripping, ambulatory phlebectomy, foam sclerotherapy, sclerotherapy, lasers or compression. # Deep vein thrombosis Deep vein thrombosis is a condition where a blood clot forms in a deep vein, which can lead to pulmonary embolism and chronic venous insufficiency. # Phlebology Phlebology is the medical discipline that involves the diagnosis and treatment of disorders of venous origin. Diagnostic techniques used include the history and physical examination, venous imaging techniques and laboratory evaluation related to venous thromboembolism. The American Medical Association has added Phlebology to their list of Self-Designated Practice Specialties. # Notable veins and vein systems The pulmonary veins carry relatively oxygenated blood from the lungs to the heart. The superior and inferior venae cavae carry relatively deoxygenated blood from the upper and lower systemic circulations, respectively. A portal venous system is a series of veins or venules that directly connect two capillary beds. Examples of such systems include the hepatic portal vein and hypophyseal portal system. # Color The blood carried by veins is dark red due to its high percentage of CO2 as it returns to the heart (in contrast to the high levels of O2 in arterial blood, which is bright red). Veins appear blue because the subcutaneous fat in the skin absorbs lower-frequency light, permitting only the highly energetic blue wavelengths to penetrate through to the dark vein and reflect off. This physical effect can also be seen in the iris of blue eyes (pigmentless iris in the front, dark retina in the back) and is called Rayleigh scattering. # Types of veins Veins can be classified into: - portal vein vs. non-portal (most common) - superficial veins vs. deep veins - pulmonary veins vs. systemic veins List of important named veins - Jugular veins - Pulmonary veins - Portal vein - Superior vena cava - Inferior vena cava - Iliac vein - Femoral vein - Popliteal vein - Great saphenous vein - Small saphenous vein Names of important venule systems - Portal venous system - Systemic venous system

https://www.wikidoc.org/index.php/Phlebology

e85b112ed0ba49bec6959205d2f0463dfe6f7b53

wikidoc

Pica

Pica Synonyms and keywords: Pica syndrome, geophagia eating disorder, geophagy # Overview # Historical Perspective - Pica is derived from the Latin word 'pica pica' which means magpie, a bird known for its behavior of gathering and eating almost everything. - It was first documented in the 13th century in Latin work of Bartholomeus de Glanville, although the actual term was not used. - The first time term ‘Pica’ was mentioned in a medical context was in 1563 in a surgical work, ‘An Excellent Treatise of Wounds made with Gonne Shot’, by Thomas Gale, where pica was addressed in pregnant women and children. - Historically, clay ingestion had been used for medical purposes probably due to its effect on gastrointestinal (GI) system. It was particularly suggested as a treatment of intestinal infection and spasm. # Classification Pica may be classified according to the name of the eaten substance; the most common types by far are geophagia and amylophagia: - Acuphagia (sharp objects) - Amylophagia (purified starch) - Cautopyreiophagia (burnt matches) - Coniophagia (dust, dirt) - Coprophagia (feces) - Emetophagia (vomit) - Geomelophagia (raw potatoes) - Geophagia (earth, soil, clay, chalk) - Hyalophagia (glass) - Lithophagia (stones) - Metallophagia (metal) - Mucophagia (mucus) - Pagophagia (ice) - Plumbophagia (lead, paint chips) - Trichophagia (hair, wool, fibers) - Urophagia (urine) - Hematophagia (blood) - Xylophagia (wood, paper) - Hyalophagia (glass) - Ryzophagia (raw rice) - Sapophagia (soap) # Pathophysiology The exact pathogenesis of Pica is not fully understood. However, there are different theories on developing Pica: ## Nutritional Theory - Children with anemia and low plasma zinc levels may develop Pica and crave for substances rich in the insufficient nutrients. - Kaolinite, a clay mineral, which has negative surface charge commonly ingested in Pica and can absorb the ions with positive surface charge, such as iron and causes iron-deficiency anemia. - There is not enough evidence to determine whether Pica is the cause of nutritional deficiency or nutritional deficiency leads to Pica development. ## Gastrointestinal Distress Geophagia causes increase in gastrointestinal PH. This effect can soothe gastric pain and gastroesophageal reflux disease. It also results in reduction of bioavailability of pathogens and toxins in gastrointestinal tract, a phenomenon on which a hypothesis is based. The hypothesis states that non-nutritive substances bind to toxins and lead to less toxins absorption. This event occurs in the most vulnerable period of cell replication and growth (childhood and pregnancy) in order to protect the body from dangerous toxins. ## Neurological Theory - Various human studies revealed that lesions in eating center of hypothalamus and anterior cingulate gyrus may lead hyperphagia and Pica especially in individuals with history of brain damage. - Animal studies indicated that rats with iron deficiency anemia have fewer D2 receptors in the central nervous system (CNS). This proposes a theory stating that reduction of dopaminergic neurotransmission leads to development of Pica, and not the iron deficiency anemia. ## Psychiatric Theory A hypothesis states that Pica can be attributed to obsessive-compulsive spectrum disorders because Pica-related behaviors are mostly involuntary, recurrent, and persistent to soothe the anxiety and distress, and resistance to stop the behaviors causes increased level of anxiety and distress. This hypothesis is supported by studies that have found that Pica has the same treatment as OCD, i.e selective serotonin reuptake inhibitors. # Causes The cause of Pica has not been identified. To review risk factors for the development of Pica, click here. # Differentiating ((Page name)) from other Diseases Pica must be differentiated from other psychiatric diseases including autism, schizophrenia, other eating disorders, developmental delay in children, substance abuse. # Epidemiology and Demographics - The prevalence and incidence of Pica is challenging to estimate due to several reasons such as: under-reporting the cases, cultural and social issues, different definition of Pica in studies. - Pica is more common in pregnant women and young children. - The incidence of Pica decreases with age. Studies show 20-30% of children who are between 1-6 years old have developed Pica. - Boys are slightly more affected by Pica than girls. - The majority of Pica cases are reported in Africa. # Risk Factors Common risk factors in the development of Pica include: - Nutritional deficiency - Pregnancy - Stress - Child abuse, child neglect, family problem, parental separation, low socioeconomic status - Cultural factors - Mental disorders - Learning and developmental disability such as autistic spectrum disorder, attention-deficit hyperactivity disorder - Epilepsy # Screening There is insufficient evidence to recommend routine screening for Pica. # Natural History, Complications, and Prognosis If left untreated, patients with Pica may progress to develop: - Iron deficiency anemia especially during pregnancy. This complication may occur due to binding of clay particle to iron or acting as an ion exchanger resin. - Lead poisoning - Parasite infection (e.g. ,toxocariasis, toxoplasmosis, ascariasis, giardiasis, cysticercosis) - Electrolyte abnormalities such as zinc deficiency, hypokalemia, hyperkalemia, hyperphosphatemia and metabolic alkalosis. - Constipation and intestinal obstruction, bleeding and perforation. - Social stigmatization especially in children. - Tooth decay and sensitivity. - High blood sugar and obesity due to amylophagia. - Maternal Pica may lead to neurological disability and delayed motor function in newborns. # Diagnosis ## Diagnostic Study of Choice The diagnosis of Pica is based on the criteria from Diagnosis and Statistical Manual of Mental Disorders (DSM-5), which include: 1.Person must have been eating non-nutritive nonfoods for at least one month. 2.This eating must be considered abnormal for the person's stage of development. 3.Eating these substances cannot be associated with a cultural practice that is considered normal in the social context of the individual. 4.For people who currently have a medical condition (e.g.: pregnancy) or a mental disorder (e.g.: autism spectrum disorder), the action of eating non-nutritive nonfoods should only be considered pica if it is dangerous and requires extra medical investigation or treatment on top of what they are already receiving for their pre-existing condition. ## History and Symptoms Symptoms of Pica are variable and depend on the material which is ingested. Physicians should seek the details of the exposure, including: - the substance type, - the amount of substance, - duration of exposure, - situations where behavior usually happens, - any co-ingestions, and - symptoms of toxicity ## Physical Examination Patients with Pica usually appear normal. However, sings of poisoning and complications of the ingested substance should be sought: - Ingestion of some substances may lead to bezoar formation and consequently, intestinal obstruction, ulceration, and perforation, - Lead poisoning symptoms include: lethargy, headache, seizure, encephalopathy, cranial nerve palsy, papilledema, cognitive impairment, peripheral neuropathy, abdominal pain and constipation, lead-line at the junction of gums and teeth, and developmental delay in children. - lethargy, - headache, - seizure, - encephalopathy, - cranial nerve palsy, - papilledema, - cognitive impairment, - peripheral neuropathy, - abdominal pain and constipation, - lead-line at the junction of gums and teeth, and - developmental delay in children. - Signs of parasitic infections (Toxocara and Ascaris) due to clay ingestion include: fever, cough, myocarditis, encephalitis, hepatomegaly, and visual disturbance. - fever, - cough, - myocarditis, - encephalitis, - hepatomegaly, and - visual disturbance. - Malnourishment, especially in children - Signs of iron deficiency anemia: pallor, easy fatigability, poor appetite, tachycardia and a soft ejection systolic flow murmur in severe cases. - pallor, - easy fatigability, - poor appetite, - tachycardia and a soft ejection systolic flow murmur in severe cases. - Dental complications such as severe abrasion and tooth damages. ## Laboratory Findings Laboratory findings consistent with the diagnosis of Pica include: - CBC (anemia) - Electrolyte and nutrient evaluation (zinc deficiency, hyperkalemia) - Liver function test - Stool exam for parasite infections - Blood lead concentration ## Electrocardiogram There are no ECG findings associated with Pica. ## X-ray There are no x-ray findings associated with Pica. However, an x-ray may be helpful in the diagnosis of complications of Pica, which include lead lines at the metaphysis of long bones and foreign bodies in chest or abdominal x-ray. ## Echocardiography or Ultrasound There are no echocardiography/ultrasound findings associated with Pica. However, an ultrasound may be helpful to reveal the location, size and the nature of the substance. ## CT scan There are no CT scan findings associated with Pica. ## MRI There are no MRI findings associated with Pica. ## Other Imaging Findings There are no other imaging findings associated with Pica. ## Other Diagnostic Studies There are no other diagnostic studies associated with Pica. # Treatment ## Medical Therapy The majority of cases of Pica are self-limited and require only supportive care. Supportive therapy for Pica includes: - nutrient supplements such as iron and zinc in case of deficiency. - Behavioral therapy, psychotherapy and family counseling particularly in children. ## Surgery Surgical intervention is not recommended for the management of Pica Unless it causes severe obstruction or perforation. ## Primary Prevention Effective measures for the primary prevention of Pica include: - Identifying high- risk populations such as pregnant women and children who live in old house with lead paint, - Nutrition education in at-risk populations about the danger and consequences of Pica, - Educating parents to supervise their children and make their home and environment safe. ## Secondary Prevention There are no established measures for the secondary prevention of pica.

Pica ## For patient information, click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maryam Hadipour, M.D.[2] Synonyms and keywords: Pica syndrome, geophagia eating disorder, geophagy # Overview # Historical Perspective - Pica is derived from the Latin word 'pica pica' which means magpie, a bird known for its behavior of gathering and eating almost everything. - It was first documented in the 13th century in Latin work of Bartholomeus de Glanville, although the actual term was not used.[1] - The first time term ‘Pica’ was mentioned in a medical context was in 1563 in a surgical work, ‘An Excellent Treatise of Wounds made with Gonne Shot’, by Thomas Gale, where pica was addressed in pregnant women and children.[1] - Historically, clay ingestion had been used for medical purposes probably due to its effect on gastrointestinal (GI) system. It was particularly suggested as a treatment of intestinal infection and spasm.[2] # Classification Pica may be classified according to the name of the eaten substance; the most common types by far are geophagia and amylophagia: - Acuphagia (sharp objects) - Amylophagia (purified starch) - Cautopyreiophagia (burnt matches) - Coniophagia (dust, dirt) - Coprophagia (feces) - Emetophagia (vomit) - Geomelophagia (raw potatoes) - Geophagia (earth, soil, clay, chalk) - Hyalophagia (glass) - Lithophagia (stones) - Metallophagia (metal) - Mucophagia (mucus) - Pagophagia (ice) - Plumbophagia (lead, paint chips) - Trichophagia (hair, wool, fibers) - Urophagia (urine) - Hematophagia (blood) - Xylophagia (wood, paper) - Hyalophagia (glass) - Ryzophagia (raw rice) - Sapophagia (soap) # Pathophysiology The exact pathogenesis of Pica is not fully understood. However, there are different theories on developing Pica: ## Nutritional Theory - Children with anemia and low plasma zinc levels may develop Pica and crave for substances rich in the insufficient nutrients.[3] - Kaolinite, a clay mineral, which has negative surface charge commonly ingested in Pica and can absorb the ions with positive surface charge, such as iron and causes iron-deficiency anemia.[4] [5] - There is not enough evidence to determine whether Pica is the cause of nutritional deficiency or nutritional deficiency leads to Pica development.[4] [6] ## Gastrointestinal Distress Geophagia causes increase in gastrointestinal PH. This effect can soothe gastric pain and gastroesophageal reflux disease.[7] It also results in reduction of bioavailability of pathogens and toxins in gastrointestinal tract[8], a phenomenon on which a hypothesis is based. The hypothesis states that non-nutritive substances bind to toxins and lead to less toxins absorption. This event occurs in the most vulnerable period of cell replication and growth (childhood and pregnancy) in order to protect the body from dangerous toxins.[9][10][11] ## Neurological Theory - Various human studies revealed that lesions in eating center of hypothalamus and anterior cingulate gyrus may lead hyperphagia and Pica especially in individuals with history of brain damage.[6][12] - Animal studies indicated that rats with iron deficiency anemia have fewer D2 receptors in the central nervous system (CNS). This proposes a theory stating that reduction of dopaminergic neurotransmission leads to development of Pica, and not the iron deficiency anemia.[13] ## Psychiatric Theory A hypothesis states that Pica can be attributed to obsessive-compulsive spectrum disorders because Pica-related behaviors are mostly involuntary, recurrent, and persistent to soothe the anxiety and distress, and resistance to stop the behaviors causes increased level of anxiety and distress.[14][15] This hypothesis is supported by studies that have found that Pica has the same treatment as OCD, i.e selective serotonin reuptake inhibitors.[16] # Causes The cause of Pica has not been identified. To review risk factors for the development of Pica, click here. # Differentiating ((Page name)) from other Diseases Pica must be differentiated from other psychiatric diseases including autism, schizophrenia, other eating disorders, developmental delay in children, substance abuse.[17][18] # Epidemiology and Demographics - The prevalence and incidence of Pica is challenging to estimate due to several reasons such as: under-reporting the cases, cultural and social issues, different definition of Pica in studies.[19] - Pica is more common in pregnant women and young children.[20] - The incidence of Pica decreases with age. Studies show 20-30% of children who are between 1-6 years old have developed Pica.[21][22] - Boys are slightly more affected by Pica than girls.[23] - The majority of Pica cases are reported in Africa.[24] # Risk Factors Common risk factors in the development of Pica include:[25][26][27][28][29] - Nutritional deficiency - Pregnancy - Stress - Child abuse, child neglect, family problem, parental separation, low socioeconomic status - Cultural factors - Mental disorders - Learning and developmental disability such as autistic spectrum disorder, attention-deficit hyperactivity disorder - Epilepsy # Screening There is insufficient evidence to recommend routine screening for Pica. # Natural History, Complications, and Prognosis If left untreated, patients with Pica may progress to develop: - Iron deficiency anemia especially during pregnancy.[17] This complication may occur due to binding of clay particle to iron or acting as an ion exchanger resin.[6] - Lead poisoning [29] - Parasite infection (e.g. ,toxocariasis, toxoplasmosis, ascariasis, giardiasis, cysticercosis)[22][30] - Electrolyte abnormalities such as zinc deficiency, hypokalemia, hyperkalemia, hyperphosphatemia and metabolic alkalosis.[31][2] - Constipation and intestinal obstruction, bleeding and perforation.[32][25] - Social stigmatization especially in children.[33] - Tooth decay and sensitivity.[34] - High blood sugar and obesity due to amylophagia.[35] - Maternal Pica may lead to neurological disability and delayed motor function in newborns.[36][37] # Diagnosis ## Diagnostic Study of Choice The diagnosis of Pica is based on the criteria from Diagnosis and Statistical Manual of Mental Disorders (DSM-5),[38] which include: 1.Person must have been eating non-nutritive nonfoods for at least one month. 2.This eating must be considered abnormal for the person's stage of development. 3.Eating these substances cannot be associated with a cultural practice that is considered normal in the social context of the individual. 4.For people who currently have a medical condition (e.g.: pregnancy) or a mental disorder (e.g.: autism spectrum disorder), the action of eating non-nutritive nonfoods should only be considered pica if it is dangerous and requires extra medical investigation or treatment on top of what they are already receiving for their pre-existing condition. ## History and Symptoms Symptoms of Pica are variable and depend on the material which is ingested. Physicians should seek the details of the exposure, including[33]: - the substance type, - the amount of substance, - duration of exposure, - situations where behavior usually happens, - any co-ingestions, and - symptoms of toxicity ## Physical Examination Patients with Pica usually appear normal[39]. However, sings of poisoning and complications of the ingested substance should be sought:[33][40][41] - Ingestion of some substances may lead to bezoar formation and consequently, intestinal obstruction, ulceration, and perforation, - Lead poisoning symptoms include:[42] lethargy, headache, seizure, encephalopathy, cranial nerve palsy, papilledema, cognitive impairment, peripheral neuropathy, abdominal pain and constipation, lead-line at the junction of gums and teeth, and developmental delay in children. - lethargy, - headache, - seizure, - encephalopathy, - cranial nerve palsy, - papilledema, - cognitive impairment, - peripheral neuropathy, - abdominal pain and constipation, - lead-line at the junction of gums and teeth, and - developmental delay in children. - Signs of parasitic infections (Toxocara and Ascaris) due to clay ingestion include: fever, cough, myocarditis, encephalitis, hepatomegaly, and visual disturbance. - fever, - cough, - myocarditis, - encephalitis, - hepatomegaly, and - visual disturbance. - Malnourishment, especially in children[43][44] - Signs of iron deficiency anemia: pallor, easy fatigability, poor appetite, tachycardia and a soft ejection systolic flow murmur in severe cases. - pallor, - easy fatigability, - poor appetite, - tachycardia and a soft ejection systolic flow murmur in severe cases. - Dental complications such as severe abrasion and tooth damages.[45] ## Laboratory Findings Laboratory findings consistent with the diagnosis of Pica include:[46][1][47] - CBC (anemia) - Electrolyte and nutrient evaluation (zinc deficiency, hyperkalemia) - Liver function test - Stool exam for parasite infections - Blood lead concentration ## Electrocardiogram There are no ECG findings associated with Pica. ## X-ray There are no x-ray findings associated with Pica. However, an x-ray may be helpful in the diagnosis of complications of Pica, which include lead lines at the metaphysis of long bones[6] and foreign bodies in chest or abdominal x-ray.[48] ## Echocardiography or Ultrasound There are no echocardiography/ultrasound findings associated with Pica. However, an ultrasound may be helpful to reveal the location, size and the nature of the substance.[6] ## CT scan There are no CT scan findings associated with Pica. ## MRI There are no MRI findings associated with Pica. ## Other Imaging Findings There are no other imaging findings associated with Pica. ## Other Diagnostic Studies There are no other diagnostic studies associated with Pica. # Treatment ## Medical Therapy The majority of cases of Pica are self-limited and require only supportive care.[29] Supportive therapy for Pica includes: - nutrient supplements such as iron and zinc in case of deficiency.[49][50][51] - Behavioral therapy, psychotherapy and family counseling particularly in children.[52][26] ## Surgery Surgical intervention is not recommended for the management of Pica Unless it causes severe obstruction or perforation. ## Primary Prevention Effective measures for the primary prevention of Pica include: - Identifying high- risk populations such as pregnant women and children who live in old house with lead paint,[53][54][55] - Nutrition education in at-risk populations about the danger and consequences of Pica,[56][57] - Educating parents to supervise their children and make their home and environment safe.[2] ## Secondary Prevention There are no established measures for the secondary prevention of pica.

https://www.wikidoc.org/index.php/Pica

1a402ae292522db77d1e4bf91cc8235267cafbec

wikidoc

Piwi

Piwi The piwi (sometimes also PIWI; originally P-element induced wimpy testis in Drosophila) class of genes was originally identified as encoding regulatory proteins responsible for maintaining incomplete differentiation in stem cells and maintaining the stability of cell division rates in germ line cells. Piwi proteins are highly conserved across evolutionary lineages and are present in both plants and animals. One of the major human homologs, whose upregulation is implicated in the formation of tumors such as seminomas, is called hiwi; other variants on the theme include the miwi protein in mice. # Role in RNA interference The piwi domain is a protein domain homologous to piwi proteins and present in a large number of nucleic acid-binding proteins, especially those that bind and cleave RNA. The best-studied such family of proteins is the argonaute family; argonautes are RNase H-like enzymes that carry out the catalytic functions of the RNA-induced silencing complex (RISC). In the well-known cellular process of RNA interference, the argonaute protein in the RISC complex binds small interfering RNA (siRNA) generated from exogenous double-stranded RNA or microRNA (miRNA) generated from endogenous non-coding RNA, both the ribonuclease dicer. The RNA-RISC complex binds and cleaves complementary base pairing messenger RNA, destroying it and preventing its translation into a protein. Crystallized piwi domains have a conserved basic binding site for the 5' end of bound RNA; in the case of argonaute proteins binding siRNA strands, the last unpaired nucleotide base of the siRNA is also stabilized by base stacking interactions between the base and neighboring tyrosine residues. Recent evidence suggests that the germ-line determination function of piwi proteins relies on their interaction with miRNAs, which are known to play a key role in early development and morphogenesis of Drosophila melanogaster embryos, in which germ-line maintenance has been extensively studied. # piRNAs and transposon silencing Recently, a novel class of longer-than-average miRNAs known as Piwi-interacting RNAs (piRNAs) has been defined in mammalian cells, about 26-31 nucleotides long as compared to the more typical miRNA or siRNA of about 21 nucleotides. These piRNAs are expressed specifically in spermatogenic cells in the testes of mammals. piRNAs have been identified in the genomes of mice, rats, and humans, with an unusual "clustered" genomic organization that may originate from repetitive regions of the genome such as retrotransposons or regions normally organized into heterochromatin, and which are normally derived exclusively from the antisense strand of double-stranded RNA. piRNAs have thus been classified as repeat-associated small interfering RNAs (rasiRNAs). Although their biogenesis is not yet well understood, piRNAs and Piwi proteins are thought to form an endogenous system for silencing the expression of selfish genetic elements such as retrotransposons and thus preventing the gene products of such sequences from interfering with germ cell formation.

Piwi The piwi (sometimes also PIWI; originally P-element induced wimpy testis in Drosophila[1]) class of genes was originally identified as encoding regulatory proteins responsible for maintaining incomplete differentiation in stem cells and maintaining the stability of cell division rates in germ line cells.[2] Piwi proteins are highly conserved across evolutionary lineages and are present in both plants and animals.[3] One of the major human homologs, whose upregulation is implicated in the formation of tumors such as seminomas, is called hiwi;[4] other variants on the theme include the miwi protein in mice.[5] # Role in RNA interference The piwi domain is a protein domain homologous to piwi proteins and present in a large number of nucleic acid-binding proteins, especially those that bind and cleave RNA. The best-studied such family of proteins is the argonaute family; argonautes are RNase H-like enzymes that carry out the catalytic functions of the RNA-induced silencing complex (RISC). In the well-known cellular process of RNA interference, the argonaute protein in the RISC complex binds small interfering RNA (siRNA) generated from exogenous double-stranded RNA or microRNA (miRNA) generated from endogenous non-coding RNA, both the ribonuclease dicer. The RNA-RISC complex binds and cleaves complementary base pairing messenger RNA, destroying it and preventing its translation into a protein. Crystallized piwi domains have a conserved basic binding site for the 5' end of bound RNA; in the case of argonaute proteins binding siRNA strands, the last unpaired nucleotide base of the siRNA is also stabilized by base stacking interactions between the base and neighboring tyrosine residues.[6] Recent evidence suggests that the germ-line determination function of piwi proteins relies on their interaction with miRNAs, which are known to play a key role in early development and morphogenesis of Drosophila melanogaster embryos, in which germ-line maintenance has been extensively studied.[7] # piRNAs and transposon silencing Recently, a novel class of longer-than-average miRNAs known as Piwi-interacting RNAs (piRNAs) has been defined in mammalian cells, about 26-31 nucleotides long as compared to the more typical miRNA or siRNA of about 21 nucleotides. These piRNAs are expressed specifically in spermatogenic cells in the testes of mammals.[8] piRNAs have been identified in the genomes of mice, rats, and humans, with an unusual "clustered" genomic organization[9] that may originate from repetitive regions of the genome such as retrotransposons or regions normally organized into heterochromatin, and which are normally derived exclusively from the antisense strand of double-stranded RNA.[10] piRNAs have thus been classified as repeat-associated small interfering RNAs (rasiRNAs).[1] Although their biogenesis is not yet well understood, piRNAs and Piwi proteins are thought to form an endogenous system for silencing the expression of selfish genetic elements such as retrotransposons and thus preventing the gene products of such sequences from interfering with germ cell formation.[10]

https://www.wikidoc.org/index.php/Piwi

41ef264f51df44ef25d8e9954055b2541afc1e2c

wikidoc

Pump

Pump Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. # Overview A pump is a device used to move gases, liquids or slurries. A pump moves liquids or gases from lower pressure to higher pressure, and overcomes this difference in pressure by adding energy to the system (such as a water system). A gas pump is generally called a compressor, except in very low pressure-rise applications, such as in heating, ventilating, and air-conditioning, where the operative equipment consists of fans or blowers. Pumps work by using mechanical forces to push the material, either by physically lifting, or by the force of compression. The earliest type of pump was the Archimedes screw, first used by Sennacherib, King of Assyria, for the water systems at the Hanging Gardens of Babylon and Nineveh in the 7th century BC, and later described in more detail by Archimedes in the 3rd century BC. In the 13th century AD, al-Jazari described and illustrated different types of pumps, including a reciprocating pump, double-action pump with suction pipes, water pump, and piston pump. # Types Pumps fall into two major groups: rotodynamic pumps and positive displacement pumps. Their names describe the method for moving a fluid. ## Positive displacement pumps A positive displacement pump causes a liquid or gas to move by trapping a fixed amount of fluid and then forcing (displacing) that trapped volume into the discharge pipe. The periodic fluid displacement results in a direct increase in pressure. A positive displacement pump can be further classified as either - a rotary-type (for example the rotary vane), - lobe pump similar to oil pumps used in car engines, or - the Wendelkolben pump or the helical twisted Roots pump. ### Roots-type pumps The low pulsation rate and gentle performance of this Roots-type positive displacement pump is achieved due to a combination of its two 90° helical twisted rotors, and a triangular shaped sealing line configuration, both at the point of suction and at the point of discharge. This design produces a continuous and non-vorticuless flow with equal volume. High capacity industrial "air compressors" have been designed to employ this principle as well as most "superchargers" used on internal combustion engines. ### Reciprocating-type pumps Reciprocating-type pumps use a piston and cylinder arrangement with suction and discharge valves integrated into the pump. Pumps in this category range from having "simplex" one cylinder, to in some cases "quad" four cylinders or more. Most reciprocating-type pumps are "duplex" (two) or "triplex" (three) cylinder. Furthermore, they are either "single acting" independent suction and discharge strokes or "double acting" suction and discharge in both directions. The pumps can be powered by air, steam or through a belt drive from an engine or motor. This type of pump was used extensively in the early days of steam propulsion (19th century) as boiler feed water pumps. Though still used today, reciprocating pumps are typically used for pumping highly viscous fluids including concrete and heavy oils. ### Compressed-air-powered double-diaphragm pumps Another modern application of positive displacement pumps are compressed-air-powered double-diaphragm pumps, commonly called SandPiper or Wilden Pumps after their major manufacturers. They are relatively inexpensive and are used extensively for pumping water out of bunds, or pumping low volumes of reactants out of storage drums. ## Kinetic Pumps - Continuous energy addition - Conversion of added energy to increase in kinetic energy (increase in velocity) - Conversion of increased velocity to increase in pressure - Conversion of Kinetic head to Pressure Head. - Meet all heads like Kinetic , Potential, and Pressure # Application Pumps are used throughout society for a variety of purposes. Early applications includes the use of the windmill or watermill to pump water. Today, the pump is used for irrigation, water supply, gasoline supply, air conditioning systems, refrigeration (usually called a compressor), chemical movement, sewage movement, flood control, marine services, etc. Because of the wide variety of applications, pumps have a plethora of shapes and sizes: from very large to very small, from handling gas to handling liquid, from high pressure to low pressure, and from high volume to low volume. # Pumps as public water supplies One sort of pump once common worldwide was a hand-powered water pump over a water well where people could work it to extract water, before most houses had individual water supplies. From this came the expression "parish pump" for "the sort of matter chattered about by people when they meet when they go to get water", "matter of only local interest". Today, hand operated village pumps are considered the most sustainable low cost option for safe water supply in resource poor settings, often in rural areas in developing countries. A hand pump opens access to deeper groundwater that is often not polluted and also improves the safety of a well by protecting the water source from contaminated buckets. Pumps like the Afridev pump (pictured) are designed to be cheap to build and install, and easy to maintain with simple parts. It was assumed that spare parts would become available in the local market by for-profit wholesalers. However, it became clear with time that often spare parts are not available locally, because of the low profit margins for wholesalers, especially in Africa. This means that communities are often stuck without spares and cannot use their handpump anymore and have to go back to traditional and sometimes distant, polluted resources. This is unfortunate, as water projects often have put in a lot of resources to provide that community with a handpump. As a result, spare parts free handpumps are now being developed, like the Afripump. # Power source Pumps have been powered by water flow (as with the noria), an internal combustion engine, electric motor, manually (as with the hand pump used for pumping groundwater, called walking beam pump), or by wind power (common for irrigation). Solar power has been used to power an electric motor, for remote locations.

Pump Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. # Overview A pump is a device used to move gases, liquids or slurries. A pump moves liquids or gases from lower pressure to higher pressure, and overcomes this difference in pressure by adding energy to the system (such as a water system). A gas pump is generally called a compressor, except in very low pressure-rise applications, such as in heating, ventilating, and air-conditioning, where the operative equipment consists of fans or blowers. Pumps work by using mechanical forces to push the material, either by physically lifting, or by the force of compression. The earliest type of pump was the Archimedes screw, first used by Sennacherib, King of Assyria, for the water systems at the Hanging Gardens of Babylon and Nineveh in the 7th century BC, and later described in more detail by Archimedes in the 3rd century BC.[1] In the 13th century AD, al-Jazari described and illustrated different types of pumps, including a reciprocating pump, double-action pump with suction pipes, water pump, and piston pump.[2][3] # Types Pumps fall into two major groups: rotodynamic pumps and positive displacement pumps. Their names describe the method for moving a fluid. ## Positive displacement pumps A positive displacement pump causes a liquid or gas to move by trapping a fixed amount of fluid and then forcing (displacing) that trapped volume into the discharge pipe. The periodic fluid displacement results in a direct increase in pressure. A positive displacement pump can be further classified as either - a rotary-type (for example the rotary vane), - lobe pump similar to oil pumps used in car engines, or - the Wendelkolben pump or the helical twisted Roots pump. ### Roots-type pumps The low pulsation rate and gentle performance of this Roots-type positive displacement pump is achieved due to a combination of its two 90° helical twisted rotors, and a triangular shaped sealing line configuration, both at the point of suction and at the point of discharge. This design produces a continuous and non-vorticuless flow with equal volume. High capacity industrial "air compressors" have been designed to employ this principle as well as most "superchargers" used on internal combustion engines. ### Reciprocating-type pumps Reciprocating-type pumps use a piston and cylinder arrangement with suction and discharge valves integrated into the pump. Pumps in this category range from having "simplex" one cylinder, to in some cases "quad" four cylinders or more. Most reciprocating-type pumps are "duplex" (two) or "triplex" (three) cylinder. Furthermore, they are either "single acting" independent suction and discharge strokes or "double acting" suction and discharge in both directions. The pumps can be powered by air, steam or through a belt drive from an engine or motor. This type of pump was used extensively in the early days of steam propulsion (19th century) as boiler feed water pumps. Though still used today, reciprocating pumps are typically used for pumping highly viscous fluids including concrete and heavy oils. ### Compressed-air-powered double-diaphragm pumps Another modern application of positive displacement pumps are compressed-air-powered double-diaphragm pumps, commonly called SandPiper or Wilden Pumps after their major manufacturers. They are relatively inexpensive and are used extensively for pumping water out of bunds, or pumping low volumes of reactants out of storage drums. ## Kinetic Pumps - Continuous energy addition - Conversion of added energy to increase in kinetic energy (increase in velocity) - Conversion of increased velocity to increase in pressure - Conversion of Kinetic head to Pressure Head. - Meet all heads like Kinetic , Potential, and Pressure # Application Pumps are used throughout society for a variety of purposes. Early applications includes the use of the windmill or watermill to pump water. Today, the pump is used for irrigation, water supply, gasoline supply, air conditioning systems, refrigeration (usually called a compressor), chemical movement, sewage movement, flood control, marine services, etc. Because of the wide variety of applications, pumps have a plethora of shapes and sizes: from very large to very small, from handling gas to handling liquid, from high pressure to low pressure, and from high volume to low volume. # Pumps as public water supplies One sort of pump once common worldwide was a hand-powered water pump over a water well where people could work it to extract water, before most houses had individual water supplies. From this came the expression "parish pump" for "the sort of matter chattered about by people when they meet when they go to get water", "matter of only local interest". Today, hand operated village pumps are considered the most sustainable low cost option for safe water supply in resource poor settings, often in rural areas in developing countries. A hand pump opens access to deeper groundwater that is often not polluted and also improves the safety of a well by protecting the water source from contaminated buckets. Pumps like the Afridev pump (pictured) are designed to be cheap to build and install, and easy to maintain with simple parts. It was assumed that spare parts would become available in the local market by for-profit wholesalers. However, it became clear with time that often spare parts are not available locally, because of the low profit margins for wholesalers, especially in Africa. This means that communities are often stuck without spares and cannot use their handpump anymore and have to go back to traditional and sometimes distant, polluted resources. This is unfortunate, as water projects often have put in a lot of resources to provide that community with a handpump. As a result, spare parts free handpumps are now being developed, like the Afripump. # Power source Pumps have been powered by water flow (as with the noria), an internal combustion engine, electric motor, manually (as with the hand pump used for pumping groundwater, called walking beam pump), or by wind power (common for irrigation). Solar power has been used to power an electric motor, for remote locations.[2]

https://www.wikidoc.org/index.php/Pump

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wikidoc

Puto

Puto This article is about the Filipino food. For the Spanish homophobic epithet, see Spanish Profanity, or faggot for the English equivalent. Puto is a type of fermented rice cake eaten in the Philippines. It is produced by fermenting a mixture of soaked ground rice and sugar with a culture of bacteria such as Leuconostoc mesenteroides and Streptococcus faecalis.

Puto This article is about the Filipino food. For the Spanish homophobic epithet, see Spanish Profanity, or faggot for the English equivalent. Puto is a type of fermented rice cake eaten in the Philippines. It is produced by fermenting a mixture of soaked ground rice and sugar with a culture of bacteria such as Leuconostoc mesenteroides and Streptococcus faecalis. [1]

https://www.wikidoc.org/index.php/Puto

34f0a8b8e493f39a1af7dcf9fb5fb0c0977e021b

wikidoc

QDPR

QDPR QDPR (quinoid dihydropteridine reductase) is a human gene that produces the enzyme quinoid dihydropteridine reductase. This enzyme is part of the pathway that recycles a substance called tetrahydrobiopterin, also known as BH4. Tetrahydrobiopterin works with an enzyme called phenylalanine hydroxylase to process a substance called phenylalanine. Phenylalanine is an amino acid (a building block of proteins) that is obtained through the diet; it is found in all proteins and in some artificial sweeteners. When tetrahydrobiopterin interacts with phenylalanine hydroxylase, tetrahydrobiopterin is altered and must be recycled to a usable form. The regeneration of this substance is critical for the proper processing of several other amino acids in the body. Tetrahydrobiopterin also helps produce certain chemicals in the brain called neurotransmitters, which transmit signals between nerve cells. The QDPR gene is located on the short (p) arm of chromosome 4 at position 15.31, from base pair 17,164,291 to base pair 17,189,981. In melanocytic cells QDPR gene expression may be regulated by MITF. # Related conditions Mutations in the QDPR gene are a common cause of tetrahydrobiopterin deficiency. More than 30 disorder-causing mutations in this gene have been identified, including aberrant splicing, amino acid substitutions, insertions, or premature terminations. These mutations completely, or almost completely, inactivate quinoid dihydropteridine reductase, which prevents the normal recycling of tetrahydrobiopterin. In the absence of usable tetrahydrobiopterin, the body cannot process phenylalanine correctly. As a result, phenylalanine from the diet builds up in the bloodstream and other tissues and can lead to brain damage. Neurotransmitters in the brain are also affected, resulting in delayed development, seizures, movement disorders, and other symptoms. In addition, a reduction in the activity of quinoid dihydropteridine reductase may cause calcium to build up abnormally in certain parts of the brain, resulting in damage to nerve cells.

QDPR QDPR (quinoid dihydropteridine reductase) is a human gene that produces the enzyme quinoid dihydropteridine reductase. This enzyme is part of the pathway that recycles a substance called tetrahydrobiopterin, also known as BH4. Tetrahydrobiopterin works with an enzyme called phenylalanine hydroxylase to process a substance called phenylalanine. Phenylalanine is an amino acid (a building block of proteins) that is obtained through the diet; it is found in all proteins and in some artificial sweeteners. When tetrahydrobiopterin interacts with phenylalanine hydroxylase, tetrahydrobiopterin is altered and must be recycled to a usable form. The regeneration of this substance is critical for the proper processing of several other amino acids in the body. Tetrahydrobiopterin also helps produce certain chemicals in the brain called neurotransmitters, which transmit signals between nerve cells. The QDPR gene is located on the short (p) arm of chromosome 4 at position 15.31, from base pair 17,164,291 to base pair 17,189,981. In melanocytic cells QDPR gene expression may be regulated by MITF.[1] # Related conditions Mutations in the QDPR gene are a common cause of tetrahydrobiopterin deficiency. More than 30 disorder-causing mutations in this gene have been identified, including aberrant splicing, amino acid substitutions, insertions, or premature terminations. These mutations completely, or almost completely, inactivate quinoid dihydropteridine reductase, which prevents the normal recycling of tetrahydrobiopterin. In the absence of usable tetrahydrobiopterin, the body cannot process phenylalanine correctly. As a result, phenylalanine from the diet builds up in the bloodstream and other tissues and can lead to brain damage. Neurotransmitters in the brain are also affected, resulting in delayed development, seizures, movement disorders, and other symptoms. In addition, a reduction in the activity of quinoid dihydropteridine reductase may cause calcium to build up abnormally in certain parts of the brain, resulting in damage to nerve cells.

https://www.wikidoc.org/index.php/QDPR

71bd0e15cfd8cfdb40ba26585b2090e36a996188

wikidoc

RAC1

RAC1 Lua error in Module:Redirect at line 65: could not parse redirect on page "Rac1". Rac1, also known as Ras-related C3 botulinum toxin substrate 1, is a protein found in human cells. It is encoded by the RAC1 gene. This gene can produce a variety of alternatively spliced versions of the Rac1 protein, which appear to carry out different functions. # Function Rac1 is a small (~21 kDa) signaling G protein (more specifically a GTPase), and is a member of the Rac subfamily of the family Rho family of GTPases. Members of this superfamily appear to regulate a diverse array of cellular events, including the control of GLUT4 translocation to glucose uptake, cell growth, cytoskeletal reorganization, antimicrobial cytotoxicity, and the activation of protein kinases. Rac1 is a pleiotropic regulator of many cellular processes, including the cell cycle, cell-cell adhesion, motility (through the actin network), and of epithelial differentiation (proposed to be necessary for maintaining epidermal stem cells). # Role in cancer Along with other subfamily of Rac and Rho proteins, they exert an important regulatory role specifically in cell motility and cell growth. Rac1 has ubiquitous tissue expression, and drives cell motility by formation of lamellipodia. In order for cancer cells to grow and invade local and distant tissues, deregulation of cell motility is one of the hallmark events in cancer cell invasion and metastasis. Overexpression of a constitutively active Rac1 V12 in mice caused a tumor that's phenotypically indistinguishable from human Kaposi's sarcoma. Activating or gain-of-function mutations of Rac1 are shown to play active roles in promoting mesenchymal-type of cell movement assisted by NEDD9 and DOCK3 protein complex. Such abnormal cell motility may result in epithelial mesenchymal transition (EMT) – a driving mechanism for tumor metastasis as well as drug-resistant tumor relapse. # Role in glucose transport Rac1 is expressed in significant amounts in insulin sensitive tissues, such as adipose tissue and skeletal muscle. Here Rac1 regulated the translocation of glucose transporting GLUT4 vesicles from intracellular compartments to the plasma membrane. In response to insulin, this allows for blood glucose to enter the cell to lower blood glucose. In conditions of obesity and type 2 diabetes, Rac1 signaling in skeletal muscle is dysfunctional, suggesting that Rac1 contributes to the progression of the disease. Rac1 protein is also necessary for glucose uptake in skeletal muscle activated by exercise and muscle stretching # Clinical significance Activating mutations in Rac1 have been recently discovered in large-scale genomic studies involving melanoma and non-small cell lung cancer. As a result, Rac1 is considered a therapeutic target for many of these diseases. A few recent studies have also exploited targeted therapy to suppress tumor growth by pharmacological inhibition of Rac1 activity in metastatic melanoma and liver cancer as well as in human breast cancer. For example, Rac1-dependent pathway inhibition resulted in the reversal of tumor cell phenotypes, suggesting Rac1 as a predictive marker and therapeutic target for trastuzumab-resistant breast cancer. However, given Rac1's role in glucose transport, drugs that inhibits Rac1 could potentially be harmful to glucose homeostasis. Dominant negative or constitutively active germline RAC1 mutations cause diverse phenotypes that have been grouped together as Mental Retardation Type 48. Most mutations cause microcephaly while some specific changes appear to result in macrocephaly. # Interactions RAC1 has been shown to interact with: - ARFIP2, - ARHGDIA, - BAIAP2, - FHOD1, - FMNL1, - IQGAP1, - IQGAP2, - Myd88, - DMPK, - NCKAP1, - PAK1, - PAK3, - PARD6A, - PARD6B, - RICS - STAT3, and - TIAM1.

RAC1 Lua error in Module:Redirect at line 65: could not parse redirect on page "Rac1". Rac1, also known as Ras-related C3 botulinum toxin substrate 1, is a protein found in human cells. It is encoded by the RAC1 gene.[1][2] This gene can produce a variety of alternatively spliced versions of the Rac1 protein, which appear to carry out different functions.[3] # Function Rac1 is a small (~21 kDa) signaling G protein (more specifically a GTPase), and is a member of the Rac subfamily of the family Rho family of GTPases. Members of this superfamily appear to regulate a diverse array of cellular events, including the control of GLUT4[4][5] translocation to glucose uptake, cell growth, cytoskeletal reorganization, antimicrobial cytotoxicity,[6] and the activation of protein kinases.[7] Rac1 is a pleiotropic regulator of many cellular processes, including the cell cycle, cell-cell adhesion, motility (through the actin network), and of epithelial differentiation (proposed to be necessary for maintaining epidermal stem cells). # Role in cancer Along with other subfamily of Rac and Rho proteins, they exert an important regulatory role specifically in cell motility and cell growth. Rac1 has ubiquitous tissue expression, and drives cell motility by formation of lamellipodia.[8] In order for cancer cells to grow and invade local and distant tissues, deregulation of cell motility is one of the hallmark events in cancer cell invasion and metastasis.[9] Overexpression of a constitutively active Rac1 V12 in mice caused a tumor that's phenotypically indistinguishable from human Kaposi's sarcoma.[10] Activating or gain-of-function mutations of Rac1 are shown to play active roles in promoting mesenchymal-type of cell movement assisted by NEDD9 and DOCK3 protein complex.[11] Such abnormal cell motility may result in epithelial mesenchymal transition (EMT) – a driving mechanism for tumor metastasis as well as drug-resistant tumor relapse.[12][13] # Role in glucose transport Rac1 is expressed in significant amounts in insulin sensitive tissues, such as adipose tissue and skeletal muscle. Here Rac1 regulated the translocation of glucose transporting GLUT4 vesicles from intracellular compartments to the plasma membrane.[5][14][15] In response to insulin, this allows for blood glucose to enter the cell to lower blood glucose. In conditions of obesity and type 2 diabetes, Rac1 signaling in skeletal muscle is dysfunctional, suggesting that Rac1 contributes to the progression of the disease. Rac1 protein is also necessary for glucose uptake in skeletal muscle activated by exercise[4][16] and muscle stretching[17] # Clinical significance Activating mutations in Rac1 have been recently discovered in large-scale genomic studies involving melanoma [18][19][20] and non-small cell lung cancer.[21] As a result, Rac1 is considered a therapeutic target for many of these diseases.[22] A few recent studies have also exploited targeted therapy to suppress tumor growth by pharmacological inhibition of Rac1 activity in metastatic melanoma and liver cancer as well as in human breast cancer.[23][24][25] For example, Rac1-dependent pathway inhibition resulted in the reversal of tumor cell phenotypes, suggesting Rac1 as a predictive marker and therapeutic target for trastuzumab-resistant breast cancer.[24] However, given Rac1's role in glucose transport, drugs that inhibits Rac1 could potentially be harmful to glucose homeostasis. Dominant negative or constitutively active germline RAC1 mutations cause diverse phenotypes that have been grouped together as Mental Retardation Type 48.[26] Most mutations cause microcephaly while some specific changes appear to result in macrocephaly. # Interactions RAC1 has been shown to interact with: - ARFIP2,[27][28][29] - ARHGDIA,[30][31][32][33][34][35] - BAIAP2,[36] - FHOD1,[37] - FMNL1,[38] - IQGAP1,[39][40][41][42] - IQGAP2,[43] - Myd88,[44] - DMPK,[45] - NCKAP1,[46] - PAK1,[39][47][48] - PAK3,[27] - PARD6A,[49][50] - PARD6B,[49] - RICS[51][52] - STAT3,[53] and - TIAM1.[54][55]

https://www.wikidoc.org/index.php/RAC1

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RAC2

RAC2 Rac2 (Ras-related C3 botulinum toxin substrate 2) is a small (~21 kDa) signaling G protein (to be specific, a GTPase), and is a member of the Rac subfamily of the family Rho family of GTPases. It is encoded by the gene RAC2. Members of Rho family of GTPases appear to regulate a diverse array of cellular events, including the control of cell growth, cytoskeletal reorganization, and the activation of protein kinases. # Interactions Rac2 has been shown to interact with ARHGDIA and Nitric oxide synthase 2A.

RAC2 Rac2 (Ras-related C3 botulinum toxin substrate 2) is a small (~21 kDa) signaling G protein (to be specific, a GTPase), and is a member of the Rac subfamily of the family Rho family of GTPases.[1] It is encoded by the gene RAC2.[2] Members of Rho family of GTPases appear to regulate a diverse array of cellular events, including the control of cell growth, cytoskeletal reorganization, and the activation of protein kinases.[2] # Interactions Rac2 has been shown to interact with ARHGDIA[3][4] and Nitric oxide synthase 2A.[5]

https://www.wikidoc.org/index.php/RAC2

eabe250b4ef10a192dc36adb38c35a2324d2a6b1

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RAG1

RAG1 Recombination activating gene 1 also known as RAG-1 is a protein that in humans is encoded by the RAG1 gene. The protein encoded by this gene is involved in activation of immunoglobulin V-D-J recombination. The encoded protein is involved in recognition of the DNA substrate, but stable binding and cleavage activity also requires RAG2. The RAG-1/2 complex recognizes the Recombination Signal Sequence (RSS) that flank the V, D and J regions in the gene that codes for the constant region of both the heavy chain and light chain in an antibody. The complex binds to the Recombination Signal Sequences and nicks the DNA. This leads to the removal of the RSS and the eventual binding of the V D and J sequences. Defects in this gene can be the cause of several diseases. Because of these effects, Rag1 deletion is used in mouse models of disease to impair and maturation, and functionally deletes mature T and B cells from the immune system.

RAG1 Recombination activating gene 1 also known as RAG-1 is a protein that in humans is encoded by the RAG1 gene.[1] The protein encoded by this gene is involved in activation of immunoglobulin V-D-J recombination. The encoded protein is involved in recognition of the DNA substrate, but stable binding and cleavage activity also requires RAG2. The RAG-1/2 complex recognizes the Recombination Signal Sequence (RSS) that flank the V, D and J regions in the gene that codes for the constant region of both the heavy chain and light chain in an antibody. The complex binds to the Recombination Signal Sequences and nicks the DNA. This leads to the removal of the RSS and the eventual binding of the V D and J sequences.[2] Defects in this gene can be the cause of several diseases.[1] Because of these effects, Rag1 deletion is used in mouse models of disease to impair [T cell] and [B cell] maturation, and functionally deletes mature T and B cells from the immune system.[3]

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01e93c65e554dbb744fa06151a677fefbb55f316

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RAG2

RAG2 Recombination activating gene 2 protein (also known as RAG-2) is a lymphocyte-specific protein encoded by RAG2 gene on human chromosome 11. Together with RAG1 protein, RAG2 forms a V(D)J recombinase, a protein complex required for the process of V(D)J recombination during which the variable regions of immunoglobulin and T cell receptor genes are assembled in developing B and T lymphocytes. Therefore, RAG2 is essential for generation of mature B and T lymphocytes. # Structure RAG2 is a 527-amino acid long protein. Its N-terminal part is thought to form a six-bladed propeller in the active core. RAG2 is conserved among all species that carry out V(D)J recombination and its expression pattern correlates precisely with V(D)J recombinase activity. RAG2 is expressed in immature lymphoid cells. While amount of RAG1 is constant during the cell cycle, RAG2 accumulates mainly in G0 and G1 phase of cell cycle and it undergoes rapid degradation when the cell enters S phase. This serves as an important regulatory mechanism of V(D)J recombination and a prevention of genomic instability. # Function RAG2 is one of the two core components of the RAG complex. RAG complex is a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination. This complex can make double-strand breaks by cleaving DNA at conserved recombination signal sequences (RSS). The other core component of this complex is RAG1. This protein is thought to possess most of the catalytic activity of the RAG complex. The RAG1 protein is the component that actually binds to DNA and cleaves it. Unlike RAG1, RAG2 protein does not appear to possess any endonuclease activity or to even bind to DNA strand. RAG2 plays a role of an accessory factor. Its primary function seems to be to interact with RAG1 protein and activate its endonuclease functions. RAG2 also enhances RSS recognition and thereby decreases nonspecific DNA binding by RAG complex. The N-terminal of the recombination activating gene 2 component is thought to form a six-bladed propeller in the active core that serves as a binding scaffold for the tight association of the complex with DNA. A C-terminal plant homeodomain finger-like motif in this protein is necessary for interactions with chromatin components, specifically with histone H3 that is trimethylated at lysine 4. As recombination does not occur in the absence of RAG2, its interactions with RAG1 are thought to be crucial for catalytic function of RAG1 protein. Therefore, presence of both RAG1 and RAG2 is essential for generation of mature B and T lymphocytes. # Clinical significance As mentioned, RAG2 is crucial for maturation of B and T cells. Therefore, mutations of RAG2 gene can result in severe immune disorders such as SCID (Severe Combined Immunodeficiency) or Omenn syndrome. Omenn Syndrom is caused by a hypomorphic mutation of RAG2 gene, which leads to reduced but still present function of the RAG complex. Although patients do not have any circulating B cells, a small number of oligoclonal T cells is developed. # RAG2 knockout mice In 1992, a RAG2 knockout mice strain was generated. Since then, it became a widely used mouse model in immunological research. This mice strain has an inactivated RAG2 gene, therefore homozygous mice are inable to initiate V(D)J rearrangement and consequently fail to generate mature T and B lymphocytes. As such RAG2 knockout mice represent a very valuable research tool used in transplantation experiments, vaccine development and hematopoiesis research. Also, the RAG2 mutation can be combined with other mutations in order to develop further models useful for basic immunology research.

RAG2 Recombination activating gene 2 protein (also known as RAG-2) is a lymphocyte-specific protein encoded by RAG2 gene on human chromosome 11. Together with RAG1 protein, RAG2 forms a V(D)J recombinase, a protein complex required for the process of V(D)J recombination during which the variable regions of immunoglobulin and T cell receptor genes are assembled in developing B and T lymphocytes. Therefore, RAG2 is essential for generation of mature B and T lymphocytes. # Structure RAG2 is a 527-amino acid long protein. Its N-terminal part is thought to form a six-bladed propeller in the active core.[1][1] RAG2 is conserved among all species that carry out V(D)J recombination and its expression pattern correlates precisely with V(D)J recombinase activity.[2] RAG2 is expressed in immature lymphoid cells. While amount of RAG1 is constant during the cell cycle, RAG2 accumulates mainly in G0 and G1 phase of cell cycle and it undergoes rapid degradation when the cell enters S phase.[3][4] This serves as an important regulatory mechanism of V(D)J recombination and a prevention of genomic instability. # Function RAG2 is one of the two core components of the RAG complex. RAG complex is a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination. This complex can make double-strand breaks by cleaving DNA at conserved recombination signal sequences (RSS). The other core component of this complex is RAG1. This protein is thought to possess most of the catalytic activity of the RAG complex. The RAG1 protein is the component that actually binds to DNA and cleaves it.[5][6] Unlike RAG1, RAG2 protein does not appear to possess any endonuclease activity or to even bind to DNA strand. RAG2 plays a role of an accessory factor. Its primary function seems to be to interact with RAG1 protein and activate its endonuclease functions. RAG2 also enhances RSS recognition and thereby decreases nonspecific DNA binding by RAG complex.[7][8] The N-terminal of the recombination activating gene 2 component is thought to form a six-bladed propeller in the active core that serves as a binding scaffold for the tight association of the complex with DNA. A C-terminal plant homeodomain finger-like motif in this protein is necessary for interactions with chromatin components, specifically with histone H3 that is trimethylated at lysine 4. As recombination does not occur in the absence of RAG2, its interactions with RAG1 are thought to be crucial for catalytic function of RAG1 protein.[9] Therefore, presence of both RAG1 and RAG2 is essential for generation of mature B and T lymphocytes. # Clinical significance As mentioned, RAG2 is crucial for maturation of B and T cells. Therefore, mutations of RAG2 gene can result in severe immune disorders such as SCID (Severe Combined Immunodeficiency) or Omenn syndrome.[10] Omenn Syndrom is caused by a hypomorphic mutation of RAG2 gene, which leads to reduced but still present function of the RAG complex.[11] Although patients do not have any circulating B cells, a small number of oligoclonal T cells is developed. # RAG2 knockout mice In 1992, a RAG2 knockout mice strain was generated. Since then, it became a widely used mouse model in immunological research. This mice strain has an inactivated RAG2 gene, therefore homozygous mice are inable to initiate V(D)J rearrangement and consequently fail to generate mature T and B lymphocytes.[9] As such RAG2 knockout mice represent a very valuable research tool used in transplantation experiments, vaccine development and hematopoiesis research. Also, the RAG2 mutation can be combined with other mutations in order to develop further models useful for basic immunology research.

https://www.wikidoc.org/index.php/RAG2

96d7e13461e193e62cc9d01520ddbc3b3b32515a

wikidoc

RALA

RALA Ras-related protein Ral-A (RalA) is a protein that in humans is encoded by the RALA gene on chromosome 7. This protein is one of two paralogs of the Ral protein, the other being RalB, and part of the Ras GTPase family. RalA functions as a molecular switch to activate a number of biological processes, majorly cell division and transport, via signaling pathways. Its biological role thus implicates it in many cancers. # Structure The Ral isoforms share an 80% overall match in amino acid sequence and 100% match in their effector-binding region. The two isoforms mainly differ in the C-terminal hypervariable region, which contains multiple sites for post-translational modification, leading to diverging subcellular localization and biological function. For example, phosphorylation of Serine 194 on RalA by the kinase Aurora A results in the relocation of RalA to the inner mitochondrial membrane, where RalA helps carry out mitochondrial fission; whereas phosphorylation of Serine 198 on RalB by the kinase PKC results in the relocation of RalB to other internal membranes and activation of its tumorigenic function. # Function RalA is one of two proteins in the Ral family, which is itself a subfamily within the Ras family of small GTPases. As a Ras GTPase, RalA functions as a molecular switch that becomes active when bound to GTP and inactive when bound to GDP. RalA can be activated by RalGEFs and, in turn, activate effectors in signal transduction pathways leading to biological outcomes. For instance, RalA interacts with two components of the exocyst, Exo84 and Sec5, to promote autophagosome assembly, secretory vesicle trafficking, and tethering. Other downstream functions include exocytosis, receptor-mediated endocytosis, tight junction biogenesis, filopodia formation, mitochondrial fission, and cytokinesis. Ral-mediated exocytosis is also involved such biological processes as platelet activation, immune cell functions, neuronal plasticity, and regulation of insulin action. While the above functions appear to be shared between the two Ral isoforms, their differential subcellular localizations result in their differing involvement in certain biological processes. In particular, RalA is more involved in anchorage-independent cell growth, vesicle trafficking, and cytoskeletal organization. Moreover, RalA specifically interacts with Exo84 and Sec5 to regulate transport of membrane proteins in polarized epithelial cells and GLUT4 to the plasma membrane, as well as mitochondrial fission for cell division. # Clinical significance Ral proteins have been associated with the progression of several cancers, including bladder cancer and prostate cancer. Though the exact mechanisms remain unclear, studies reveal that RalA promotes anchorage-independent growth in cancer cells. As a result, inhibition of RalA inhibits cancer initiation. Due to its exocytotic role in platelets, immune cells, neurons, and insulin regulation, downregulation of Ral may lead to pathological conditions such as thrombosis and metabolic syndrome. In chronic thromboembolic pulmonary hypertension patients, Ral GTPases have been observed to be highly active in their platelets. # Interactions RalA has been shown to interact with: - EXOC8, - Filamin, - PLD1, - Sec5, and - RALBP1.

RALA Ras-related protein Ral-A (RalA) is a protein that in humans is encoded by the RALA gene on chromosome 7.[1][2] This protein is one of two paralogs of the Ral protein, the other being RalB, and part of the Ras GTPase family.[3] RalA functions as a molecular switch to activate a number of biological processes, majorly cell division and transport, via signaling pathways.[3][4][5] Its biological role thus implicates it in many cancers.[5] # Structure The Ral isoforms share an 80% overall match in amino acid sequence and 100% match in their effector-binding region. The two isoforms mainly differ in the C-terminal hypervariable region, which contains multiple sites for post-translational modification, leading to diverging subcellular localization and biological function. For example, phosphorylation of Serine 194 on RalA by the kinase Aurora A results in the relocation of RalA to the inner mitochondrial membrane, where RalA helps carry out mitochondrial fission; whereas phosphorylation of Serine 198 on RalB by the kinase PKC results in the relocation of RalB to other internal membranes and activation of its tumorigenic function.[5] # Function RalA is one of two proteins in the Ral family, which is itself a subfamily within the Ras family of small GTPases.[3] As a Ras GTPase, RalA functions as a molecular switch that becomes active when bound to GTP and inactive when bound to GDP. RalA can be activated by RalGEFs and, in turn, activate effectors in signal transduction pathways leading to biological outcomes.[3][4] For instance, RalA interacts with two components of the exocyst, Exo84 and Sec5, to promote autophagosome assembly, secretory vesicle trafficking, and tethering. Other downstream functions include exocytosis, receptor-mediated endocytosis, tight junction biogenesis, filopodia formation, mitochondrial fission, and cytokinesis.[3][5][6] Ral-mediated exocytosis is also involved such biological processes as platelet activation, immune cell functions, neuronal plasticity, and regulation of insulin action.[7] While the above functions appear to be shared between the two Ral isoforms, their differential subcellular localizations result in their differing involvement in certain biological processes. In particular, RalA is more involved in anchorage-independent cell growth, vesicle trafficking, and cytoskeletal organization.[4][8] Moreover, RalA specifically interacts with Exo84 and Sec5 to regulate transport of membrane proteins in polarized epithelial cells and GLUT4 to the plasma membrane, as well as mitochondrial fission for cell division.[3] # Clinical significance Ral proteins have been associated with the progression of several cancers, including bladder cancer and prostate cancer.[5] Though the exact mechanisms remain unclear, studies reveal that RalA promotes anchorage-independent growth in cancer cells.[4] As a result, inhibition of RalA inhibits cancer initiation.[5] Due to its exocytotic role in platelets, immune cells, neurons, and insulin regulation, downregulation of Ral may lead to pathological conditions such as thrombosis and metabolic syndrome. In chronic thromboembolic pulmonary hypertension patients, Ral GTPases have been observed to be highly active in their platelets.[7] # Interactions RalA has been shown to interact with: - EXOC8,[3] - Filamin,[9] - PLD1,[10][11] - Sec5,[3][5] and - RALBP1.[12][13][14][15]

https://www.wikidoc.org/index.php/RALA

1b61e6275567252f3bc1e79665fcaa12520c0611

wikidoc

RALB

RALB Ras-related protein Ral-B (RalB) is a protein that in humans is encoded by the RALB gene on chromosome 2. This protein is one of two paralogs of the Ral protein, the other being RalA, and part of the Ras GTPase family. RalA functions as a molecular switch to activate a number of biological processes, majorly cell division and transport, via signaling pathways. Its biological role thus implicates it in many cancers. # Structure The Ral isoforms share an 80% overall match in amino acid sequence and 100% match in their effector-binding region. The two isoforms mainly differ in the C-terminal hypervariable region, which contains multiple sites for post-translational modification, leading to diverging subcellular localization and biological function. For example, phosphorylation of Serine 194 on RalA by the kinase Aurora A results in the relocation of RalA to the inner mitochondrial membrane, where RalA helps carry out mitochondrial fission; whereas phosphorylation of Serine 198 on RalB by the kinase PKC results in the relocation of RalB to other internal membranes and activation of its tumorigenic function. # Function RalB is one of two proteins in the Ral family, which is itself a subfamily within the Ras family of small GTPases. As a Ras GTPase, RalB functions as a molecular switch that becomes active when bound to GTP and inactive when bound to GDP. RalB can be activated by RalGEFs and, in turn, activate effectors in signal transduction pathways leading to biological outcomes. For instance, RalB interacts with two components of the exocyst, Exo84 and Sec5, to promote autophagosome assembly, secretory vesicle trafficking, and tethering. Other downstream biological functions include exocytosis, receptor-mediated endocytosis, tight junction biogenesis, filopodia formation, mitochondrial fission, and cytokinesis. While the above functions appear to be shared between the two Ral isoforms, their differential subcellular localizations result in their differing involvement in certain biological processes. In particular, RalB is more involved in apoptosis and cell motility. Moreover, RalB specifically interacts with Exo84 to assemble the beclin-1–VPS34 autophagy initiation complex, and with Sec5 to activate the innate immune response via the Tank-binding kinase 1 (TBK1). # Clinical significance Ral proteins have been associated with the progression of several cancers, including bladder cancer and prostate cancer. Though the exact mechanisms remain unclear, studies reveal that RalB promotes tumor invasion and metastasis. As a result, inhibition of RalB inhibits further progression of cancer. In addition, RalB regulates p53 levels in a K-Ras-independent manner during cancer development. RalB also promotes cell survival during infection by double-stranded DNA viruses by activating TBK1 to carry out an immune response. # Interactions RalB has been shown to interact with: - CDC42, - EXOC8, - RALBP1, and - Sec5.

RALB Ras-related protein Ral-B (RalB) is a protein that in humans is encoded by the RALB gene on chromosome 2.[1] This protein is one of two paralogs of the Ral protein, the other being RalA, and part of the Ras GTPase family.[2] RalA functions as a molecular switch to activate a number of biological processes, majorly cell division and transport, via signaling pathways.[2][3][4] Its biological role thus implicates it in many cancers.[4] # Structure The Ral isoforms share an 80% overall match in amino acid sequence and 100% match in their effector-binding region. The two isoforms mainly differ in the C-terminal hypervariable region, which contains multiple sites for post-translational modification, leading to diverging subcellular localization and biological function. For example, phosphorylation of Serine 194 on RalA by the kinase Aurora A results in the relocation of RalA to the inner mitochondrial membrane, where RalA helps carry out mitochondrial fission; whereas phosphorylation of Serine 198 on RalB by the kinase PKC results in the relocation of RalB to other internal membranes and activation of its tumorigenic function.[4] # Function RalB is one of two proteins in the Ral family, which is itself a subfamily within the Ras family of small GTPases.[2] As a Ras GTPase, RalB functions as a molecular switch that becomes active when bound to GTP and inactive when bound to GDP. RalB can be activated by RalGEFs and, in turn, activate effectors in signal transduction pathways leading to biological outcomes.[2][3] For instance, RalB interacts with two components of the exocyst, Exo84 and Sec5, to promote autophagosome assembly, secretory vesicle trafficking, and tethering. Other downstream biological functions include exocytosis, receptor-mediated endocytosis, tight junction biogenesis, filopodia formation, mitochondrial fission, and cytokinesis.[2][4][5] While the above functions appear to be shared between the two Ral isoforms, their differential subcellular localizations result in their differing involvement in certain biological processes. In particular, RalB is more involved in apoptosis and cell motility.[3][4] Moreover, RalB specifically interacts with Exo84 to assemble the beclin-1–VPS34 autophagy initiation complex, and with Sec5 to activate the innate immune response via the Tank-binding kinase 1 (TBK1).[2] # Clinical significance Ral proteins have been associated with the progression of several cancers, including bladder cancer and prostate cancer.[4] Though the exact mechanisms remain unclear, studies reveal that RalB promotes tumor invasion and metastasis. As a result, inhibition of RalB inhibits further progression of cancer.[4] In addition, RalB regulates p53 levels in a K-Ras-independent manner during cancer development.[3] RalB also promotes cell survival during infection by double-stranded DNA viruses by activating TBK1 to carry out an immune response.[2][4] # Interactions RalB has been shown to interact with: - CDC42,[3] - EXOC8,[6] - RALBP1,[6][7][8] and - Sec5.[2][4]

https://www.wikidoc.org/index.php/RALB

ea7363c7316e4b5d3b90e212ed14192c8bffc7b0

wikidoc

RANK

RANK Receptor activator of nuclear factor κ B (RANK), also known as TRANCE receptor or TNFRSF11A, is a member of the tumor necrosis factor receptor (TNFR) molecular sub-family. RANK is the receptor for RANK-Ligand (RANKL) and part of the RANK/RANKL/OPG signaling pathway that regulates osteoclast differentiation and activation. It is associated with bone remodeling and repair, immune cell function, lymph node development, thermal regulation, and mammary gland development. Osteoprotegerin (OPG) is a decoy receptor for RANK, and regulates the stimulation of the RANK signaling pathway by competing for RANKL. The cytoplasmic domain of RANK binds TRAFs 1, 2, 3, 5, and 6 which transmit signals to downstream targets such as NF-κB and JNK. RANK is constitutively expressed in skeletal muscle, thymus, liver, colon, small intestine, adrenal gland, osteoclast, mammary gland epithelial cells, prostate, vascular cell, and pancreas. Most commonly, activation of NF-κB is mediated by RANKL, but over-expression of RANK alone is sufficient to activate the NF-κB pathway. RANKL (receptor activator for nuclear factor κ B ligand) is found on the surface of stromal cells, osteoblasts, and T cells. # Structure RANK is a 616 amino acid type I transmembrane protein. Its extracellular domain consists of 184 amino acids, its transmembrane domain has 21 amino acids, and its cytoplasmic domain consists of 383 amino acids. Like other members of the TNFR family, it has four extracellular cysteine-rich pseudo-repeat domains (CRDs). It shares 40% amino acid identity with CD40. RANK is encoded on human chromosome 18q22.1. It shows 85% homology between mouse and human homologues. There are two monomers of RANK related by noncrystallographic 2-fold symmetry perpendicular to the long axis of the molecules in the asymmetric unit. RANK contains four CRDs spanning a length of 100 Angstroms which makes it the longest member of the TNFR family to date. The binding of RANKL to RANK trimerizes the receptor and activates a signaling pathway. The RANK-RANKL complex forms a heterohexameric complex. Only two of the four RANK CRDs are in direct contact with the RANKL. The majority of the complex’s residues are hydrophilic. Unlike other members of the TNFSF, each surface interaction in RANK-RANKL is continuous. # Function ## Osteoclastogenesis TRAF6 has been shown to be imperative to the RANK-related osteoclastogenesis pathway. RANKL binds to RANK, which then binds to TRAF6. TRAF6 stimulates the activation of the c-jun N-terminal kinase (JNK) and nuclear factor kappa-b (NF-kB) pathways which trigger differentiation and activation of osteoclasts. This system is balanced by the relative expression of OPG to RANKL, which are highly regulated by many factors including hormones, immune signals, and growth factors. An overexpression of RANKL can cause an overproduction and activation of osteoclasts, which break down bone. The balance between RANKL and OPG is a target for therapy in many diseases including estrogen deficiency-associated osteoporosis, rheumatoid arthritis, Paget’s disease, periodontal disease, and bone tumors and malignancies. ## Thermoregulation RANK has also been shown to be a key in the thermoregulation signaling in females, which seems to be regulated by ovarian sex hormones. RANK is expressed in key regions of the brain associated with thermoregulation. Inactivation of RANK in these regions causes a loss of fever response to increased levels of RANKL. It has also been shown to be a critical mediator of fever response to lipopolysaccharide-induced fever and pro-inflammatory cytokines IL-1B and TNFa. This key role of the RANK-RANKL system may link the osteoporosis and hot flashes seen as symptoms of hormonal changes in post-menopausal women. ## Mammary gland development RANK is constitutively expressed in mammary epithelial tissues. Calcium transferred from mother to fetus and neonate is provided by the degradation of the female bone by increased osteoclastic activity, which is regulated by the RANK/RANKL axis. RANKL also works through RANK to provide proliferative and survival signals to promote the final stages of lactating mammary gland development. Dysfunctional RANK or RANKL causes the arrest of differentiation and expansion of the alveolar bunds into mature lobulo-alveolar mammary structures, disabling the production of milk. # Clinical significance ## Cancer RANK and RANKL have been reported to be expressed in some breast cancer and prostate cancer cell lines. RANKL expression in infiltrating T cells within mammary carcinomas activate RANK-expressing neoplastic mammary epithelial cells which stimulate metastasis. The expression of RANKL in these cells and the expression of RANK in bone cells may be the biological presentation of Paget’s seed and soil idea. The affinity for RANK of RANKL may be the reason these cancers tend to metastasize to bone. Once the tumor is seeded in the bone, the tumor cells stimulate bone resorption by secreting factors such as RANKL or prompting the surrounding stroma to express growth factors. These growth factors then upregulate production of RANKL which leads to osteoclastogenesis and bone destruction. The destruction of bone releases more growth factors and RANKL which induces more osteoclastogenesis, triggering a vicious cycle of bone destruction that is seen in metastatic bone tumors. ## Targeted therapies Most therapies that target the RANK/RANKL/OPG axis aim to either down-regulate expression of RANKL or upregulate the expression of the decoy receptor OPG. For example, denosumab is a fully human monoclonal antibody that is directed against RANKL. In phase I and II trials, denosumab led to a decrease in bone resorption in multiple myeloma, prostate cancer and breast cancer patients. Another study looked into developing small mimetics based on the structure of OPG that bind to RANK as well as RANKL and cause defective coupling between the two. # Interactions RANK has been shown to interact with: - TRAF1, - TRAF2, - TRAF3, - TRAF5, and - TRAF6.

RANK Receptor activator of nuclear factor κ B (RANK), also known as TRANCE receptor or TNFRSF11A, is a member of the tumor necrosis factor receptor (TNFR) molecular sub-family. RANK is the receptor for RANK-Ligand (RANKL) and part of the RANK/RANKL/OPG signaling pathway that regulates osteoclast differentiation and activation. It is associated with bone remodeling and repair, immune cell function, lymph node development, thermal regulation, and mammary gland development. Osteoprotegerin (OPG) is a decoy receptor for RANK, and regulates the stimulation of the RANK signaling pathway by competing for RANKL. The cytoplasmic domain of RANK binds TRAFs 1, 2, 3, 5, and 6 which transmit signals to downstream targets such as NF-κB and JNK. RANK is constitutively expressed in skeletal muscle, thymus, liver, colon, small intestine, adrenal gland, osteoclast, mammary gland epithelial cells, prostate, vascular cell,[1] and pancreas. Most commonly, activation of NF-κB is mediated by RANKL, but over-expression of RANK alone is sufficient to activate the NF-κB pathway.[2] RANKL (receptor activator for nuclear factor κ B ligand) is found on the surface of stromal cells, osteoblasts, and T cells.[3][4][5] # Structure RANK is a 616 amino acid type I transmembrane protein. Its extracellular domain consists of 184 amino acids, its transmembrane domain has 21 amino acids, and its cytoplasmic domain consists of 383 amino acids.[6] Like other members of the TNFR family, it has four extracellular cysteine-rich pseudo-repeat domains (CRDs). It shares 40% amino acid identity with CD40. RANK is encoded on human chromosome 18q22.1. It shows 85% homology between mouse and human homologues.[2] There are two monomers of RANK related by noncrystallographic 2-fold symmetry perpendicular to the long axis of the molecules in the asymmetric unit. RANK contains four CRDs spanning a length of 100 Angstroms which makes it the longest member of the TNFR family to date.[7] The binding of RANKL to RANK trimerizes the receptor and activates a signaling pathway. The RANK-RANKL complex forms a heterohexameric complex. Only two of the four RANK CRDs are in direct contact with the RANKL. The majority of the complex’s residues are hydrophilic. Unlike other members of the TNFSF, each surface interaction in RANK-RANKL is continuous.[7] # Function ## Osteoclastogenesis TRAF6 has been shown to be imperative to the RANK-related osteoclastogenesis pathway.[8] RANKL binds to RANK, which then binds to TRAF6. TRAF6 stimulates the activation of the c-jun N-terminal kinase (JNK) and nuclear factor kappa-b (NF-kB) pathways which trigger differentiation and activation of osteoclasts. This system is balanced by the relative expression of OPG to RANKL, which are highly regulated by many factors including hormones, immune signals, and growth factors. An overexpression of RANKL can cause an overproduction and activation of osteoclasts, which break down bone. The balance between RANKL and OPG is a target for therapy in many diseases including estrogen deficiency-associated osteoporosis, rheumatoid arthritis, Paget’s disease, periodontal disease, and bone tumors and malignancies.[9] ## Thermoregulation RANK has also been shown to be a key in the thermoregulation signaling in females, which seems to be regulated by ovarian sex hormones. RANK is expressed in key regions of the brain associated with thermoregulation. Inactivation of RANK in these regions causes a loss of fever response to increased levels of RANKL. It has also been shown to be a critical mediator of fever response to lipopolysaccharide-induced fever and pro-inflammatory cytokines IL-1B and TNFa. This key role of the RANK-RANKL system may link the osteoporosis and hot flashes seen as symptoms of hormonal changes in post-menopausal women.[10] ## Mammary gland development RANK is constitutively expressed in mammary epithelial tissues. Calcium transferred from mother to fetus and neonate is provided by the degradation of the female bone by increased osteoclastic activity, which is regulated by the RANK/RANKL axis. RANKL also works through RANK to provide proliferative and survival signals to promote the final stages of lactating mammary gland development. Dysfunctional RANK or RANKL causes the arrest of differentiation and expansion of the alveolar bunds into mature lobulo-alveolar mammary structures, disabling the production of milk.[11] # Clinical significance ## Cancer RANK and RANKL have been reported to be expressed in some breast cancer and prostate cancer cell lines. RANKL expression in infiltrating T cells within mammary carcinomas activate RANK-expressing neoplastic mammary epithelial cells which stimulate metastasis. The expression of RANKL in these cells and the expression of RANK in bone cells may be the biological presentation of Paget’s seed and soil idea. The affinity for RANK of RANKL may be the reason these cancers tend to metastasize to bone. Once the tumor is seeded in the bone, the tumor cells stimulate bone resorption by secreting factors such as RANKL or prompting the surrounding stroma to express growth factors. These growth factors then upregulate production of RANKL which leads to osteoclastogenesis and bone destruction. The destruction of bone releases more growth factors and RANKL which induces more osteoclastogenesis, triggering a vicious cycle of bone destruction that is seen in metastatic bone tumors.[6] ## Targeted therapies Most therapies that target the RANK/RANKL/OPG axis aim to either down-regulate expression of RANKL or upregulate the expression of the decoy receptor OPG. For example, denosumab is a fully human monoclonal antibody that is directed against RANKL. In phase I and II trials, denosumab led to a decrease in bone resorption in multiple myeloma, prostate cancer and breast cancer patients.[6] Another study looked into developing small mimetics based on the structure of OPG that bind to RANK as well as RANKL and cause defective coupling between the two.[12] # Interactions RANK has been shown to interact with: - TRAF1,[13][14] - TRAF2,[13][14][15][16] - TRAF3,[13][14] - TRAF5,[13][15][16] and - TRAF6.[13][14][15][16][17]

https://www.wikidoc.org/index.php/RANK

99f4da0128f9ba4facdd73326a86ceae34a1acca

wikidoc

RBM3

RBM3 Putative RNA-binding protein 3 is a protein that in humans is encoded by the RBM3 gene. # Function This gene is a member of the glycine-rich RNA-binding protein family and encodes a protein with one RNA recognition motif (RRM) domain. Expression of this gene is induced by cold shock and low oxygen tension. A pseudogene exists on chromosome 1. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. RBM3 is cold-induced RNA binding protein and is involved in mRNA biogenesis exerts anti-apoptotic effects. According to antibody-based profiling and transcriptomics analysis, RBM3 protein is present in all analysed human tissues and based on confocal microscopy mainly localised to the nucleoplasm. # Clinical significance RBM3 is a proto-oncogene that is associated with tumor progression and metastasis and is a potential cancer biomarker. Based on patient survival data, high levels of RBM3 protein in tumor cells is a favourable prognostic biomarker in colorectal cancer.

RBM3 Putative RNA-binding protein 3 is a protein that in humans is encoded by the RBM3 gene.[1][2] # Function This gene is a member of the glycine-rich RNA-binding protein family and encodes a protein with one RNA recognition motif (RRM) domain. Expression of this gene is induced by cold shock and low oxygen tension. A pseudogene exists on chromosome 1. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[2] RBM3 is cold-induced RNA binding protein and is involved in mRNA biogenesis exerts anti-apoptotic effects.[3] According to antibody-based profiling and transcriptomics analysis, RBM3 protein is present in all analysed human tissues[4] and based on confocal microscopy mainly localised to the nucleoplasm.[5] # Clinical significance RBM3 is a proto-oncogene that is associated with tumor progression and metastasis and is a potential cancer biomarker.[3] Based on patient survival data, high levels of RBM3 protein in tumor cells is a favourable prognostic biomarker in colorectal cancer.[6]

https://www.wikidoc.org/index.php/RBM3

c79153d1b8440f353fb45c680b4c613e122a293e

wikidoc

RBMX

RBMX Heterogeneous nuclear ribonucleoprotein G is a protein that in humans is encoded by the RBMX gene. # Function This gene belongs to the RBMY gene family which includes candidate Y chromosome spermatogenesis genes. This gene, an active X chromosome homolog of the Y chromosome RBMY gene, is widely expressed whereas the RBMY gene evolved a male-specific function in spermatogenesis. Pseudogenes of this gene, found on chromosomes 1, 4, 9, 11, and 6, were likely derived by retrotransposition from the original gene. Alternatively spliced transcript variants encoding different isoforms have been identified but their biological nature has not been determined. # Interactions RBMX has been shown to interact with SFRS10 and CDC5L. # Model organisms Model organisms have been used in the study of RBMX function. A conditional knockout mouse line called Rbmxtm2b(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping

RBMX Heterogeneous nuclear ribonucleoprotein G is a protein that in humans is encoded by the RBMX gene.[1][2][3] # Function This gene belongs to the RBMY gene family which includes candidate Y chromosome spermatogenesis genes. This gene, an active X chromosome homolog of the Y chromosome RBMY gene, is widely expressed whereas the RBMY gene evolved a male-specific function in spermatogenesis. Pseudogenes of this gene, found on chromosomes 1, 4, 9, 11, and 6, were likely derived by retrotransposition from the original gene. Alternatively spliced transcript variants encoding different isoforms have been identified but their biological nature has not been determined.[3] # Interactions RBMX has been shown to interact with SFRS10[4] and CDC5L.[5] # Model organisms Model organisms have been used in the study of RBMX function. A conditional knockout mouse line called Rbmxtm2b(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[6] Male and female animals underwent a standardized phenotypic screen[7] to determine the effects of deletion.[8][9][10][11] Additional screens performed: - In-depth immunological phenotyping[12]

https://www.wikidoc.org/index.php/RBMX

29586e3cff0954e8dc280d5e9c8b3f282d8009e1

wikidoc

RBP1

RBP1 Retinol binding protein 1, cellular, also known as RBP1, is a protein that in humans is encoded by the RBP1 gene. # Function RBP1 is the carrier protein involved in the transport of retinol (vitamin A alcohol) from the liver storage site to peripheral tissue. Vitamin A is a fat-soluble vitamin necessary for growth, reproduction, differentiation of epithelial tissues, and vision. The gene harbors four exons encoding 24, 59, 33, and 16 amino acid residues, respectively. The second intervening sequence alone occupies 19 kb of the 21 kb of the gene. # Clinical significance Cellular retinol-binding protein-1 (CRBP-1) contributes to the maintenance of the differentiative state of endometrial cells through the regulation of bioavailability of retinol. On the converse, loss of CRBP-1 is associated with development of endometrial cancer.

RBP1 Retinol binding protein 1, cellular, also known as RBP1, is a protein that in humans is encoded by the RBP1 gene.[1][2][3] # Function RBP1 is the carrier protein involved in the transport of retinol (vitamin A alcohol) from the liver storage site to peripheral tissue. Vitamin A is a fat-soluble vitamin necessary for growth, reproduction, differentiation of epithelial tissues, and vision. The gene harbors four exons encoding 24, 59, 33, and 16 amino acid residues, respectively. The second intervening sequence alone occupies 19 kb of the 21 kb of the gene.[1] # Clinical significance Cellular retinol-binding protein-1 (CRBP-1) contributes to the maintenance of the differentiative state of endometrial cells through the regulation of bioavailability of retinol. On the converse, loss of CRBP-1 is associated with development of endometrial cancer.[4]

https://www.wikidoc.org/index.php/RBP1

68bb6081cbd1f7e6b146e344083d88c4bd1f1705

wikidoc

RBP3

RBP3 Retinol-binding protein 3, interstitial (RBP3), also known as IRBP is a protein that in humans is encoded by the RBP3 gene. RBP3 orthologs have been identified in most eutherians except tenrecs and armadillos. # Function The inter-photoreceptor retinoid-binding protein is a large glycoprotein known to bind retinoids and found primarily in the interphotoreceptor matrix of the retina between the retinal pigment epithelium and the photoreceptor cells. It is thought to transport retinoids between the retinal pigment epithelium and the photoreceptors, a critical role in the visual process. # Gene The human IRBP gene is approximately 9.5 kbp in length and consists of four exons separated by three introns. The introns are 1.6-1.9 kbp long. The gene is transcribed by photoreceptor and retinoblastoma cells into an approximately 4.3-kilobase mRNA that is translated and processed into a glycosylated protein of 135,000 Da. # Structure The amino acid sequence of human IRBP can be divided into four contiguous homology domains with 33-38% identity, suggesting a series of gene duplication events. In the gene, the boundaries of these domains are not defined by exon-intron junctions, as might have been expected. The first three homology domains and part of the fourth are all encoded by the first large exon, which is 3,180 base pairs long. The remainder of the fourth domain is encoded in the last three exons, which are 191, 143, and approximately 740 base pairs long, respectively. # Application The rbp3 gene is commonly used in animals as a nuclear DNA phylogenetic marker. The exon 1 has first been used in a pioneer study to provide evidence for monophyly of Chiroptera. Then, it has been used to infer the phylogeny of placental mammal orders, and of the major clades of Rodentia, Macroscelidea, and Primates. RBP3 is also useful at lower taxonomic levels, e.g., in muroid rodents and Malagasy primates, at the phylogeography level in Geomys and Apodemus rodents, and even for carnivora species identification purposes. Note that the RBP3 intron 1 has also been used to investigate the platyrrhine primates phylogenetics.

RBP3 Retinol-binding protein 3, interstitial (RBP3), also known as IRBP is a protein that in humans is encoded by the RBP3 gene.[1] RBP3 orthologs [2] have been identified in most eutherians except tenrecs and armadillos. # Function The inter-photoreceptor retinoid-binding protein is a large glycoprotein known to bind retinoids and found primarily in the interphotoreceptor matrix of the retina between the retinal pigment epithelium and the photoreceptor cells. It is thought to transport retinoids between the retinal pigment epithelium and the photoreceptors, a critical role in the visual process. # Gene The human IRBP gene is approximately 9.5 kbp in length and consists of four exons separated by three introns. The introns are 1.6-1.9 kbp long. The gene is transcribed by photoreceptor and retinoblastoma cells into an approximately 4.3-kilobase mRNA that is translated and processed into a glycosylated protein of 135,000 Da. # Structure The amino acid sequence of human IRBP can be divided into four contiguous homology domains with 33-38% identity, suggesting a series of gene duplication events. In the gene, the boundaries of these domains are not defined by exon-intron junctions, as might have been expected. The first three homology domains and part of the fourth are all encoded by the first large exon, which is 3,180 base pairs long. The remainder of the fourth domain is encoded in the last three exons, which are 191, 143, and approximately 740 base pairs long, respectively.[1] # Application The rbp3 gene is commonly used in animals as a nuclear DNA phylogenetic marker.[2] The exon 1 has first been used in a pioneer study to provide evidence for monophyly of Chiroptera.[3] Then, it has been used to infer the phylogeny of placental mammal orders,[4][5] and of the major clades of Rodentia,[6] Macroscelidea,[7] and Primates.[8] RBP3 is also useful at lower taxonomic levels, e.g., in muroid rodents[9] and Malagasy primates,[10] at the phylogeography level in Geomys and Apodemus rodents,[11][12] and even for carnivora species identification purposes.[13] Note that the RBP3 intron 1 has also been used to investigate the platyrrhine primates phylogenetics.[14]

https://www.wikidoc.org/index.php/RBP3

f938e690f9ddedf23315d08e3b5646ab412ee62a

wikidoc

RCC1

RCC1 Regulator of chromosome condensation 1, also known as RCC1, Ran guanine nucleotide exchange factor and RanGEF, is the name for a human gene and protein. RCC1 also functions as a guanine nucleotide exchange factor for Ran GTPase. # Interactions RCC1 has been shown to interact with RANBP3 and Ran (biology).

RCC1 Regulator of chromosome condensation 1, also known as RCC1, Ran guanine nucleotide exchange factor and RanGEF, is the name for a human gene and protein.[1] RCC1 also functions as a guanine nucleotide exchange factor for Ran GTPase. # Interactions RCC1 has been shown to interact with RANBP3[2][3] and Ran (biology).[4][5][6][7]

https://www.wikidoc.org/index.php/RCC1

873ed3513cb0216fe0bf2a349c37dd0e683526ea

wikidoc

REC8

REC8 Meiotic recombination protein REC8 homolog is a protein that in humans is encoded by the REC8 gene. Rec8 is a meiosis-specific component of the cohesin complex that binds sister chromatids in preparation for the two divisions of meiosis. Rec8 is sequentially removed from sister chromatids. It is removed from the arms of chromosomes in the first division - separating homologous chromosomes from each other. However, Rec8 is maintained at centromeres so that sister chromatids are kept joined until anaphase of meiosis II, at which point removal of remaining cohesin leads to the separation of sister chromatids. # Function This gene encodes a member of the kleisin family of SMC (structural maintenance of chromosome) protein partners. The protein localizes to the axial elements of chromosomes during meiosis in both oocytes and spermatocytes. REC8 protein appears to participate with other cohesins STAG3, SMC1ß and SMC3 in sister chromatid cohesion throughout the whole meiotic process in human oocytes. In the mouse, the homologous protein is a key component of the meiotic cohesion complex, which regulates sister chromatid cohesion and recombination between homologous chromosomes. Multiple alternatively spliced variants, encoding the same protein, have been found for this gene. Rec8 remains in complex with SMC proteins until anaphase, where it is degraded by Separase once the spindle assembly checkpoint is bypassed. Unlike the other Kleisin family member, Scc1, Rec8 must be phosphorylated prior to degradation. Prior to anaphase, Rec8 is protected from phosphorylation by Protein Phosphatase 2 (PP2A-B56) in mouse. PP2A is recruited to cohesin by Shugoshin 2 (Sgo2; SGOL2 in yeast). Bypass of the spindle assembly checkpoint activates Separase, which then degrades phosphorylated Rec8 and untethers Cohesin from sister chromatids, allowing for segregation of chromosomes. # Interactions REC8 has been shown to interact with SMC3.

REC8 Meiotic recombination protein REC8 homolog is a protein that in humans is encoded by the REC8 gene.[1][2][3][4] Rec8 is a meiosis-specific component of the cohesin complex that binds sister chromatids in preparation for the two divisions of meiosis. Rec8 is sequentially removed from sister chromatids. It is removed from the arms of chromosomes in the first division - separating homologous chromosomes from each other. However, Rec8 is maintained at centromeres so that sister chromatids are kept joined until anaphase of meiosis II, at which point removal of remaining cohesin leads to the separation of sister chromatids. # Function This gene encodes a member of the kleisin family of SMC (structural maintenance of chromosome) protein partners. The protein localizes to the axial elements of chromosomes during meiosis in both oocytes and spermatocytes. REC8 protein appears to participate with other cohesins STAG3, SMC1ß and SMC3 in sister chromatid cohesion throughout the whole meiotic process in human oocytes.[5] In the mouse, the homologous protein is a key component of the meiotic cohesion complex, which regulates sister chromatid cohesion and recombination between homologous chromosomes. Multiple alternatively spliced variants, encoding the same protein, have been found for this gene.[4] Rec8 remains in complex with SMC proteins until anaphase, where it is degraded by Separase once the spindle assembly checkpoint is bypassed. Unlike the other Kleisin family member, Scc1, Rec8 must be phosphorylated prior to degradation. Prior to anaphase, Rec8 is protected from phosphorylation by Protein Phosphatase 2 (PP2A-B56) in mouse. PP2A is recruited to cohesin by Shugoshin 2 (Sgo2; SGOL2 in yeast). Bypass of the spindle assembly checkpoint activates Separase, which then degrades phosphorylated Rec8 and untethers Cohesin from sister chromatids, allowing for segregation of chromosomes. # Interactions REC8 has been shown to interact with SMC3.[3]

https://www.wikidoc.org/index.php/REC8

05d6c2e8a08fd2a8efcbed36b52e1e3f4c83bdc4

wikidoc

RELA

RELA Transcription factor p65 also known as nuclear factor NF-kappa-B p65 subunit is a protein that in humans is encoded by the RELA gene. RELA, also known as p65, is a REL-associated protein involved in NF-κB heterodimer formation, nuclear translocation and activation. NF-κB is an essential transcription factor complex involved in all types of cellular processes, including cellular metabolism, chemotaxis, etc. Phosphorylation and acetylation of RELA are crucial post-translational modifications required for NF-κB activation. RELA has also been shown to modulate immune responses, and activation of RELA is positively associated with multiple types of cancer. # Gene and expression RELA, or v-rel avian reticuloendotheliosis viral oncogene homolog A, is also known as p65 or NFKB3. It is located on chromosome 11 q13, and its nucleotide sequence is 1473 nucleotide long. RELA protein has four isoforms, the longest and the predominant one being 551 amino acids. RELA is expressed alongside p50 in various cell types, including epithelial/endothelial cells and neuronal tissues. # Structure RELA is one member of the NF-κB family, one of the most essential transcription factors under intensive study. Seven proteins encoded by five genes are involved in the NF-κB complex, namely p105, p100, p50, p52, RELA, c-REL and RELB. Like other proteins in this complex, RELA contains a N-terminal REL-homology domain (RHD), and also a C-terminal transactivation domain (TAD). RHD is involved in DNA binding, dimerization and NF-κB/REL inhibitor interaction. On the other hand, TAD is responsible for interacting with the basal transcription complex including many coactivators of transcription such as TBP, TFIIB and CREB-CBP. RELA and p50 is the mostly commonly found heterodimer complex among NF-κB homodimers and heterodimers, and is the functional component participating in nuclear translocation and activation of NF-κB. ## Phosphorylation Phosphorylation of RELA plays a key role in regulating NF-κB activation and function. Subsequent to NF-κB nuclear translocation, RELA undergoes site-specific post-translational modifications to further enhance the NF-κB function as a transcription factor. RELA can either be phosphorylated in the RHD region or the TAD region, attracting different interaction partners. Triggered by lipopolysaccharide (LPS), protein kinase A (PKA) specifically phosphorylates serine 276 in the RHD domain in the cytoplasm, controlling NF-κB DNA-binding and oligomerization. On the other hand, mitogen and stress-activated kinase 1 (MSK1) are also able to phosphorylate RELA at residue 276 under TNFα induction in the nucleus, increasing NF-κB response at the transcriptional level. Phosphorylation of serine 311 by protein kinase C zeta type (PKCζ) serves the same purpose. Two residues in the TAD region are targeted by phosphorylation. After IL-1or TNFα stimulation, serine 529 is phosphorylated by casein kinase II (CKII), while serine 536 is phosphorylated by IκB kinases (IKKs). In response to DNA damage, ribosomal subunit kinase-1 (RSK1) also has the ability to phosphorylate RELA at serine 536 in a p53-dependent manner. A couple of other kinases are also able to phosphorylate RELA at different conditions, including glycogen-synthase kinase-3β (GSK3β), AKT/phosphatidylinositol 3-kinase (PI3K) and NF-κB activating kinase (NAK, i.e. TANK-binding kinase-1 (TBK1) and TRAF2-associated kinase (T2K)). The fact that RELA can be modified by a collection of kinases via phosphorylation at different sites/regions within the protein under different stimulations might suggest a synergistic effect of these modifications. Phosphorylation at these sites enhances NF-κB transcriptional response via tightened binding to transcription coactivators. For example, CBP and p300 binding to RELA are enhanced when serine 276 or 311 is phosphorylated. Status of several phosphorylation sites determines RELA stability mediated by the ubiquitin-mediated proteolysis. Cell-type-specific phosphorylation is also observed for RELA. Multiple-site phosphorylation is common in endothelial cells, and different cell types may contain different stimuli, leading to targeted phosphorylation of RELA by different kinases. For instance, IKK2 is found to be mainly responsible for phosphorylating serine 536 in monocytes and macrophages, or in CD40 receptor binding in hepatic stellate cells. IKK1 functions as the major kinase phosphorylating serine 536 under different stimuli, such as the ligand activation of the lymphotoxin-β receptor (LTβR). ## Acetylation In vivo studies revealed that RELA is also under acetylation modification in the nucleus, which is just as important as phosphorylation as a post-translational modification of proteins. Lysines 218, 221 and 310 are acetylation targets within RELA, and response to actylation is site-specific. For instance, lysine 221 acetylation facilitates RELA dissociation from IκBα and enhances its DNA-binding affinity. Lysine 310 acetylation is indispensable for the full transcriptional activity of RELA, but does not affect its DNA-binding ability. Hypothesis about RELA acetylation suggests acetylation aids its subsequent recognition by transcriptional co-activators with bromodomains, which are specialized in recognizing acetylated lysine residues. Lysine 122 and 123 acetylation are found to be negatively correlated with RELA transcriptional activation. Unknown mechanisms mediate the acetylation of RELA possibly using p300/CBP and p300/CBP factor associated coactivators under TNFα or phorbol myristate acetate (PMF) stimulation both in vivo and in vitro. RELA is also under the control of deactylation via HDAC, and HDAC3 is the mediator of this process both in vivo and in vitro. ## Methylation Methylation of lysine 218 and 221 together or lysine 37 alone in the RHD domain of RELA can lead to increased response to cytokines such as IL-1 in mammalian cell culture. # Interactions As the prototypical heterodimer complex member of the NF-κB, together with p50, RELA/p65 interacts with various proteins in both the cytoplasm and in the nucleus during the process of classical NF-κB activation and nuclear translocation. In the inactive state, RELA/p50 complex is mainly sequestered by IκBα in the cytosol. TNFα, LPS and other factors serve as activation inducers, followed by phosphorylation at residue 32 and 36 of IκBα, leading to rapid degradation of IκBα via the ubiquitin-proteasomal system and subsequent release of RELA/p50 complex. RELA nuclear localization signal used to be sequestered by IκBα is now exposed, and rapid translocation of the NF-κB occurs. In parallel, there is a non-classical NF-κB activation pathway involving the proteolytic cleavage of p100 into p52 instead of p50. This process does not require RELA, hence will not be discussed in detail here. After NF-κB nuclear localization due to TNFα stimulation, p50/RELA heterodimer will function as a transcription factor and bind to a variety of genes involved in all kinds of biological processes, such as leukocyte activation/chemotaxis, negative regulation of TNFIKK pathway, cellular metabolism, antigen processing, just to name a few . Phosphorylation of RELA at different residues also enables its interaction with CDKs and P-TEFb. Phosphorylation at serine 276 in RELA allows its interaction with P-TEFb containing CDK9 and cyclin T1 subunits, and phospho-ser276 RELA-P-TEFb complex is necessary for IL-8 and Gro-β activation. Another mechanism is involved in the activation of genes preloaded with Pol II in a RELA serine 276 phosphorylation independent manner. RELA has been shown to interact with: - APBA2, - AHR, - ASCC3, - BRCA1, - BTRC, - c-Fos, - c-Jun, - C22orf25, - CDK9, - CEBPB, - CEBPE, - CREBBP, - CSNK2A1, - CSNK2A2, - DHX9, - EP300, - ETHE1, - FUS, - GCN5, - HDAC1, - HDAC2, - HDAC3, - ING4, - IκBα, - KLF5, - MDM2, - MEN1, - MSK1, - MTPN, - NCF1, - NFKB1, - NFKB2, - NFKBIB, - NFKBIE, - NR3C1, - NCOR2, - PARP1, - PDLIM2, - PIAS3, - PIM1, - PIN1, - PKA, - POU2F1, - PPARG, - PPP1R13L, - PRKCZ, - REL, - RFC1, - RNF25, - SIRT1, - SOCS1, - SP1, - STAT3, - TAF4B, - TBP, - TP53, and - TRIB3. # Role in immune system Gene knockout of NF-κB genes via homologous recombination in mice showed the role of these components in innate and adaptive immune responses. RELA knockout mice is embryonic lethal due to liver apoptosis. Lymphocyte activation failure is also observed, suggesting that RELA is indispensable in the proper development of the immune system. In comparison, deletion of other REL-related genes will not cause embryonic development failure, though different levels of defects are also noted. The fact that cytokines such as TNFα and IL-1 can stimulate the activation of RELA also supports its participation in immune response. In general, RELA participates in adaptive immunity and responses to invading pathogens via NF-κB activation. Mice without individual NF-κB proteins are deficient in B- and T-cell activation and proliferation, cytoline production and isotype switching. Mutations in RELA is found responsible for inflammatory bowel disease as well. # Cancer NF-κB/RELA activation has been found to be correlated with cancer development, suggesting the potential of RELA as a cancer biomarker. Specific modification patterns of RELA have also been observed in many cancer types. ## Prostate RELA may have a potential role as biomarker for prostate cancer progression and metastases, as suggested by the association found between RELA nuclear localization and prostate cancer aggressiveness and biochemical recurrence. ## Thyroid Strong correlation between nuclear localization of RELA and clinicopathological parameters for papillary thyroid carcinoma (PTC), suggesting the role of NF-κB activation in tumor growth and aggressiveness in PTC. Other than usage as an biomarker, serine 536 phosphorylation in RELA is also correlated with nuclear translocation and the expression of some transactivating genes such as COX-2, IL-8 and GST-pi in follicular thyroid carcinomas via morphoproteomic analysis. ## Leukemia Mutations in the transactivation domain of RELA can lead to decrease in transactivating ability and this mutation can be found in lymphoid neoplasia. ## Head and Neck Nuclear localization of NF-κB/RELA is positively correlated with tumor micrometastases into lymph and blood and negatively correlated with patient survival outcome in patients with head and neck squamous cell carcinoma (HNSCC). This suggests a role of NF-κB/RELA as a possible target for targeted-therapy. ## Breast There is both a physical and a functional association between RELA and aryl hydrocarbon receptor (AhR), and the subsequent activation of c-myc gene transcription in breast cancer cells. Another paper reported interactions between estrogen receptor (ER) and NF-κB members, including p50 and RELA. It is shown that ERα interacts with both p50 and RELA in vitro and in vivo, and RELA antibody can reduce ERα:ERE complex formation. The paper claims a mutual repression between ER and NF-κB.

RELA Transcription factor p65 also known as nuclear factor NF-kappa-B p65 subunit is a protein that in humans is encoded by the RELA gene.[1] RELA, also known as p65, is a REL-associated protein involved in NF-κB heterodimer formation, nuclear translocation and activation. NF-κB is an essential transcription factor complex involved in all types of cellular processes, including cellular metabolism, chemotaxis, etc. Phosphorylation and acetylation of RELA are crucial post-translational modifications required for NF-κB activation. RELA has also been shown to modulate immune responses, and activation of RELA is positively associated with multiple types of cancer. # Gene and expression RELA, or v-rel avian reticuloendotheliosis viral oncogene homolog A, is also known as p65 or NFKB3.[2] It is located on chromosome 11 q13, and its nucleotide sequence is 1473 nucleotide long.[3] RELA protein has four isoforms, the longest and the predominant one being 551 amino acids. RELA is expressed alongside p50 in various cell types, including epithelial/endothelial cells and neuronal tissues.[4] # Structure RELA is one member of the NF-κB family, one of the most essential transcription factors under intensive study. Seven proteins encoded by five genes are involved in the NF-κB complex, namely p105, p100, p50, p52, RELA, c-REL and RELB.[5] Like other proteins in this complex, RELA contains a N-terminal REL-homology domain (RHD), and also a C-terminal transactivation domain (TAD). RHD is involved in DNA binding, dimerization and NF-κB/REL inhibitor interaction. On the other hand, TAD is responsible for interacting with the basal transcription complex including many coactivators of transcription such as TBP, TFIIB and CREB-CBP.[5] RELA and p50 is the mostly commonly found heterodimer complex among NF-κB homodimers and heterodimers, and is the functional component participating in nuclear translocation and activation of NF-κB. ## Phosphorylation Phosphorylation of RELA plays a key role in regulating NF-κB activation and function. Subsequent to NF-κB nuclear translocation, RELA undergoes site-specific post-translational modifications to further enhance the NF-κB function as a transcription factor. RELA can either be phosphorylated in the RHD region or the TAD region, attracting different interaction partners. Triggered by lipopolysaccharide (LPS), protein kinase A (PKA) specifically phosphorylates serine 276 in the RHD domain in the cytoplasm, controlling NF-κB DNA-binding and oligomerization.[6] On the other hand, mitogen and stress-activated kinase 1 (MSK1) are also able to phosphorylate RELA at residue 276 under TNFα induction in the nucleus, increasing NF-κB response at the transcriptional level.[7] Phosphorylation of serine 311 by protein kinase C zeta type (PKCζ) serves the same purpose.[8] Two residues in the TAD region are targeted by phosphorylation. After IL-1or TNFα stimulation, serine 529 is phosphorylated by casein kinase II (CKII),[9] while serine 536 is phosphorylated by IκB kinases (IKKs). In response to DNA damage, ribosomal subunit kinase-1 (RSK1) also has the ability to phosphorylate RELA at serine 536 in a p53-dependent manner.[10] A couple of other kinases are also able to phosphorylate RELA at different conditions, including glycogen-synthase kinase-3β (GSK3β), AKT/phosphatidylinositol 3-kinase (PI3K) and NF-κB activating kinase (NAK, i.e. TANK-binding kinase-1 (TBK1) and TRAF2-associated kinase (T2K)).[5] The fact that RELA can be modified by a collection of kinases via phosphorylation at different sites/regions within the protein under different stimulations might suggest a synergistic effect of these modifications. Phosphorylation at these sites enhances NF-κB transcriptional response via tightened binding to transcription coactivators. For example, CBP and p300 binding to RELA are enhanced when serine 276 or 311 is phosphorylated.[5] Status of several phosphorylation sites determines RELA stability mediated by the ubiquitin-mediated proteolysis.[11][12][13] Cell-type-specific phosphorylation is also observed for RELA. Multiple-site phosphorylation is common in endothelial cells, and different cell types may contain different stimuli, leading to targeted phosphorylation of RELA by different kinases. For instance, IKK2 is found to be mainly responsible for phosphorylating serine 536 in monocytes and macrophages, or in CD40 receptor binding in hepatic stellate cells.[4] IKK1 functions as the major kinase phosphorylating serine 536 under different stimuli, such as the ligand activation of the lymphotoxin-β receptor (LTβR).[4] ## Acetylation In vivo studies revealed that RELA is also under acetylation modification in the nucleus, which is just as important as phosphorylation as a post-translational modification of proteins. Lysines 218, 221 and 310 are acetylation targets within RELA, and response to actylation is site-specific.[5] For instance, lysine 221 acetylation facilitates RELA dissociation from IκBα and enhances its DNA-binding affinity. Lysine 310 acetylation is indispensable for the full transcriptional activity of RELA, but does not affect its DNA-binding ability. Hypothesis about RELA acetylation suggests acetylation aids its subsequent recognition by transcriptional co-activators with bromodomains, which are specialized in recognizing acetylated lysine residues.[5] Lysine 122 and 123 acetylation are found to be negatively correlated with RELA transcriptional activation. Unknown mechanisms mediate the acetylation of RELA possibly using p300/CBP and p300/CBP factor associated coactivators under TNFα or phorbol myristate acetate (PMF) stimulation both in vivo and in vitro.[5] RELA is also under the control of deactylation via HDAC, and HDAC3 is the mediator of this process both in vivo and in vitro.[4][5] ## Methylation Methylation of lysine 218 and 221 together or lysine 37 alone in the RHD domain of RELA can lead to increased response to cytokines such as IL-1 in mammalian cell culture.[14] # Interactions As the prototypical heterodimer complex member of the NF-κB, together with p50, RELA/p65 interacts with various proteins in both the cytoplasm and in the nucleus during the process of classical NF-κB activation and nuclear translocation. In the inactive state, RELA/p50 complex is mainly sequestered by IκBα in the cytosol. TNFα, LPS and other factors serve as activation inducers, followed by phosphorylation at residue 32 and 36 of IκBα, leading to rapid degradation of IκBα via the ubiquitin-proteasomal system and subsequent release of RELA/p50 complex.[5] RELA nuclear localization signal used to be sequestered by IκBα is now exposed, and rapid translocation of the NF-κB occurs. In parallel, there is a non-classical NF-κB activation pathway involving the proteolytic cleavage of p100 into p52 instead of p50. This process does not require RELA, hence will not be discussed in detail here.[5] After NF-κB nuclear localization due to TNFα stimulation, p50/RELA heterodimer will function as a transcription factor and bind to a variety of genes involved in all kinds of biological processes, such as leukocyte activation/chemotaxis, negative regulation of TNFIKK pathway, cellular metabolism, antigen processing, just to name a few .[15] Phosphorylation of RELA at different residues also enables its interaction with CDKs and P-TEFb. Phosphorylation at serine 276 in RELA allows its interaction with P-TEFb containing CDK9 and cyclin T1 subunits, and phospho-ser276 RELA-P-TEFb complex is necessary for IL-8 and Gro-β activation.[15] Another mechanism is involved in the activation of genes preloaded with Pol II in a RELA serine 276 phosphorylation independent manner. RELA has been shown to interact with: - APBA2,[16] - AHR,[17][18] - ASCC3,[19] - BRCA1,[20] - BTRC,[21] - c-Fos,[22] - c-Jun,[22] - C22orf25,[23] - CDK9,[24] - CEBPB,[25][26] - CEBPE,[27] - CREBBP,[28][29][30][31][32][33] - CSNK2A1,[34] - CSNK2A2,[34] - DHX9,[35] - EP300,[32][36] - ETHE1,[37] - FUS,[38] - GCN5,[39] - HDAC1,[29][36][40] - HDAC2,[36][41] - HDAC3,[42] - ING4,[43] - IκBα,[21][36][42][44][45][46][47] - KLF5,[48] - MDM2,[49] - MEN1,[50] - MSK1,[7] - MTPN,[51] - NCF1,[52] - NFKB1,[53][54] - NFKB2,[53][55] - NFKBIB,[56][57] - NFKBIE,[58] - NR3C1,[59][60][61] - NCOR2,[62][63] - PARP1,[64] - PDLIM2,[65] - PIAS3,[28] - PIM1,[13] - PIN1,[11] - PKA,[66] - POU2F1,[67] - PPARG,[68] - PPP1R13L,[69][70] - PRKCZ,[71] - REL,[45][53][72] - RFC1,[73] - RNF25,[74] - SIRT1,[75] - SOCS1,[11][76][77] - SP1,[78][79] - STAT3,[80][81] - TAF4B,[82] - TBP,[83][84] - TP53,[81] and - TRIB3.[85] # Role in immune system Gene knockout of NF-κB genes via homologous recombination in mice showed the role of these components in innate and adaptive immune responses. RELA knockout mice is embryonic lethal due to liver apoptosis.[4] Lymphocyte activation failure is also observed, suggesting that RELA is indispensable in the proper development of the immune system. In comparison, deletion of other REL-related genes will not cause embryonic development failure, though different levels of defects are also noted.[4] The fact that cytokines such as TNFα and IL-1 can stimulate the activation of RELA also supports its participation in immune response. In general, RELA participates in adaptive immunity and responses to invading pathogens via NF-κB activation. Mice without individual NF-κB proteins are deficient in B- and T-cell activation and proliferation, cytoline production and isotype switching.[4] Mutations in RELA is found responsible for inflammatory bowel disease as well.[4] # Cancer NF-κB/RELA activation has been found to be correlated with cancer development, suggesting the potential of RELA as a cancer biomarker. Specific modification patterns of RELA have also been observed in many cancer types. ## Prostate RELA may have a potential role as biomarker for prostate cancer progression and metastases, as suggested by the association found between RELA nuclear localization and prostate cancer aggressiveness and biochemical recurrence.[86] ## Thyroid Strong correlation between nuclear localization of RELA and clinicopathological parameters for papillary thyroid carcinoma (PTC), suggesting the role of NF-κB activation in tumor growth and aggressiveness in PTC.[87] Other than usage as an biomarker, serine 536 phosphorylation in RELA is also correlated with nuclear translocation and the expression of some transactivating genes such as COX-2, IL-8 and GST-pi in follicular thyroid carcinomas via morphoproteomic analysis.[88] ## Leukemia Mutations in the transactivation domain of RELA can lead to decrease in transactivating ability and this mutation can be found in lymphoid neoplasia.[89] ## Head and Neck Nuclear localization of NF-κB/RELA is positively correlated with tumor micrometastases into lymph and blood and negatively correlated with patient survival outcome in patients with head and neck squamous cell carcinoma (HNSCC).[90] This suggests a role of NF-κB/RELA as a possible target for targeted-therapy. ## Breast There is both a physical and a functional association between RELA and aryl hydrocarbon receptor (AhR), and the subsequent activation of c-myc gene transcription in breast cancer cells.[17] Another paper reported interactions between estrogen receptor (ER) and NF-κB members, including p50 and RELA. It is shown that ERα interacts with both p50 and RELA in vitro and in vivo, and RELA antibody can reduce ERα:ERE complex formation. The paper claims a mutual repression between ER and NF-κB.[91]

https://www.wikidoc.org/index.php/RELA

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wikidoc

REV1

REV1 DNA repair protein REV1 is a protein that in humans is encoded by the REV1 gene. This gene encodes a protein with similarity to the S. cerevisiae mutagenesis protein Rev1. The Rev1 proteins contain a BRCT domain, which is important in protein-protein interactions. A suggested role for the human Rev1-like protein is as a scaffold that recruits DNA polymerases involved in translesion synthesis (TLS) of damaged DNA. Two alternatively spliced transcript variants that encode different proteins have been found. Rev1 is a Y family DNA polymerase; it is sometimes referred to as a deoxycytidyl transferase because it only inserts deoxycytidine (dC) across from lesions. Whether G, A, T, C, or an abasic site, Rev1 will always add a C. Rev1 has the ability to always add a C, because it uses an arginine as a template which complements well with C. Yet it is believed that Rev1 rarely uses its polymerase activity; rather it is thought that Rev1's primary role is as a protein landing pad, whereby it helps direct the recruitment of TLS proteins, especially Pol ζ (Rev3/Rev7). # Interactions REV1 has been shown to interact with MAD2L2. It is believed that Rev1 may interact with PCNA, once ubiquitylated due to a lesion, and help recruit Pol ζ (Rev3/Rev7) a B family polymerase involved in TLS.

REV1 DNA repair protein REV1 is a protein that in humans is encoded by the REV1 gene.[1][2] This gene encodes a protein with similarity to the S. cerevisiae mutagenesis protein Rev1. The Rev1 proteins contain a BRCT domain, which is important in protein-protein interactions. A suggested role for the human Rev1-like protein is as a scaffold that recruits DNA polymerases involved in translesion synthesis (TLS) of damaged DNA. Two alternatively spliced transcript variants that encode different proteins have been found.[2] Rev1 is a Y family DNA polymerase; it is sometimes referred to as a deoxycytidyl transferase because it only inserts deoxycytidine (dC) across from lesions. Whether G, A, T, C, or an abasic site, Rev1 will always add a C. Rev1 has the ability to always add a C, because it uses an arginine as a template which complements well with C.[3] Yet it is believed[by whom?] that Rev1 rarely uses its polymerase activity; rather it is thought that Rev1's primary role is as a protein landing pad, whereby it helps direct the recruitment of TLS proteins, especially Pol ζ (Rev3/Rev7). # Interactions REV1 has been shown to interact with MAD2L2.[4] It is believed that Rev1 may interact with PCNA, once ubiquitylated due to a lesion, and help recruit Pol ζ (Rev3/Rev7) a B family polymerase involved in TLS.

https://www.wikidoc.org/index.php/REV1

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wikidoc

RFC2

RFC2 Replication factor C subunit 2 is a protein that in humans is encoded by the RFC2 gene. # Function The elongation of primed DNA templates by DNA polymerase delta and epsilon requires the action of the accessory proteins, proliferating cell nuclear antigen (PCNA) and replication factor C (RFC). RFC, also called activator 1, is a protein complex consisting of five distinct subunits of 145, 40, 38, 37, and 36.5 kD. This gene encodes the 40 kD subunit, which has been shown to be responsible for binding ATP. Deletion of this gene has been associated with Williams syndrome. Alternatively spliced transcript variants encoding distinct isoforms have been described. # Interactions RFC2 has been shown to interact with BRD4, CHTF18, PCNA, RFC4 and RFC5.

RFC2 Replication factor C subunit 2 is a protein that in humans is encoded by the RFC2 gene.[1][2][3] # Function The elongation of primed DNA templates by DNA polymerase delta and epsilon requires the action of the accessory proteins, proliferating cell nuclear antigen (PCNA) and replication factor C (RFC). RFC, also called activator 1, is a protein complex consisting of five distinct subunits of 145, 40, 38, 37, and 36.5 kD. This gene encodes the 40 kD subunit, which has been shown to be responsible for binding ATP. Deletion of this gene has been associated with Williams syndrome. Alternatively spliced transcript variants encoding distinct isoforms have been described.[3] # Interactions RFC2 has been shown to interact with BRD4,[4] CHTF18,[5][6] PCNA,[7][8][9] RFC4[7][10] and RFC5.[7][10]

https://www.wikidoc.org/index.php/RFC2

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wikidoc

RFX1

RFX1 MHC class II regulatory factor RFX1 is a protein that, in humans, is encoded by the RFX1 gene located on the short arm of chromosome 19. # Structure The RFX1 gene is a member of the regulatory factor X (RFX) gene family, which encodes transcription factors that contain five conserved domains including a highly conserved, centrally located, winged helix DNA binding domain as well as a dimerization domain located in the C-terminal region of the sequence. Apart from the five conserved domains, the RFX proteins diverge significantly. The DNA binding and dimerization domains of the RFX family proteins show no similarities to the other domains with the same functions in other proteins. # Species distribution The RFX protein family is conserved in S. pombe, S. cerevisiae, C. elegans, mice and humans. There are seven known RFX proteins in humans, five in mice, and one in C. elegans as well as one in each of the two species of yeast. # Function The protein encoded by this gene is structurally related to regulatory factors X2, X3, X4, and X5. It is a transcriptional activator that can bind DNA as a monomer or as a heterodimer with RFX family members X2, X3, and X5, but not with X4. This protein binds to the Xboxes of MHC class II genes and is essential for their expression. Also, it can bind to an inverted repeat that is required for expression of hepatitis B virus genes. The RFX proteins were originally cloned and characterized due to their high affinity for a cis-acting promoter sequence, called the Xbox, found in all MHC class II genes. Levels of mRNA encoding this protein as well as RFX2 and RFX3 are found to be consistently elevated in the testis and are variable in other tissues throughout the body. RFX1 contains a C-terminal sequence with no apparent homology to other RFX proteins. This C-terminal tail contains an acidic region that is thought to aid in crossing the nuclear membrane. Two major functions are hypothesized to this exist for this domain: a contribution to the nuclear localization signal (NLS) as well as the contradictory down-regulation of DNA binding as well as nuclear association. These two functions were originally identified through sequence mutations and translational fusions with gfp (green fluorescent protein) and remain to be confirmed. # Interactions RFX1 has been shown to interact with Abl gene.

RFX1 MHC class II regulatory factor RFX1 is a protein that, in humans, is encoded by the RFX1 gene located on the short arm of chromosome 19.[1][2][3] # Structure The RFX1 gene is a member of the regulatory factor X (RFX) gene family, which encodes transcription factors that contain five conserved domains including a highly conserved, centrally located, winged helix DNA binding domain as well as a dimerization domain located in the C-terminal region of the sequence.[4] Apart from the five conserved domains, the RFX proteins diverge significantly. The DNA binding and dimerization domains of the RFX family proteins show no similarities to the other domains with the same functions in other proteins.[2] # Species distribution The RFX protein family is conserved in S. pombe, S. cerevisiae, C. elegans, mice and humans.[5] There are seven known RFX proteins in humans, five in mice, and one in C. elegans as well as one in each of the two species of yeast.[5][6] # Function The protein encoded by this gene is structurally related to regulatory factors X2, X3, X4, and X5. It is a transcriptional activator that can bind DNA as a monomer or as a heterodimer with RFX family members X2, X3, and X5, but not with X4. This protein binds to the Xboxes of MHC class II genes and is essential for their expression. Also, it can bind to an inverted repeat that is required for expression of hepatitis B virus genes.[3] The RFX proteins were originally cloned and characterized due to their high affinity for a cis-acting promoter sequence, called the Xbox, found in all MHC class II genes.[2] Levels of mRNA encoding this protein as well as RFX2 and RFX3 are found to be consistently elevated in the testis and are variable in other tissues throughout the body.[2] RFX1 contains a C-terminal sequence with no apparent homology to other RFX proteins. This C-terminal tail contains an acidic region that is thought to aid in crossing the nuclear membrane. Two major functions are hypothesized to this exist for this domain: a contribution to the nuclear localization signal (NLS) as well as the contradictory down-regulation of DNA binding as well as nuclear association. These two functions were originally identified through sequence mutations and translational fusions with gfp (green fluorescent protein) and remain to be confirmed.[7] # Interactions RFX1 has been shown to interact with Abl gene.[5]

https://www.wikidoc.org/index.php/RFX1

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wikidoc

RFX6

RFX6 Regulatory factor X, 6 also known as DNA-binding protein RFX6 is a protein that in humans is encoded by the RFX6 gene. # Function The nuclear protein encoded by this gene is a member of the regulatory factor X (RFX) family of transcription factors. Studies in mice suggest that this gene is specifically required for the differentiation of islet cells for the production of insulin, but not for the differentiation of pancreatic polypeptide-producing cells. It regulates the transcription factors involved in beta-cell maturation and function, thus, restricting the expression of the beta-cell differentiation and specification genes. # Clinical significance Mutations in this gene are associated with Mitchell-Riley syndrome, which is characterized by neonatal diabetes with pancreatic hypoplasia, duodenal and jejunal atresia, and gall bladder agenesis.

RFX6 Regulatory factor X, 6 also known as DNA-binding protein RFX6 is a protein that in humans is encoded by the RFX6 gene.[1] # Function The nuclear protein encoded by this gene is a member of the regulatory factor X (RFX) family of transcription factors. Studies in mice suggest that this gene is specifically required for the differentiation of islet cells for the production of insulin, but not for the differentiation of pancreatic polypeptide-producing cells. It regulates the transcription factors involved in beta-cell maturation and function, thus, restricting the expression of the beta-cell differentiation and specification genes. # Clinical significance Mutations in this gene are associated with Mitchell-Riley syndrome, which is characterized by neonatal diabetes with pancreatic hypoplasia, duodenal and jejunal atresia, and gall bladder agenesis.[1]

https://www.wikidoc.org/index.php/RFX6

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wikidoc

RGS2

RGS2 Regulator of G-protein signaling 2 is a protein that in humans is encoded by the RGS2 gene. It is part of a larger family of RGS proteins that control signalling through G-protein coupled receptors (GPCR). # Function RGS2 is thought to have protective effects against myocardial hypertrophy as well as atrial arrhythmias. Increased stimulation of Gs coupled β1-adrenergic receptors and Gq coupled α1-adrenergic receptors in the heart can result in cardiac hypertrophy. In the case of Gq protein coupled receptor (GqPCR) mediated hypertrophy, Gαq will activate the intracellular affectors phospholipase Cβ and rho guanine nucleotide exchange factor to stimulate cell processes which lead to cardiomyocyte hypertrophy. RGS2 functions as a GTPase Activating Protein (GAP) which acts to increase the natural GTPase activity of the Gα subunit. By increasing the GTPase activity of the Gα subunit, RGS2 promotes GTP hydrolysis back to GDP, thus converting the Gα subunit back to its inactive state and reducing its signalling ability. Both GsPCR and GqPCR activation can contribute to cardiac hypertrophy via activation of MAP Kinases as well. RGS2 has been shown to decrease phosphorylation of those MAP kinases and therefore decrease their activation in response to Gαs signalling. In the case of GsPCR mediated hypertrophy, the main mechanism by which signalling contributes to hypertrophy is through the Gβγ subunit; Gαs signalling by itself is not sufficient. Nevertheless, RGS2 has been shown to inhibit Gs mediated hypertrophy. The mechanism of how RGS2 regulates increased Gβγ signalling is not well understood, apart from the fact that it is unrelated to RGS2’s GAP function. A deficiency in RGS2 has been linked with increased cardiac hypertrophy in mice. RGS2 deficient hearts appear normal until confronted with an increased workload, to which they respond readily with increased Gαq signalling and hypertrophy. Gαs subunits increase adenyl cyclase activity, which in turn leads to cAMP accumulation in the myocyte nucleus to trigger hypertrophy. RGS2 regulates the effects of increased Gαs signalling through its GAP function. Stimulation of GsPCRs not only leads to hypertrophy but it has also been shown to selectively induce higher expression levels of RGS2 which in turn, protects against hypertrophy, providing a mechanism for maintaining homeostatic conditions. There has also been some evidence of a role of RGS2 in atrial arrhythmias where RGS2 deficient mice exhibited prolonged and greater susceptibility to electrically induced atrial fibrillation. This was attributed to a decrease in RGS2’s inhibitory effects on Gq coupled M3 muscarinic receptor signalling, resulting in increased Gαq activity. The M3 muscarinic receptor normally activates delayed rectifier potassium channels in the atria, thus increased Gαq activity is thought to result in an altered potassium flux, a decreased refractory period, increased chance of current re-entry and inappropriate contraction. # Interactions RGS2 has been shown to interact with PRKG1 and ADCY5.

RGS2 Regulator of G-protein signaling 2 is a protein that in humans is encoded by the RGS2 gene.[1][2] It is part of a larger family of RGS proteins that control signalling through G-protein coupled receptors (GPCR). # Function RGS2 is thought to have protective effects against myocardial hypertrophy as well as atrial arrhythmias.[3][4] Increased stimulation of Gs coupled β1-adrenergic receptors and Gq coupled α1-adrenergic receptors in the heart can result in cardiac hypertrophy.[3] In the case of Gq protein coupled receptor (GqPCR) mediated hypertrophy, Gαq will activate the intracellular affectors phospholipase Cβ and rho guanine nucleotide exchange factor to stimulate cell processes which lead to cardiomyocyte hypertrophy.[3][5] RGS2 functions as a GTPase Activating Protein (GAP) which acts to increase the natural GTPase activity of the Gα subunit.[3][5] By increasing the GTPase activity of the Gα subunit, RGS2 promotes GTP hydrolysis back to GDP, thus converting the Gα subunit back to its inactive state and reducing its signalling ability.[5] Both GsPCR and GqPCR activation can contribute to cardiac hypertrophy via activation of MAP Kinases as well. RGS2 has been shown to decrease phosphorylation of those MAP kinases and therefore decrease their activation in response to Gαs signalling.[3] In the case of GsPCR mediated hypertrophy, the main mechanism by which signalling contributes to hypertrophy is through the Gβγ subunit; Gαs signalling by itself is not sufficient.[6] Nevertheless, RGS2 has been shown to inhibit Gs mediated hypertrophy. The mechanism of how RGS2 regulates increased Gβγ signalling is not well understood, apart from the fact that it is unrelated to RGS2’s GAP function.[6] A deficiency in RGS2 has been linked with increased cardiac hypertrophy in mice.[3] RGS2 deficient hearts appear normal until confronted with an increased workload, to which they respond readily with increased Gαq signalling and hypertrophy.[3][6] Gαs subunits increase adenyl cyclase activity, which in turn leads to cAMP accumulation in the myocyte nucleus to trigger hypertrophy. RGS2 regulates the effects of increased Gαs signalling through its GAP function.[3] Stimulation of GsPCRs not only leads to hypertrophy but it has also been shown to selectively induce higher expression levels of RGS2 which in turn, protects against hypertrophy, providing a mechanism for maintaining homeostatic conditions.[3] There has also been some evidence of a role of RGS2 in atrial arrhythmias where RGS2 deficient mice exhibited prolonged and greater susceptibility to electrically induced atrial fibrillation.[4] This was attributed to a decrease in RGS2’s inhibitory effects on Gq coupled M3 muscarinic receptor signalling, resulting in increased Gαq activity.[4] The M3 muscarinic receptor normally activates delayed rectifier potassium channels in the atria, thus increased Gαq activity is thought to result in an altered potassium flux, a decreased refractory period, increased chance of current re-entry and inappropriate contraction.[4] [7] [8] # Interactions RGS2 has been shown to interact with PRKG1[9] and ADCY5.[10]

https://www.wikidoc.org/index.php/RGS2

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wikidoc

RGS4

RGS4 Regulator of G protein signaling 4 also known as RGP4 is a protein that in humans is encoded by the RGS4 gene. RGP4 regulates G protein signaling. # Function Regulator of G protein signalling (RGS) family members are regulatory molecules that act as GTPase activating proteins (GAPs) for G alpha subunits of heterotrimeric G proteins. RGS proteins are able to deactivate G protein subunits of the Gi alpha, Go alpha and Gq alpha subtypes. They drive G proteins into their inactive GDP-bound forms. Regulator of G protein signaling 4 belongs to this family. All RGS proteins share a conserved 120-amino acid sequence termed the RGS domain which conveys GAP activity. Regulator of G protein signaling 4 protein is 37% identical to RGS1 and 97% identical to rat Rgs4. This protein negatively regulates signaling upstream or at the level of the heterotrimeric G protein and is localized in the cytoplasm. # Clinical significance A number of studies associate the RGS4 gene with schizophrenia, while some fail to detect an association. RGS4 is also of interest as one of the three main RGS proteins (along with RGS9 and RGS17) involved in terminating signalling by the mu opioid receptor, and may be important in the development of tolerance to opioid drugs. # Inhibitors - cyclic peptides - CCG-4986 # Interactions RGS4 has been shown to interact with: - COPB2, - ERBB3, and - GNAQ.

RGS4 Regulator of G protein signaling 4 also known as RGP4 is a protein that in humans is encoded by the RGS4 gene. RGP4 regulates G protein signaling.[1] # Function Regulator of G protein signalling (RGS) family members are regulatory molecules that act as GTPase activating proteins (GAPs) for G alpha subunits of heterotrimeric G proteins.[2] RGS proteins are able to deactivate G protein subunits of the Gi alpha, Go alpha and Gq alpha subtypes. They drive G proteins into their inactive GDP-bound forms. Regulator of G protein signaling 4 belongs to this family. All RGS proteins share a conserved 120-amino acid sequence termed the RGS domain which conveys GAP activity.[3] Regulator of G protein signaling 4 protein is 37% identical to RGS1 and 97% identical to rat Rgs4. This protein negatively regulates signaling upstream or at the level of the heterotrimeric G protein and is localized in the cytoplasm.[1] # Clinical significance A number of studies associate the RGS4 gene with schizophrenia,[4][5][6][7] while some fail to detect an association.[8] RGS4 is also of interest as one of the three main RGS proteins (along with RGS9 and RGS17) involved in terminating signalling by the mu opioid receptor,[9] and may be important in the development of tolerance to opioid drugs.[10][11][12][13][14] # Inhibitors - cyclic peptides[15] - CCG-4986[16] # Interactions RGS4 has been shown to interact with: - COPB2,[17] - ERBB3,[18] and - GNAQ.[19][20]

https://www.wikidoc.org/index.php/RGS4

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wikidoc

RGS5

RGS5 Regulator of G-protein signaling 5 is a protein that in humans is encoded by the RGS5 gene. The regulator of G protein signaling (RGS) proteins are signal transduction molecules that have structural homology to SST2 of Saccharomyces cerevisiae and EGL-10 of Caenorhabditis elegans. Multiple genes homologous to SST2 are present in higher eukaryotes. RGS proteins are involved in the regulation of heterotrimeric G proteins by acting as GTPase activators. # Interactions RGS5 has been shown to interact with GNAO1, GNAI2 and GNAI3.

RGS5 Regulator of G-protein signaling 5 is a protein that in humans is encoded by the RGS5 gene.[1][2] The regulator of G protein signaling (RGS) proteins are signal transduction molecules that have structural homology to SST2 of Saccharomyces cerevisiae and EGL-10 of Caenorhabditis elegans. Multiple genes homologous to SST2 are present in higher eukaryotes. RGS proteins are involved in the regulation of heterotrimeric G proteins by acting as GTPase activators.[supplied by OMIM][2] # Interactions RGS5 has been shown to interact with GNAO1,[3][4] GNAI2[3][4] and GNAI3.[3][4]

https://www.wikidoc.org/index.php/RGS5

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wikidoc

RGS9

RGS9 Regulator of G-protein signalling 9, also known as RGS9, is a human gene, which codes for a protein involved in regulation of signal transduction inside cells. Members of the RGS family, such as RGS9, are signaling proteins that suppress the activity of G proteins by promoting their deactivation. There are two splice isoforms of RGS9 with quite different properties and patterns of expression. RGS9-1 is mainly found in the eye and is involved in regulation of phototransduction in rod and cone cells of the retina, while RGS9-2 is found in the brain, and regulates dopamine and opioid signaling in the basal ganglia. RGS9-2 is of particular interest as the most important RGS protein involved in terminating signalling by the mu opioid receptor (although RGS4 and RGS17 are also involved), and is thought to be important in the development of tolerance to opioid drugs. RGS9-deficient mice exhibit some motor and cognitive difficulties however, so inhibition of this protein is likely to cause similar side effects. RGS9 is differentially regulated by Guanine nucleotide-binding protein subunit beta-5 (GNB5) via the DEP domain and DEP helical-extension domain in protein stability and membrane anchor association.

RGS9 Regulator of G-protein signalling 9, also known as RGS9, is a human gene,[1] which codes for a protein involved in regulation of signal transduction inside cells. Members of the RGS family, such as RGS9, are signaling proteins that suppress the activity of G proteins by promoting their deactivation.[supplied by OMIM][1] There are two splice isoforms of RGS9 with quite different properties and patterns of expression. RGS9-1 is mainly found in the eye and is involved in regulation of phototransduction in rod and cone cells of the retina, while RGS9-2 is found in the brain, and regulates dopamine and opioid signaling in the basal ganglia.[2] RGS9-2 is of particular interest as the most important RGS protein involved in terminating signalling by the mu opioid receptor (although RGS4 and RGS17 are also involved), and is thought to be important in the development of tolerance to opioid drugs.[3][4][5][6][7][8][9] RGS9-deficient mice exhibit some motor and cognitive difficulties however, so inhibition of this protein is likely to cause similar side effects.[10] RGS9 is differentially regulated by Guanine nucleotide-binding protein subunit beta-5 (GNB5) via the DEP domain and DEP helical-extension domain in protein stability and membrane anchor association.[11]

https://www.wikidoc.org/index.php/RGS9

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wikidoc

RHEB

RHEB RHEB also known as Ras homolog enriched in brain (RHEB) is a GTP-binding protein that is ubiquitously expressed in humans and other mammals. The protein is largely involved in the mTOR pathway and the regulation of the cell cycle. RHEB is a recently discovered member of the Ras superfamily. Being a relative of Ras, the overexpression of RHEB can be seen in multiple human carcinomas. For this reason, ways to inhibit RHEB to control the mTOR pathway are studied as possible treatments for uncontrollable tumor cell growth in several diseases, especially in tuberous sclerosis. # Structure Rheb is a 21-kDa protein monomer composed of 184 amino acids. The first 169 amino acids by the N-terminus make up the GTPase domain, and the remaining amino acids are part of a hypervariable region ending at the C-terminus in a CAAX motif (C – cysteine, A – aliphatic amino acid, X – C-terminus amino acid). The protein is a lipid-anchored, cell-membrane protein with five repeats of the RAS-related GTP-binding region. Also present are “switch” regions, I and II, which undergo conformational changes when shuttling between GTP-bound(activated) and GDP-bound(inactive) forms. RHEB is expressed by the RHEB gene in humans. Three pseudogenes have been mapped, two on chromosome 10 and one on chromosome 22. # Function ## Activation of mTORC1 RHEB is vital in regulation of growth and cell cycle progression due to its role in the insulin/TOR/S6K signaling pathway. Mechanistic Target of Rapamycin Complex 1 (mTORC1) is a serine/threonine kinase whose activation leads to phosphorylation cascades within the cell that lead to cell growth and proliferation. RHEB localizes at the lysosome to activate mTORC1 and Rag7 proteins localize mTORC1 to the lysosome and the Ragulator-Rag complex, allowing RHEB to activate the protein. RHEB acts as an activator for mTORC1 in its GTP-bound form, therefore GTP-bound RHEB activates cell growth and proliferation within the cell. ## mTORC1 independent functions RHEB can serve as a regulator, for other proteins independent from mTORC1. For example, RHEB is an activator for nucleotide synthesis by binding carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), an enzyme required for de novo pyrimidine nucleotide synthesis. An increased nucleotide pool within the cell can lead to increased cell proliferation. mTORC1 is also a regulator for CAD, so both RHEB and mTORC1 are involved with the control of nucleotide level within the cell. 5' adenosine-monophospate-activated protein kinase (AMPK) has also been found to be an effector for RHEB. AMPK is a protein kinase that begins a phosphorylation cascade leading to autophagy. In rat studies, RHEB activates AMPK. RHEB has also been found to interact with effectors upstream in the mTOR pathway. Phospholipase D1 (PLD1) is upstream in the mTOR pathway and serves as a positive effector for mTORC1. ## Other functions RHEB may be involved in neural plasticity. This function is novel and not typically associated with the Ras proteins. Deficiency of RHEB in the forebrain of mice embryos is associated with decreased myelinization due to a decrease of mature oligodendrocytes. In studies of RHEB knockout mice, it was shown through hematoxylin-eosin staining that heart development is highly impaired. The cardiac myocytes do not sufficiently grow in size, indicating that RHEB mTOR function is required. This suggested that RHEB and the activation of the mTOR pathway is a necessity for proper cardiac development in mice embryos. ## Differences from Ras superfamily RHEB functions differently compared to other proteins in the Ras superfamily. Similar to those in the Ras superfamily, the protein has GTPase activity and shuttles between a GDP-bound form and a GTP-bound form, and farnesylation of the protein is required for this activity. However, unlike those in the Ras superfamily, conformational change when shuttling between forms only affects switch I, while switch II remains relatively stable, due to difference in secondary structure. Ras switch II forms a long α-helical structure between shuttling, while RHEB switch II adopts a more atypical conformation allowing for novel functions. Such a conformation causes a decreased intrinsic rate of GTP hydrolysis as compared to RAS due to the catalytic Asp65 in the switch II region of RHEB being blocked from the active site. # Regulation GTP hydrolysis activity of RHEB is intrinsically slow and the GTP-bound form is more common, thus RHEB is more likely active than not active within the cell. Its activity is strongly regulated within the cell by tumor-suppressant proteins that form the TSC complex. Specifically, the TSC2 subunit, tuberin of the complex interacts with and inhibits RHEB to regulate the protein. Tuberin stimulates RHEB to hydrolyze GTP, thus inactivating it. # Tuberous sclerosis Tuberous sclerosis is an autosomal dominant disease in which the genes required to express the tumor-suppressant proteins that form the TSC complex is mutated or missing, so the TSC complex is unable to function properly. This could lead to the disregulation of many signalling proteins and effectors within the cell, including RHEB. Unregulated activity of RHEB can lead to uncontrollable cell growth and cell division which could ultimately lead to formation of tumors. # Interactions RHEB has been shown to interact with: - Ataxia telangiectasia mutated (ATM) - Ataxia telangiectasia and Rad3 related (ATR) - 5' AMP-activated protein kinase (AMPK) - RAF proto-oncogene serine/threonine-protein kinase (C-Raf) - mammalian Target of Rapamycin Complex 1 (mTORC1), - Phospholipase D1 (PLD1) - Regulatory-associated protein of mTOR (RPTOR) - Tuberous sclerosis complex (TSC) and - Carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase (CAD)

RHEB RHEB also known as Ras homolog enriched in brain (RHEB) is a GTP-binding protein that is ubiquitously expressed in humans and other mammals. The protein is largely involved in the mTOR pathway and the regulation of the cell cycle.[1] RHEB is a recently discovered member of the Ras superfamily. Being a relative of Ras, the overexpression of RHEB can be seen in multiple human carcinomas.[2] For this reason, ways to inhibit RHEB to control the mTOR pathway are studied as possible treatments for uncontrollable tumor cell growth in several diseases, especially in tuberous sclerosis.[3] # Structure Rheb is a 21-kDa protein monomer composed of 184 amino acids.[1] The first 169 amino acids by the N-terminus make up the GTPase domain, and the remaining amino acids are part of a hypervariable region ending at the C-terminus in a CAAX motif (C – cysteine, A – aliphatic amino acid, X – C-terminus amino acid).[4] The protein is a lipid-anchored, cell-membrane protein with five repeats of the RAS-related GTP-binding region.[1] Also present are “switch” regions, I and II, which undergo conformational changes when shuttling between GTP-bound(activated) and GDP-bound(inactive) forms.[4] RHEB is expressed by the RHEB gene in humans.[5] Three pseudogenes have been mapped, two on chromosome 10 and one on chromosome 22.[1] # Function ## Activation of mTORC1 RHEB is vital in regulation of growth and cell cycle progression due to its role in the insulin/TOR/S6K signaling pathway.[6] Mechanistic Target of Rapamycin Complex 1 (mTORC1) is a serine/threonine kinase whose activation leads to phosphorylation cascades within the cell that lead to cell growth and proliferation.[7] RHEB localizes at the lysosome to activate mTORC1 and Rag7 proteins localize mTORC1 to the lysosome and the Ragulator-Rag complex, allowing RHEB to activate the protein.[8] RHEB acts as an activator for mTORC1 in its GTP-bound form, therefore GTP-bound RHEB activates cell growth and proliferation within the cell. ## mTORC1 independent functions RHEB can serve as a regulator, for other proteins independent from mTORC1. For example, RHEB is an activator for nucleotide synthesis by binding carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), an enzyme required for de novo pyrimidine nucleotide synthesis.[9] An increased nucleotide pool within the cell can lead to increased cell proliferation. mTORC1 is also a regulator for CAD, so both RHEB and mTORC1 are involved with the control of nucleotide level within the cell.[9] 5' adenosine-monophospate-activated protein kinase (AMPK) has also been found to be an effector for RHEB.[10] AMPK is a protein kinase that begins a phosphorylation cascade leading to autophagy. In rat studies, RHEB activates AMPK.[10] RHEB has also been found to interact with effectors upstream in the mTOR pathway. Phospholipase D1 (PLD1) is upstream in the mTOR pathway and serves as a positive effector for mTORC1.[11] ## Other functions RHEB may be involved in neural plasticity. This function is novel and not typically associated with the Ras proteins. Deficiency of RHEB in the forebrain of mice embryos is associated with decreased myelinization due to a decrease of mature oligodendrocytes.[4] In studies of RHEB knockout mice, it was shown through hematoxylin-eosin staining that heart development is highly impaired. The cardiac myocytes do not sufficiently grow in size, indicating that RHEB mTOR function is required. This suggested that RHEB and the activation of the mTOR pathway is a necessity for proper cardiac development in mice embryos.[12] ## Differences from Ras superfamily RHEB functions differently compared to other proteins in the Ras superfamily.[4] Similar to those in the Ras superfamily, the protein has GTPase activity and shuttles between a GDP-bound form and a GTP-bound form, and farnesylation of the protein is required for this activity. However, unlike those in the Ras superfamily, conformational change when shuttling between forms only affects switch I, while switch II remains relatively stable, due to difference in secondary structure. Ras switch II forms a long α-helical structure between shuttling, while RHEB switch II adopts a more atypical conformation allowing for novel functions.[13] Such a conformation causes a decreased intrinsic rate of GTP hydrolysis as compared to RAS due to the catalytic Asp65 in the switch II region of RHEB being blocked from the active site.[7] # Regulation GTP hydrolysis activity of RHEB is intrinsically slow and the GTP-bound form is more common, thus RHEB is more likely active than not active within the cell.[7] Its activity is strongly regulated within the cell by tumor-suppressant proteins that form the TSC complex. Specifically, the TSC2 subunit, tuberin of the complex interacts with and inhibits RHEB to regulate the protein. Tuberin stimulates RHEB to hydrolyze GTP, thus inactivating it.[14] # Tuberous sclerosis Tuberous sclerosis is an autosomal dominant disease in which the genes required to express the tumor-suppressant proteins that form the TSC complex is mutated or missing, so the TSC complex is unable to function properly.[15] This could lead to the disregulation of many signalling proteins and effectors within the cell, including RHEB. Unregulated activity of RHEB can lead to uncontrollable cell growth and cell division which could ultimately lead to formation of tumors.[4] # Interactions RHEB has been shown to interact with: - Ataxia telangiectasia mutated (ATM)[16] - Ataxia telangiectasia and Rad3 related (ATR)[16] - 5' AMP-activated protein kinase (AMPK)[10] - RAF proto-oncogene serine/threonine-protein kinase (C-Raf)[16][17][18] - mammalian Target of Rapamycin Complex 1 (mTORC1),[16][19][20][21] - Phospholipase D1 (PLD1)[11] - Regulatory-associated protein of mTOR (RPTOR)[16] - Tuberous sclerosis complex (TSC)[14][16][22][23][24][25] and - Carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase (CAD)[9]

https://www.wikidoc.org/index.php/RHEB

c61b66e1153eb2fdc1e34592d8ff5a6afa61e782

wikidoc

RHOA

RHOA Ras homolog gene family, member A (RhoA) is a small GTPase protein in the Rho family. While the effects of RhoA activity are not all well known, it is primarily associated with cytoskeleton regulation, mostly actin stress fibers formation and actomyosin contractility. In humans, it is encoded by the gene RHOA. It acts upon several effectors. Among them, ROCK1 (Rho-associated, coiled-coil containing protein kinase 1) and DIAPH1 (Diaphanous Homologue 1, a.k.a. hDia1, homologue to mDia1 in mouse, diaphanous in Drosophila) are the best described. RhoA, and the other Rho GTPases, are part of a larger family of related proteins known as the Ras superfamily, a family of proteins involved in the regulation and timing of cell division. RhoA is one of the oldest Rho GTPases, with homologues present in the genomes since 1.5 billions years. As a consequence, RhoA is somehow involved in many cellular processes which emerged throughout evolution. RhoA specifically is regarded as a prominent regulatory factor in other functions such as the regulation of cytoskeletal dynamics, transcription, cell cycle progression and cell transformation. # Structure The specific gene that encodes RhoA, RHOA, is located on chromosome 3 and consists of four exons, which has also been linked as a possible risk factor for atherothrombolic stroke. Similar to other GTPases, RhoA present a Rho insert in its primary sequence in the GTPase domain. RhoA contains also four insertion or deletion sites with an extra helical subdomain; these sites are characteristic of many GTPases in the Rho family. Most importantly, RhoA contains two switch region, Switch I and Switch II whose conformational states are modified following the activation or inactivation of the protein. Both of these switches have characteristic folding, correspond to specific regions on the RhoA coil and are uniformly stabilized via hydrogen bonds. The conformations of the Switch domains are modified depending on the binding of either GDP or GTP to RhoA. The nature of the bound nucleotide and the ensuing conformational modification of the Switch domains dictates the ability of RhoA to bind or not to partner proteins (see below). The primary protein sequences of members of the Rho family are mostly identical, with the N-terminal containing most of the protein coding for GTP binding and hydrolysis. The C-terminal of RhoA is modified via prenylation, anchoring the GTPase into membranes, which is essential for its role in cell growth and cytoskeleton organization. Key amino acids that are involved in the stabilization and regulation of GTP hydrolysis are conserved in RhoA as Gly14, Thr19, Phe30 and Gln63. Correct localization of the RhoA proteins is heavily dependent on the C-terminus; during prenylation, the anchoring of the prenyl group is essential for the stability, inhibition of and the synthesis of enzymes and proliferation. RhoA is sequestered by dissociation inhibitors (RhoGDIs) which remove the protein from the membrane while preventing its further interaction with other downstream effectors. # Activation mechanism RhoA contains both inactive GDP-bound and active GTP-bound conformational states; these states alternate between the active and inactive states via the exchange of GDP to GTP (conducted simultaneously via guanine nucleotide exchange factors and GTPase activating factor). RhoA is activated primarily by guanine nucleotide exchange factors (GEFs) via phosphorylation; due to large network of overlapping phosphorylation, a multitude of GEFs are utilized to enable specific signaling pathways. These structural arrangements provide interaction sites that can interact with effectors and guanine factors in order to stabilize and signal the hydrolysis of GTP. # Participation in cellular processes RhoA is primarily involved in these activities: actin organization, myosin contractility, cell cycle maintenance, cellular morphological polarization, cellular development and transcriptional control. ## Actin organization RhoA is prevalent in regulating cell shape, polarity and locomotion via actin polymerization, actomyosin contractility, cell adhesion, and microtubule dynamics. In addition, RhoA is believed to act primarily at the rear (uropod) of migrating cells to promote detachment, similar to the attachment and detachment process found in the focal adhesion mechanism. Signal transduction pathways regulated via RhoA link plasma membrane receptors to focal adhesion formation and the subsequent activation of relevant actin stress fibers. RhoA directly stimulates actin polymerization through activation of diaphanous-related formins, thereby structurally changing the actin monomers to filaments. ROCK kinases induce actomyosin-based contractility and phosphorylate TAU and MAP2 involved in regulating myosins and other actin-binding proteins in order to assist in cell migration and detachment. The concerted action of ROCK and Dia is essential for the regulation of cell polarity and organization of microtubules. RhoA also regulates the integrity of the extracellular matrix and the loss of corresponding cell-cell adhesions (primarily adherens and tight junctions) required for the migration of epithelial. RhoA’s role in signal transduction mediation is also attributed to the establishment of tissue polarity in epidermal structures due to its actin polymerization to coordinate vesicular motion; movement within actin filaments forms webs that move in conjunction with vesicular linear motion. As a result, mutations present in the polarity genes indicate that RhoA is critical for tissue polarity and directed intracellular movement. ## Cell development RhoA is required for processes involving cell development, some of which include outgrowth, dorsal closure, bone formation, and myogenesis. Loss of RhoA function is frequently attributed to failed gastrulation and cell migration inability. In extension, RhoA has been shown to function as an intermediary switch within the overall mechanically mediated process of stem cell commitment and differentiation. For example, human mesenchymal stem cells and their differentiation into adipocytes or osteocytes are direct results of RhoA’s impact on cell shape, signaling and cytoskeletal integrity. Cell shape acts as the primary mechanical cue that drives RhoA activity and downstream effector ROCK activity to control stem cell commitment and cytoskeletal maintenance. Transforming growth factor (TGF)-mediated pathways that control tumor progression and identity are also frequently noted to be RhoA-dependent mechanisms. TGF-β1, a tumor suppressive growth factor, is known to regulate growth, differentiation and epithelial transformation in tumorigenesis. Instead of blocking growth, TGF-β1 directly activates RhoA in epithelial cells while blocking its downstream target, p160; as a result, activated RhoA-dependent pathways induce stress fiber formation and subsequent mesenchymal properties . ## Transcriptional control Activated RhoA also participates in regulating transcriptional control over other signal transduction pathways via various cellular factors. RhoA proteins help potentiate the transcription independent of ternary complex factors when activated while simultaneously modulating subsequent extracellular signal activity. It has also been shown that RhoA mediates serum-, LPA- and AIF4-induced signaling pathways in addition to regulating the transcription of the c-fos promoter, a key component in the formation of the ternary complex producing the serum and ternary factors. RhoA signaling and modulation of actin polymerization also regulates Sox9 expression via controlling transcriptional Sox9 activity. The expression and transcriptional activity of Sox9 is directly linked with the loss of RhoA activity and illustrates how RhoA participates in the transcriptional control of specific protein expression. ## Cell cycle maintenance RhoA as well as several other members of the Rho family are identified as having roles in the regulation of the cytoskeleton and cell division. RhoA plays a pivotal role in G1 cell cycle progression, primarily through regulation of cyclin D1 and cyclin-dependent kinase inhibitors (p21 and p27) expression. These regulation pathways activate protein kinases, which subsequently modulate transcription factor activity. RhoA specifically suppresses p21 levels in normal and transformed cell lines via a p53-independent transcriptional mechanism while p27 levels are regulated using effector Rho-associated kinases. Cytokinesis is defined by actomyosin-based contraction. RhoA-dependent diaphanous-related formins (DRFs) localize to the cleavage furrow during cytokinesis while stimulating local actin polymerization by coordinating microtubules with actin filaments at the site of the myosin contractile ring. Differences in effector binding distinguish RhoA amongst other related Ras homologs GTPases. Integrins can modulate RhoA activity depending on the extracellular matrix composition and other relevant factors. Similarly, RhoA’s stimulation of PKN2 kinase activity regulates cell-cell adhesion through apical junction formation and disassembly. Though RhoA is most notably recognized from its unique contributions in actin-myosin contractility and stress fiber formation, new research has also identified it as a key factor in the mediation of membrane ruffling, lamellae formation and membrane blebbing. A majority of this activity occurs in the leading edge of cells during migration in coordination with membrane protrusions of breast carcinoma. # RhoA pathway Molecules act on various receptors, such as NgR1, LINGO1, p75, TROY and other unknown receptors (e.g. by CSPGs), which stimulates RhoA. RhoA activates ROCK (RhoA kinase) which stimulates LIM kinase, which then inhibits cofilin, which effectively reorganizes the actin cytoskeleton of the cell. In the case of neurons, activation of this pathway results in growth cone collapse, therefore inhibits the growth and repair of neural pathways and axons. Inhibition of this pathway by its various components usually results in some level of improved re-myelination. After global ischemia, hyperbaric oxygen (at least at 3 ATA) appears to partially suppress expression of RhoA, in addition to Nogo protein (Reticulon 4), and a subunit of its receptor Ng-R. The MEMO1-RhoA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. A recent study shows that RhoA-Rho kinase signaling mediates thrombin-induced brain damage. # Interactions RHOA has been shown to interact with: - ARHGAP1, - ARHGAP5, - ARHGDIA, - ARHGEF11, - ARHGEF12, - ARHGEF3, - CIT - DGKQ, - DIAPH1, - GEFT, - ITPR1, - KCNA2, - KTN1, - PKN2, - PLCG1, - Phospholipase D1, - Protein kinase N1, - RAP1GDS1, - RICS, - ROCK1, - TRIO, and - TRPC1. # Clinical significance ## Cancer Given that its overexpression is found in many malignancies, RhoA activity has been linked within several cancer applications due to its significant involvement in cancer signaling cascades. Serum response factors (SRFs) are known to mediate androgen receptors in prostate cancer cells, including roles ranging from distinguishing benign from malignant prostate and identifying aggressive disease. RhoA mediates androgen-responsiveness of these SRF genes; as a result, interference with RhoA has been shown to prevent the androgen regulation of SRF genes. In application, RhoA expression is notably higher in malignant prostate cancer cells compared to benign prostate cells, with elevated RhoA expression being associated with elevated lethality and aggressive proliferation. On the other hand, silencing RhoA lessened androgen-regulated cell viability and handicapped prostate cancer cell migration. RhoA has also been found to be hyper activated in gastric cancer cells; in consequence, suppression of RhoA activity partially reversed the proliferation phenotype of gastric cancer cells via the down-regulation of the RhoA-mammalian Diaphanous 1 pathway. Doxorubicin has been referred to frequently as a highly-promising anti-cancer drug that is also being utilized in chemotherapy treatments; however, as with nearly all chemotherapeutics, the issue of drug resistance remains. Minimizing or postponing this resistance would the necessary dose to eradicate the tumor, thus diminishing drug toxicity. Subsequent RhoA expression decrease has also been associated with increased sensitivity to doxorubicin and the complete reversion of doxorubicin resistance in certain cells; his shows the resilience of RhoA as a consistent indicator anti-cancer activity. In addition to promoting tumor-suppression activity, RhoA also has inherent impact upon the efficacy of drugs in relation to cancer functionality and could be applied to gene therapy protocols in future research. Protein expression of RhoA has been identified to be significantly higher in testicular tumor tissue than that in nontumor tissue; expression of protein for RhoA, ROCK-I, ROCK-II, Rac1, and Cdc42 was greater in tumors of higher stages than lower stages, coinciding with greater lymph metastasis and invasion in upper urinary tract cancer. Although both RhoA and RhoC proteins comprise a significant part of the Rho GTPases that are linked to promoting the invasive behavior of breast carcinomas, attributing specific functions to these individual members has been difficult. We have used a stable retroviral RNA interference approach to generate invasive breast carcinoma cells (SUM-159 cells) that lack either RhoA or RhoC expression. Analysis of these cells enabled us to deduce that RhoA impedes and RhoC stimulates invasion. Unexpectedly, this analysis also revealed a compensatory relationship between RhoA and RhoC at the level of both their expression and activation, and a reciprocal relationship between RhoA and Rac1 activation. Chronic Myeloid Leukemia (CML), a stem cell disorder that prevents myeloid cells from functioning correctly, has been linked to actin polymerization. Signaling proteins like RhoA, regulate polymerization of actin. Due to differences proteins exhibited between normal and affected neutrocytes, RhoA has become the key element; further experimentation has also shown that RhoA-inhibiting pathways prevent the overall growth of CML cells. As a result, RhoA has significant potential as a therapeutic target in gene therapy techniques to treating CML. Therefore, RhoA’s role in the proliferation of cancer cell phenotypes is a key application that can be applied to targeted cancer therapeutics and the development for pharmaceuticals. ## Drug applications In June 2012, a new drug candidate named "Rhosin" was synthesized by researchers at the Cincinnati Children’s Hospital, a drug with the full intention to inhibit cancer proliferation and promote nerve cell regeneration. This inhibitor specifically targets Rho GTPases to prevent cell growth related to cancer. When tested on breast cancer cells, Rhosin inhibited growth and the growth of mammary spheres in a dose dependent manner, functioning as targets for RhoA while simultaneously maintaining the integrity of normal cellular processes and normal breast cells. These promising results indicate Rhosin’s general effectiveness in preventing breast cancer proliferation via RhoA targeting. ## Possible target for asthma and diabetes drugs RhoA’s physiological functions have been linked to the contraction and migration of cells which are manifested as symptoms in both asthma and diabetes (i.e. airflow limitation and hyper-responsiveness, desensitization, etc.). Due to pathophysiological overlap of RhoA and Rho-kinase in asthma, both RhoA and Rho-kinase have become promising new target molecules for pharmacological research to develop alternate forms of treatment for asthma. RhoA and Rho kinase mechanisms have been linked to diabetes due to the up-regulated expression of targets within type 1 and 2 diabetic animals. Inhibition of this pathway prevented and ameliorated pathologic changes in diabetic complications, indicating that RhoA pathway is a promising target for therapeutic development in diabetes treatment

RHOA Ras homolog gene family, member A (RhoA) is a small GTPase protein in the Rho family. While the effects of RhoA activity are not all well known, it is primarily associated with cytoskeleton regulation, mostly actin stress fibers formation and actomyosin contractility. In humans, it is encoded by the gene RHOA.[1] It acts upon several effectors. Among them, ROCK1 (Rho-associated, coiled-coil containing protein kinase 1) and DIAPH1 (Diaphanous Homologue 1, a.k.a. hDia1, homologue to mDia1 in mouse, diaphanous in Drosophila) are the best described. RhoA, and the other Rho GTPases, are part of a larger family of related proteins known as the Ras superfamily, a family of proteins involved in the regulation and timing of cell division. RhoA is one of the oldest Rho GTPases, with homologues present in the genomes since 1.5 billions years. As a consequence, RhoA is somehow involved in many cellular processes which emerged throughout evolution. RhoA specifically is regarded as a prominent regulatory factor in other functions such as the regulation of cytoskeletal dynamics, transcription, cell cycle progression and cell transformation. # Structure The specific gene that encodes RhoA, RHOA, is located on chromosome 3 and consists of four exons,[2] which has also been linked as a possible risk factor for atherothrombolic stroke. Similar to other GTPases, RhoA present a Rho insert in its primary sequence in the GTPase domain. RhoA contains also four insertion or deletion sites with an extra helical subdomain; these sites are characteristic of many GTPases in the Rho family. Most importantly, RhoA contains two switch region, Switch I and Switch II whose conformational states are modified following the activation or inactivation of the protein. Both of these switches have characteristic folding, correspond to specific regions on the RhoA coil and are uniformly stabilized via hydrogen bonds. The conformations of the Switch domains are modified depending on the binding of either GDP or GTP to RhoA. The nature of the bound nucleotide and the ensuing conformational modification of the Switch domains dictates the ability of RhoA to bind or not to partner proteins (see below). The primary protein sequences of members of the Rho family are mostly identical, with the N-terminal containing most of the protein coding for GTP binding and hydrolysis. The C-terminal of RhoA is modified via prenylation, anchoring the GTPase into membranes, which is essential for its role in cell growth and cytoskeleton organization. Key amino acids that are involved in the stabilization and regulation of GTP hydrolysis are conserved in RhoA as Gly14, Thr19, Phe30 and Gln63. Correct localization of the RhoA proteins is heavily dependent on the C-terminus; during prenylation, the anchoring of the prenyl group is essential for the stability, inhibition of and the synthesis of enzymes and proliferation. RhoA is sequestered by dissociation inhibitors (RhoGDIs) which remove the protein from the membrane while preventing its further interaction with other downstream effectors.[3] # Activation mechanism RhoA contains both inactive GDP-bound and active GTP-bound conformational states; these states alternate between the active and inactive states via the exchange of GDP to GTP (conducted simultaneously via guanine nucleotide exchange factors and GTPase activating factor). RhoA is activated primarily by guanine nucleotide exchange factors (GEFs) via phosphorylation; due to large network of overlapping phosphorylation, a multitude of GEFs are utilized to enable specific signaling pathways. These structural arrangements provide interaction sites that can interact with effectors and guanine factors in order to stabilize and signal the hydrolysis of GTP.[4] # Participation in cellular processes RhoA is primarily involved in these activities: actin organization, myosin contractility, cell cycle maintenance, cellular morphological polarization, cellular development and transcriptional control. ## Actin organization RhoA is prevalent in regulating cell shape, polarity and locomotion via actin polymerization, actomyosin contractility, cell adhesion, and microtubule dynamics. In addition, RhoA is believed to act primarily at the rear (uropod) of migrating cells to promote detachment, similar to the attachment and detachment process found in the focal adhesion mechanism. Signal transduction pathways regulated via RhoA link plasma membrane receptors to focal adhesion formation and the subsequent activation of relevant actin stress fibers. RhoA directly stimulates actin polymerization through activation of diaphanous-related formins, thereby structurally changing the actin monomers to filaments. ROCK kinases induce actomyosin-based contractility and phosphorylate TAU and MAP2 involved in regulating myosins and other actin-binding proteins in order to assist in cell migration and detachment. The concerted action of ROCK and Dia is essential for the regulation of cell polarity and organization of microtubules. RhoA also regulates the integrity of the extracellular matrix and the loss of corresponding cell-cell adhesions (primarily adherens and tight junctions) required for the migration of epithelial. RhoA’s role in signal transduction mediation is also attributed to the establishment of tissue polarity in epidermal structures due to its actin polymerization to coordinate vesicular motion;[5] movement within actin filaments forms webs that move in conjunction with vesicular linear motion. As a result, mutations present in the polarity genes indicate that RhoA is critical for tissue polarity and directed intracellular movement. ## Cell development RhoA is required for processes involving cell development, some of which include outgrowth, dorsal closure, bone formation, and myogenesis. Loss of RhoA function is frequently attributed to failed gastrulation and cell migration inability. In extension, RhoA has been shown to function as an intermediary switch within the overall mechanically mediated process of stem cell commitment and differentiation. For example, human mesenchymal stem cells and their differentiation into adipocytes or osteocytes are direct results of RhoA’s impact on cell shape, signaling and cytoskeletal integrity. Cell shape acts as the primary mechanical cue that drives RhoA activity and downstream effector ROCK activity to control stem cell commitment and cytoskeletal maintenance.[6] Transforming growth factor (TGF)-mediated pathways that control tumor progression and identity are also frequently noted to be RhoA-dependent mechanisms. TGF-β1, a tumor suppressive growth factor, is known to regulate growth, differentiation and epithelial transformation in tumorigenesis. Instead of blocking growth, TGF-β1 directly activates RhoA in epithelial cells while blocking its downstream target, p160; as a result, activated RhoA-dependent pathways induce stress fiber formation and subsequent mesenchymal properties .[7] ## Transcriptional control Activated RhoA also participates in regulating transcriptional control over other signal transduction pathways via various cellular factors. RhoA proteins help potentiate the transcription independent of ternary complex factors when activated while simultaneously modulating subsequent extracellular signal activity. It has also been shown that RhoA mediates serum-, LPA- and AIF4-induced signaling pathways in addition to regulating the transcription of the c-fos promoter, a key component in the formation of the ternary complex producing the serum and ternary factors.[8] RhoA signaling and modulation of actin polymerization also regulates Sox9 expression via controlling transcriptional Sox9 activity. The expression and transcriptional activity of Sox9 is directly linked with the loss of RhoA activity and illustrates how RhoA participates in the transcriptional control of specific protein expression.[9] ## Cell cycle maintenance RhoA as well as several other members of the Rho family are identified as having roles in the regulation of the cytoskeleton and cell division. RhoA plays a pivotal role in G1 cell cycle progression, primarily through regulation of cyclin D1 and cyclin-dependent kinase inhibitors (p21 and p27) expression. These regulation pathways activate protein kinases, which subsequently modulate transcription factor activity. RhoA specifically suppresses p21 levels in normal and transformed cell lines via a p53-independent transcriptional mechanism while p27 levels are regulated using effector Rho-associated kinases. Cytokinesis is defined by actomyosin-based contraction. RhoA-dependent diaphanous-related formins (DRFs) localize to the cleavage furrow during cytokinesis while stimulating local actin polymerization by coordinating microtubules with actin filaments at the site of the myosin contractile ring. Differences in effector binding distinguish RhoA amongst other related Ras homologs GTPases. Integrins can modulate RhoA activity depending on the extracellular matrix composition and other relevant factors. Similarly, RhoA’s stimulation of PKN2 kinase activity regulates cell-cell adhesion through apical junction formation and disassembly.[3][10] Though RhoA is most notably recognized from its unique contributions in actin-myosin contractility and stress fiber formation, new research has also identified it as a key factor in the mediation of membrane ruffling, lamellae formation and membrane blebbing. A majority of this activity occurs in the leading edge of cells during migration in coordination with membrane protrusions of breast carcinoma.[11] # RhoA pathway Molecules act on various receptors, such as NgR1, LINGO1, p75, TROY and other unknown receptors (e.g. by CSPGs), which stimulates RhoA. RhoA activates ROCK (RhoA kinase) which stimulates LIM kinase, which then inhibits cofilin, which effectively reorganizes the actin cytoskeleton of the cell.[1] In the case of neurons, activation of this pathway results in growth cone collapse, therefore inhibits the growth and repair of neural pathways and axons. Inhibition of this pathway by its various components usually results in some level of improved re-myelination.[12][13][14][15] After global ischemia, hyperbaric oxygen (at least at 3 ATA) appears to partially suppress expression of RhoA, in addition to Nogo protein (Reticulon 4), and a subunit of its receptor Ng-R.[16] The MEMO1-RhoA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. A recent study shows that RhoA-Rho kinase signaling mediates thrombin-induced brain damage.[17] # Interactions RHOA has been shown to interact with: - ARHGAP1,[18][19][20][21] - ARHGAP5,[22] - ARHGDIA,[23][24][25][26][27] - ARHGEF11,[28] - ARHGEF12,[29] - ARHGEF3,[30] - CIT[31][32] - DGKQ,[33] - DIAPH1,[31] - GEFT,[34] - ITPR1,[31][35] - KCNA2,[36] - KTN1,[37][38][39] - PKN2,[40][41][42] - PLCG1,[43] - Phospholipase D1,[44][45] - Protein kinase N1,[31][41][46] - RAP1GDS1,[47] - RICS,[48][49][49] - ROCK1,[50][51] - TRIO,[52] and - TRPC1.[35] # Clinical significance ## Cancer Given that its overexpression is found in many malignancies, RhoA activity has been linked within several cancer applications due to its significant involvement in cancer signaling cascades. Serum response factors (SRFs) are known to mediate androgen receptors in prostate cancer cells, including roles ranging from distinguishing benign from malignant prostate and identifying aggressive disease. RhoA mediates androgen-responsiveness of these SRF genes; as a result, interference with RhoA has been shown to prevent the androgen regulation of SRF genes. In application, RhoA expression is notably higher in malignant prostate cancer cells compared to benign prostate cells, with elevated RhoA expression being associated with elevated lethality and aggressive proliferation. On the other hand, silencing RhoA lessened androgen-regulated cell viability and handicapped prostate cancer cell migration.[53] RhoA has also been found to be hyper activated in gastric cancer cells; in consequence, suppression of RhoA activity partially reversed the proliferation phenotype of gastric cancer cells via the down-regulation of the RhoA-mammalian Diaphanous 1 pathway.[54] Doxorubicin has been referred to frequently as a highly-promising anti-cancer drug that is also being utilized in chemotherapy treatments; however, as with nearly all chemotherapeutics, the issue of drug resistance remains. Minimizing or postponing this resistance would the necessary dose to eradicate the tumor, thus diminishing drug toxicity. Subsequent RhoA expression decrease has also been associated with increased sensitivity to doxorubicin and the complete reversion of doxorubicin resistance in certain cells; his shows the resilience of RhoA as a consistent indicator anti-cancer activity. In addition to promoting tumor-suppression activity, RhoA also has inherent impact upon the efficacy of drugs in relation to cancer functionality and could be applied to gene therapy protocols in future research.[55] Protein expression of RhoA has been identified to be significantly higher in testicular tumor tissue than that in nontumor tissue; expression of protein for RhoA, ROCK-I, ROCK-II, Rac1, and Cdc42 was greater in tumors of higher stages than lower stages, coinciding with greater lymph metastasis and invasion in upper urinary tract cancer. Although both RhoA and RhoC proteins comprise a significant part of the Rho GTPases that are linked to promoting the invasive behavior of breast carcinomas, attributing specific functions to these individual members has been difficult. We have used a stable retroviral RNA interference approach to generate invasive breast carcinoma cells (SUM-159 cells) that lack either RhoA or RhoC expression. Analysis of these cells enabled us to deduce that RhoA impedes and RhoC stimulates invasion. Unexpectedly, this analysis also revealed a compensatory relationship between RhoA and RhoC at the level of both their expression and activation, and a reciprocal relationship between RhoA and Rac1 activation. Chronic Myeloid Leukemia (CML), a stem cell disorder that prevents myeloid cells from functioning correctly, has been linked to actin polymerization. Signaling proteins like RhoA, regulate polymerization of actin. Due to differences proteins exhibited between normal and affected neutrocytes, RhoA has become the key element; further experimentation has also shown that RhoA-inhibiting pathways prevent the overall growth of CML cells. As a result, RhoA has significant potential as a therapeutic target in gene therapy techniques to treating CML.[56] Therefore, RhoA’s role in the proliferation of cancer cell phenotypes is a key application that can be applied to targeted cancer therapeutics and the development for pharmaceuticals. ## Drug applications In June 2012, a new drug candidate named "Rhosin" was synthesized by researchers at the Cincinnati Children’s Hospital, a drug with the full intention to inhibit cancer proliferation and promote nerve cell regeneration. This inhibitor specifically targets Rho GTPases to prevent cell growth related to cancer. When tested on breast cancer cells, Rhosin inhibited growth and the growth of mammary spheres in a dose dependent manner, functioning as targets for RhoA while simultaneously maintaining the integrity of normal cellular processes and normal breast cells. These promising results indicate Rhosin’s general effectiveness in preventing breast cancer proliferation via RhoA targeting.[57] ## Possible target for asthma and diabetes drugs RhoA’s physiological functions have been linked to the contraction and migration of cells which are manifested as symptoms in both asthma and diabetes (i.e. airflow limitation and hyper-responsiveness, desensitization, etc.). Due to pathophysiological overlap of RhoA and Rho-kinase in asthma, both RhoA and Rho-kinase have become promising new target molecules for pharmacological research to develop alternate forms of treatment for asthma.[58] RhoA and Rho kinase mechanisms have been linked to diabetes due to the up-regulated expression of targets within type 1 and 2 diabetic animals. Inhibition of this pathway prevented and ameliorated pathologic changes in diabetic complications, indicating that RhoA pathway is a promising target for therapeutic development in diabetes treatment[59]

https://www.wikidoc.org/index.php/RHOA

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wikidoc

RhoC

RhoC RhoC (Ras homolog gene family, member C) is a small (~21 kDa) signaling G protein (more specifically a GTPase), and is a member of the Rac subfamily of the family Rho family of GTPases. It is encoded by the gene RHOC. # Mechanism and function It is prenylated at its C-terminus, and localizes to the cytoplasm and plasma membrane. It is thought to be important in cell locomotion. It cycles between inactive GDP-bound and active GTP-bound states and function as molecular switches in signal transduction cascades. Rho proteins promote reorganization of the actin cytoskeleton and regulate cell shape and motility. RhoC can activate formins such as mDia1 and FMNL2 to remodel the cytoskeleton. Overexpression of RhoC is associated with cell proliferation and causing tumors to become malignant. It causes degradation and reconstruction of the Extracellular Matrix (ECM) which helps cells escape the tissue they are currently in. It enhances cell motility giving it the ability to become invasive. It has been found to have a direct relationship to advanced tumor stage and metastasis, with increases in stage being related to increases in RhoC expression. RhoC-deficient mice can still develop tumors but these fail to metastasize, arguing that RhoC is essential for metastasis. It has also been found to enhance the creation of angiogenic factors such as VEGF, which is necessary for a tumor to become malignant. In a study by Vega, RhoC was knocked out which resulted in cells spreading out wide in all directions. When RhoC was disabled, the cell's abilities to move in a specific direction and migrate was impaired. It also reduced the cell's speed of movement, because it was difficult, and sometimes impossible, to polarize the cell. # Associated Signaling Pathways RhoC expression has been associated with several signaling pathways and effectors. Here is a list of the ones found so far: - IQGAP1 (IQ-domain GTP-ase Activating Protein): an effector of RhoC to enhance expression of cyclin E and cyclin D1. This resulted in cells being promoted to enter S phase more rapidly - ROCK-1 - MMP9: necessary for ECM regulation - FMNL3: a Fromin downstream target, which is used to regulate where Rac1 is active - MAPK pathway: upregulating VEGF, Basic fibroblastic growth factors, and interleukins 6 and 8 expression - Notch1 - PI3K/AKt pathway: Proliferation and invasiveness - Pyk2: metastasis # Types of Cancer RhoC has been studied in RhoC has been found to be overexpressed in: - Lung Cancer - Gastric Cancer - Ovarian cancer - Breast Cancer - Hepatocellular Cancer - Pancreatic Cancer - Colorectal Cancer - Cancer of the Urogenital System - Melanoma - Prostate Cancer - Cervical Carcinoma # Potential Therapies RhoC small interfering RNA (siRNA) have been used in studies to successfully inhibit proliferation of some invasive cancers RhoC can be used as a biomarker for judging the metastatic potential of tumors One study used "recombinant adenovirus mediated RhoC shRNA in tandem linked expression" to successfully inhibit RhoC It has been found that RhoC expression is not important for embryogenesis but it is only important for metastasis, which would make it a good target for treatments.

RhoC RhoC (Ras homolog gene family, member C) is a small (~21 kDa) signaling G protein (more specifically a GTPase), and is a member of the Rac subfamily of the family Rho family of GTPases.[1] It is encoded by the gene RHOC.[2] # Mechanism and function It is prenylated at its C-terminus, and localizes to the cytoplasm and plasma membrane. It is thought to be important in cell locomotion. It cycles between inactive GDP-bound and active GTP-bound states and function as molecular switches in signal transduction cascades. Rho proteins promote reorganization of the actin cytoskeleton and regulate cell shape and motility. RhoC can activate formins such as mDia1 and FMNL2 to remodel the cytoskeleton.[3][4][5] Overexpression of RhoC is associated with cell proliferation and causing tumors to become malignant.[6] It causes degradation and reconstruction of the Extracellular Matrix (ECM) which helps cells escape the tissue they are currently in. It enhances cell motility giving it the ability to become invasive.[7] It has been found to have a direct relationship to advanced tumor stage and metastasis, with increases in stage being related to increases in RhoC expression.[8] RhoC-deficient mice can still develop tumors but these fail to metastasize, arguing that RhoC is essential for metastasis.[9] It has also been found to enhance the creation of angiogenic factors such as VEGF, which is necessary for a tumor to become malignant.[8][10] In a study by Vega,[11] RhoC was knocked out which resulted in cells spreading out wide in all directions. When RhoC was disabled, the cell's abilities to move in a specific direction and migrate was impaired. It also reduced the cell's speed of movement, because it was difficult, and sometimes impossible, to polarize the cell. # Associated Signaling Pathways RhoC expression has been associated with several signaling pathways and effectors. Here is a list of the ones found so far: - IQGAP1 (IQ-domain GTP-ase Activating Protein): an effector of RhoC to enhance expression of cyclin E and cyclin D1. This resulted in cells being promoted to enter S phase more rapidly [12] - ROCK-1 [8][13] - MMP9: necessary for ECM regulation[8] - FMNL3: a Fromin downstream target, which is used to regulate where Rac1 is active [11] - MAPK pathway: upregulating VEGF, Basic fibroblastic growth factors, and interleukins 6 and 8 expression [10][14] - Notch1 [10] - PI3K/AKt pathway: Proliferation and invasiveness [10][15] - Pyk2: metastasis [10][16] # Types of Cancer RhoC has been studied in RhoC has been found to be overexpressed in: - Lung Cancer [7] - Gastric Cancer [12] - Ovarian cancer [8] - Breast Cancer [14][17] - Hepatocellular Cancer [18] - Pancreatic Cancer [8] - Colorectal Cancer [19] - Cancer of the Urogenital System [8] - Melanoma [8] - Prostate Cancer [16] - Cervical Carcinoma [10] # Potential Therapies RhoC small interfering RNA (siRNA) have been used in studies to successfully inhibit proliferation of some invasive cancers [12][19] RhoC can be used as a biomarker for judging the metastatic potential of tumors[17][20] One study used "recombinant adenovirus mediated RhoC shRNA in tandem linked expression" to successfully inhibit RhoC [19] It has been found that RhoC expression is not important for embryogenesis but it is only important for metastasis, which would make it a good target for treatments.[10]

https://www.wikidoc.org/index.php/RHOC

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wikidoc

RhoG

RhoG RhoG (Ras homology Growth-related) (or ARGH) is a small (~21 kDa) monomeric GTP-binding protein (G protein), and is an important component of many intracellular signalling pathways. It is a member of the Rac subfamily of the Rho family of small G proteins and is encoded by the gene RHOG. # Discovery RhoG was first identified as a coding sequence upregulated in hamster lung fibroblasts upon stimulation with serum. Expression of RhoG in mammals is widespread and studies of its function have been carried out in fibroblasts, leukocytes, neuronal cells, endothelial cells and HeLa cells. RhoG belongs to the Rac subgroup and emerged as a consequence of retroposition in early vertebrates. RhoG shares a subset of common binding partners with Rac, Cdc42 and RhoU/V members but a major specificity is its inability to bind to CRIB domain proteins such as PAKs. # Function Like most small G proteins RhoG is involved in a diverse set of cellular signalling mechanisms. In mammalian cells these include cell motility (through regulation of the actin cytoskeleton), gene transcription, endocytosis, neurite outgrowth, protection from anoikis and regulation of the neutrophil NADPH oxidase. # Regulation of RhoG activity As with all small G proteins RhoG is able to signal to downstream effectors when bound to GTP (Guanosine triphosphate) and unable to signal when bound to GDP (Guanosine diphosphate). Three classes of protein interact with RhoG to regulate GTP/GDP loading. The first are known as Guanine nucleotide exchange factors (GEFs) and these facilitate the exchange of GDP for GTP so as to promote subsequent RhoG-mediated signalling. The second class are known as GTPase activating proteins (GAPs) and these promote hydrolysis of GTP to GDP (via the intrinsic GTPase activity of the G protein) thus terminating RhoG-mediated signalling. A third group, known as Guanine nucleotide dissociation inhibitors (GDIs), inhibit dissociation of GDP and thus lock the G protein in its inactive state. GDIs can also sequester G proteins in the cytosol which also prevents their activation. The dynamic regulation of G protein signalling is necessarily complex and the 130 or more GEFs, GAPs and GDIs described thus far for the Rho family are considered to be the primary determinants of their spatiotemporal activity. There are a number of GEFs reported to interact with RhoG, although in some cases the physiological significance of these interactions has yet to be proven. Well characterised examples include the dual specificity GEF TRIO which is able to promote nucleotide exchange on RhoG and Rac (via its GEFD1 domain) and also on RhoA via a separate GEF domain (GEFD2). Activation of RhoG by TRIO has been shown to promote NGF-induced neurite outgrowth in PC12 cells and phagocytosis of apoptotic cells in C. elegans. Another GEF, known as SGEF (Src homology 3 domain-containing Guanine nucleotide Exchange Factor), is thought to be RhoG-specific and has been reported to stimulate macropinocytosis (internalisation of extracellular fluid) in fibroblasts and apical cup assembly in endothelial cells (an important stage in leukocyte trans-endothelial migration). Other GEFs reported to interact with RhoG include Dbs, ECT2, VAV2 and VAV3. There have been very few interactions reported between RhoG and negative regulators of G protein function. Examples include IQGAP2 and RhoGDI3. # Signalling downstream of RhoG Activated G proteins are able to couple to multiple downstream effectors and can therefore control a number of distinct signalling pathways (a characteristic known as pleiotropy). The extent to which RhoG regulates these pathways is poorly understood thus far, however, one specific pathway downstream of RhoG has received much attention and is therefore well characterised. This pathway involves RhoG-dependent activation of Rac via the DOCK (dedicator of cytokinesis)-family of GEFs. This family is divided into four subfamilies (A-D) and it is subfamilies A and B that are involved in the pathway described here. Dock180, the archetypal member of this family, is seen as an atypical GEF in that efficient GEF activity requires the presence of the DOCK-binding protein ELMO (engulfment and cell motility) which binds RhoG at its N-terminus. The proposed model for RhoG-dependent Rac activation involves recruitment of the ELMO/Dock180 complex to activated RhoG at the plasma membrane and this relocalisation, together with an ELMO-dependent conformational change in Dock180, is sufficient to promote GTP-loading of Rac. RhoG-mediated Rac signalling has been shown to promote neurite outgrowth and cell migration in mammalian cells as well as phagocytosis of apoptotic cells in C. elegans. Other proteins known to bind RhoG in its GTP-bound state include the microtubule-associated protein kinectin, Phospholipase D1 and the MAP Kinase activator MLK3. # Interactions RhoG has been shown to interact with KTN1.

RhoG RhoG (Ras homology Growth-related) (or ARGH) is a small (~21 kDa) monomeric GTP-binding protein (G protein), and is an important component of many intracellular signalling pathways. It is a member of the Rac subfamily of the Rho family of small G proteins[1] and is encoded by the gene RHOG.[2] # Discovery RhoG was first identified as a coding sequence upregulated in hamster lung fibroblasts upon stimulation with serum.[3] Expression of RhoG in mammals is widespread and studies of its function have been carried out in fibroblasts,[4] leukocytes,[5][6] neuronal cells,[7] endothelial cells[8] and HeLa cells.[9] RhoG belongs to the Rac subgroup and emerged as a consequence of retroposition in early vertebrates.[10] RhoG shares a subset of common binding partners with Rac, Cdc42 and RhoU/V members but a major specificity is its inability to bind to CRIB domain proteins such as PAKs.[4][11] # Function Like most small G proteins RhoG is involved in a diverse set of cellular signalling mechanisms. In mammalian cells these include cell motility (through regulation of the actin cytoskeleton),[9] gene transcription,[6][12] endocytosis,[13] neurite outgrowth,[7] protection from anoikis[14] and regulation of the neutrophil NADPH oxidase.[5] # Regulation of RhoG activity As with all small G proteins RhoG is able to signal to downstream effectors when bound to GTP (Guanosine triphosphate) and unable to signal when bound to GDP (Guanosine diphosphate). Three classes of protein interact with RhoG to regulate GTP/GDP loading. The first are known as Guanine nucleotide exchange factors (GEFs) and these facilitate the exchange of GDP for GTP so as to promote subsequent RhoG-mediated signalling. The second class are known as GTPase activating proteins (GAPs) and these promote hydrolysis of GTP to GDP (via the intrinsic GTPase activity of the G protein) thus terminating RhoG-mediated signalling. A third group, known as Guanine nucleotide dissociation inhibitors (GDIs), inhibit dissociation of GDP and thus lock the G protein in its inactive state. GDIs can also sequester G proteins in the cytosol which also prevents their activation. The dynamic regulation of G protein signalling is necessarily complex and the 130 or more GEFs, GAPs and GDIs described thus far for the Rho family are considered to be the primary determinants of their spatiotemporal activity. There are a number of GEFs reported to interact with RhoG, although in some cases the physiological significance of these interactions has yet to be proven. Well characterised examples include the dual specificity GEF TRIO which is able to promote nucleotide exchange on RhoG and Rac[15] (via its GEFD1 domain) and also on RhoA[16] via a separate GEF domain (GEFD2). Activation of RhoG by TRIO has been shown to promote NGF-induced neurite outgrowth in PC12 cells[17] and phagocytosis of apoptotic cells in C. elegans.[18] Another GEF, known as SGEF (Src homology 3 domain-containing Guanine nucleotide Exchange Factor), is thought to be RhoG-specific and has been reported to stimulate macropinocytosis (internalisation of extracellular fluid) in fibroblasts[19] and apical cup assembly in endothelial cells (an important stage in leukocyte trans-endothelial migration).[8] Other GEFs reported to interact with RhoG include Dbs, ECT2, VAV2 and VAV3.[11][20][21] There have been very few interactions reported between RhoG and negative regulators of G protein function. Examples include IQGAP2[11] and RhoGDI3.[22] # Signalling downstream of RhoG Activated G proteins are able to couple to multiple downstream effectors and can therefore control a number of distinct signalling pathways (a characteristic known as pleiotropy). The extent to which RhoG regulates these pathways is poorly understood thus far, however, one specific pathway downstream of RhoG has received much attention and is therefore well characterised. This pathway involves RhoG-dependent activation of Rac via the DOCK (dedicator of cytokinesis)-family of GEFs.[23] This family is divided into four subfamilies (A-D) and it is subfamilies A and B that are involved in the pathway described here. Dock180, the archetypal member of this family, is seen as an atypical GEF in that efficient GEF activity requires the presence of the DOCK-binding protein ELMO (engulfment and cell motility)[24] which binds RhoG at its N-terminus. The proposed model for RhoG-dependent Rac activation involves recruitment of the ELMO/Dock180 complex to activated RhoG at the plasma membrane and this relocalisation, together with an ELMO-dependent conformational change in Dock180, is sufficient to promote GTP-loading of Rac.[25][26] RhoG-mediated Rac signalling has been shown to promote neurite outgrowth[7] and cell migration[9] in mammalian cells as well as phagocytosis of apoptotic cells in C. elegans.[18] Other proteins known to bind RhoG in its GTP-bound state include the microtubule-associated protein kinectin,[27] Phospholipase D1 and the MAP Kinase activator MLK3.[11] # Interactions RhoG has been shown to interact with KTN1.[28][29]

https://www.wikidoc.org/index.php/RHOG

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wikidoc

RHOQ

RHOQ Rho-related GTP-binding protein RhoQ is a protein that in humans is encoded by the RHOQ gene. TC10 is a member of the RAS superfamily of small GTP-binding proteins (see HRAS, MIM 190020) involved in insulin-stimulated glucose uptake. In melanocytic cells RHOQ gene expression may be regulated by MITF. # Interactions RHOQ has been shown to interact with EXOC7, GOPC, PARD6B, WASL, CDC42EP2, TRIP10 and CDC42EP3.

RHOQ Rho-related GTP-binding protein RhoQ is a protein that in humans is encoded by the RHOQ gene.[1][2] TC10 is a member of the RAS superfamily of small GTP-binding proteins (see HRAS, MIM 190020) involved in insulin-stimulated glucose uptake.[supplied by OMIM][2] In melanocytic cells RHOQ gene expression may be regulated by MITF.[3] # Interactions RHOQ has been shown to interact with EXOC7,[4] GOPC,[5] PARD6B,[5][6] WASL,[7] CDC42EP2,[8] TRIP10[9] and CDC42EP3.[8]

https://www.wikidoc.org/index.php/RHOQ

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wikidoc

RIT1

RIT1 GTP-binding protein Rit1 is a protein that in humans is encoded by the RIT1 gene. # Function RIT belongs to the RAS (HRAS; MIM 190020) subfamily of small GTPases (Hynds et al., 2003). # Clinical significance Mutations in RIT1 are associated to Noonan syndrome . # Interactions RIT1 has been shown to interact with KLHL12 and Merlin.

RIT1 GTP-binding protein Rit1 is a protein that in humans is encoded by the RIT1 gene.[1][2][3] # Function RIT belongs to the RAS (HRAS; MIM 190020) subfamily of small GTPases (Hynds et al., 2003).[supplied by OMIM][3] # Clinical significance Mutations in RIT1 are associated to Noonan syndrome .[4] # Interactions RIT1 has been shown to interact with KLHL12[5] and Merlin.[6]

https://www.wikidoc.org/index.php/RIT1

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wikidoc

RIT2

RIT2 GTP-binding protein Rit2 is a protein that in humans is encoded by the RIT2 gene. RIN belongs to the RAS (HRAS; MIM 190020) superfamily of small GTPases (Shao et al., 1999). RIT2 has been associated with Parkinson's disease in two large genetic studies. An gene expression study of postmortem brain has suggested RIT2 interacts with interferon-γ signalling. # Interactions RIT2 has been shown to interact with POU4F1.

RIT2 GTP-binding protein Rit2 is a protein that in humans is encoded by the RIT2 gene.[1][2][3] RIN belongs to the RAS (HRAS; MIM 190020) superfamily of small GTPases (Shao et al., 1999).[supplied by OMIM][3] RIT2 has been associated with Parkinson's disease in two large genetic studies.[4][5] An gene expression study of postmortem brain has suggested RIT2 interacts with interferon-γ signalling.[6] # Interactions RIT2 has been shown to interact with POU4F1.[7]

https://www.wikidoc.org/index.php/RIT2

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wikidoc

Rnd1

Rnd1 Rnd1 is a small (~21 kDa) signaling G protein (to be specific, a GTPase), and is a member of the Rnd subgroup of the Rho family of GTPases. It is encoded by the gene RND1. It contributes to regulating the organization of the actin cytoskeleton in response to extracellular growth factors (Nobes et al., 1998). # Interactions Rnd1 has been shown to interact with GRB7, PLXNB1, PDE6D, ARHGAP5 and UBXD5.

Rnd1 Rnd1 is a small (~21 kDa) signaling G protein (to be specific, a GTPase), and is a member of the Rnd subgroup of the Rho family of GTPases.[1] It is encoded by the gene RND1.[2] It contributes to regulating the organization of the actin cytoskeleton in response to extracellular growth factors (Nobes et al., 1998).[supplied by OMIM][2] # Interactions Rnd1 has been shown to interact with GRB7,[3] PLXNB1,[4] PDE6D,[5][6] ARHGAP5[7] and UBXD5.[8]

https://www.wikidoc.org/index.php/RND1

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wikidoc

Rnd2

Rnd2 Rnd2 is a small (~21 kDa) signaling G protein (to be specific, a GTPase), and is a member of the Rnd subgroup of the Rho family of GTPases. It is encoded by the gene RND2. # Function It contributes to regulating the organization of the actin cytoskeleton in response to extracellular growth factors (Nobes et al., 1998). This particular family member has been implicated in the regulation of neuronal morphology and endosomal trafficking. # Clinical significance The gene localizes to chromosome 17 and is the centromeric neighbor of the breast-ovarian cancer susceptibility gene BRCA1. # Interactions Rnd2 has been shown to interact with: - ARHGAP5, - RACGAP1, and - UBXD5.

Rnd2 Rnd2 is a small (~21 kDa) signaling G protein (to be specific, a GTPase), and is a member of the Rnd subgroup of the Rho family of GTPases.[1] It is encoded by the gene RND2.[2] # Function It contributes to regulating the organization of the actin cytoskeleton in response to extracellular growth factors (Nobes et al., 1998).[supplied by OMIM][3] This particular family member has been implicated in the regulation of neuronal morphology and endosomal trafficking. # Clinical significance The gene localizes to chromosome 17 and is the centromeric neighbor of the breast-ovarian cancer susceptibility gene BRCA1.[2] # Interactions Rnd2 has been shown to interact with: - ARHGAP5,[4] - RACGAP1,[5] and - UBXD5.[6]

https://www.wikidoc.org/index.php/RND2

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wikidoc

Rnd3

Rnd3 Rnd3 is a small (~21 kDa) signaling G protein (to be specific, a GTPase), and is a member of the Rnd subgroup of the Rho family of GTPases. It is encoded by the gene RND3. Like other members of the Rho family of Ras-related GTPases it regulates the organization of the actin cytoskeleton in response to extracellular growth factors. # Regulation Like Ras, Rho family members appear to cycle between an inactive GDP-bound form and an active GTP-bound form. Three major regulators of Rho activity have been identified: RhoGDIs, which interact with the GDP-bound Rho proteins to keep them in a resting complex (see MIM 601925); GEFs, which promote GDP/GTP exchange leading to activation of Rho proteins (see MIM 601855); and GAPs, which stimulate GTP hydrolysis and return the activated Rho protein to its inactive form (see MIM 602680) (Nobes et al., 1998). # Interactions Rnd3 has been shown to interact with ARHGAP5 and UBXD5.

Rnd3 Rnd3 is a small (~21 kDa) signaling G protein (to be specific, a GTPase), and is a member of the Rnd subgroup of the Rho family of GTPases.[1] It is encoded by the gene RND3.[2] Like other members of the Rho family of Ras-related GTPases it regulates the organization of the actin cytoskeleton in response to extracellular growth factors. # Regulation Like Ras, Rho family members appear to cycle between an inactive GDP-bound form and an active GTP-bound form. Three major regulators of Rho activity have been identified: RhoGDIs, which interact with the GDP-bound Rho proteins to keep them in a resting complex (see MIM 601925); GEFs, which promote GDP/GTP exchange leading to activation of Rho proteins (see MIM 601855); and GAPs, which stimulate GTP hydrolysis and return the activated Rho protein to its inactive form (see MIM 602680) (Nobes et al., 1998).[supplied by OMIM][2] # Interactions Rnd3 has been shown to interact with ARHGAP5[3] and UBXD5.[4]

https://www.wikidoc.org/index.php/RND3

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wikidoc

RNF4

RNF4 RING finger protein 4 is a protein that in humans is encoded by the RNF4 gene. The protein encoded by this gene contains a RING finger domain and acts as a transcription factor. This protein has been shown to interact with, and inhibit the activity of, TRPS1, a transcription suppressor of GATA-mediated transcription. Transcription repressor ZNF278/PATZ1 is found to interact with this protein, and thus reduce the enhancement of androgen receptor-dependent transcription mediated by this protein. Studies of the mouse and rat counterparts suggested a role of this protein in spermatogenesis. # Interactions RNF4 has been shown to interact with TCF20, PATZ1 and Androgen receptor.

RNF4 RING finger protein 4 is a protein that in humans is encoded by the RNF4 gene.[1][2] The protein encoded by this gene contains a RING finger domain and acts as a transcription factor. This protein has been shown to interact with, and inhibit the activity of, TRPS1, a transcription suppressor of GATA-mediated transcription. Transcription repressor ZNF278/PATZ1 is found to interact with this protein, and thus reduce the enhancement of androgen receptor-dependent transcription mediated by this protein. Studies of the mouse and rat counterparts suggested a role of this protein in spermatogenesis.[2] # Interactions RNF4 has been shown to interact with TCF20,[3] PATZ1[4][5] and Androgen receptor.[5][6][7]

https://www.wikidoc.org/index.php/RNF4

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wikidoc

RNF8

RNF8 E3 ubiquitin-protein ligase RNF8 is an enzyme that in humans is encoded by the RNF8 gene. RNF8 has activity both in immune system functions and in DNA repair. # Function The protein encoded by this gene contains a RING finger motif and an FHA domain. This protein has been shown to interact with several class II ubiquitin-conjugating enzymes (E2), including UBE2E1/UBCH6, UBE2E2, and UBE2E3, and may act as a ubiquitin ligase (E3) in the ubiquitination of certain nuclear proteins. Alternatively spliced transcript variants encoding distinct isoforms have been reported. RNF8 promotes repair of DNA damage through three DNA repair pathways: homologous recombinational repair (HRR), non-homologous end joining (NHEJ), and nucleotide excision repair (NER). DNA damage is considered to be the primary cause of cancer, and deficiency in DNA repair can cause mutations leading to cancer. A deficiency in RNF8 predisposes mice to cancer. # Chromatin remodeling After the occurrence of a double-strand break in DNA, the chromatin needs to be relaxed to allow DNA repair, either by HRR or by NHEJ. There are two pathways that result in chromatin relaxation, one initiated by PARP1 and one initiated by γH2AX (the phosphorylated form of the H2AX protein) (see Chromatin remodeling). Chromatin remodeling initiated by γH2AX depends on RNF8, as described below. The histone variant H2AX constitutes about 10% of the H2A histones in human chromatin. At the site of a DNA double-strand break, the extent of chromatin with phosphorylated γH2AX is about two million base pairs. γH2AX does not, by itself, cause chromatin decondensation, but within seconds of irradiation the protein “Mediator of the DNA damage checkpoint 1” (MDC1) specifically attaches to γH2AX. This is accompanied by simultaneous accumulation of RNF8 protein and the DNA repair protein NBS1 which bind to MDC1. RNF8 mediates extensive chromatin decondensation through its subsequent interaction with CHD4 protein, a component of the nucleosome remodeling and deacetylase complex NuRD. # RNF8 in Homologous Recombinational Repair DNA end resection is a pivotal step in HRR repair that produces 3’ overhangs that provide a platform to recruit proteins involved in HRR repair. The MRN complex, consisting of Mre11, Rad50 and NBS1, carries out the initial steps of this end resection. RNF8 ubiquitinates NBS1 (both before and after DNA damage occurs), and this ubiquitination is required for effective homologous recombinational repair. Ubiquitination of NBS1 by RNF8 is, however, not required for the role of NBS1 in another DNA repair process, the error-prone microhomology-mediated end joining DNA repair. RNF8 appears to have other roles in HRR as well. RNF8, acting as a ubiquitin ligase, mono-ubiquitinates γH2AX to tether DNA repair molecules at DNA lesions. In particular, RNF8 activity is required to recruit BRCA1 for homologous recombination repair. # RNF8 in Non-Homologous End Joining Ku protein is a dimeric protein complex, a heterodimer of two polypeptides, Ku70 and Ku80. Ku protein forms a ring structure. An early step in non-homologous end joining DNA repair of a double-strand break is the slipping of a Ku protein (with its ring protein structure) over each end of the broken DNA. The two Ku proteins, one on each broken end, bind to each other and form a bridge. This protects the DNA ends and forms a platform for further DNA repair enzymes to operate. After the broken ends are rejoined, the two Ku proteins still encircle the now intact DNA and can no longer slip off an end. The Ku proteins must be removed or they cause loss of cell viability. The removal of Ku protein is performed either by RNF8 ubiquitination of Ku80, allowing it to be released from the Ku protein ring, or else by NEDD8 promoted ubiquitination of Ku protein, causing its release from DNA. # RNF8 in Nucleotide Excision Repair UV-induced formation of pyrimidine dimers in DNA can lead to cell death unless the lesions are repaired. Most repair of these lesions is by nucleotide excision repair. After UV-irradiation, RNF8 is recruited to sites of UV-induced DNA damage and ubiquitinates chromatin component histone H2A. These responses provide partial protection against UV irradiation. # Impaired spermatogenesis Spermatogenesis is the process in which spermatozoa are produced from spermatogonial stem cells by way of mitosis and meiosis. A major function of meiosis is homologous recombinational repair of this germline DNA. RNF8 plays an essential role in signaling the presence of DNA double-strand breaks. Male mice with a gene knockout for RNF8 have impaired spermatogenesis, apparently due to a defect in homologous recombinational repair. # Interactions RNF8 has been shown to interact with Retinoid X receptor alpha.

RNF8 E3 ubiquitin-protein ligase RNF8 is an enzyme that in humans is encoded by the RNF8 gene.[1][2][3] RNF8 has activity both in immune system functions[4] and in DNA repair. # Function The protein encoded by this gene contains a RING finger motif and an FHA domain. This protein has been shown to interact with several class II ubiquitin-conjugating enzymes (E2), including UBE2E1/UBCH6, UBE2E2, and UBE2E3, and may act as a ubiquitin ligase (E3) in the ubiquitination of certain nuclear proteins. Alternatively spliced transcript variants encoding distinct isoforms have been reported.[3] RNF8 promotes repair of DNA damage through three DNA repair pathways: homologous recombinational repair (HRR),[5] non-homologous end joining (NHEJ),[6][7] and nucleotide excision repair (NER).[6] DNA damage is considered to be the primary cause of cancer, and deficiency in DNA repair can cause mutations leading to cancer.[8][9] A deficiency in RNF8 predisposes mice to cancer.[10][11] # Chromatin remodeling After the occurrence of a double-strand break in DNA, the chromatin needs to be relaxed to allow DNA repair, either by HRR or by NHEJ. There are two pathways that result in chromatin relaxation, one initiated by PARP1 and one initiated by γH2AX (the phosphorylated form of the H2AX protein) (see Chromatin remodeling). Chromatin remodeling initiated by γH2AX depends on RNF8, as described below. The histone variant H2AX constitutes about 10% of the H2A histones in human chromatin.[12] At the site of a DNA double-strand break, the extent of chromatin with phosphorylated γH2AX is about two million base pairs.[12] γH2AX does not, by itself, cause chromatin decondensation, but within seconds of irradiation the protein “Mediator of the DNA damage checkpoint 1” (MDC1) specifically attaches to γH2AX.[13][14] This is accompanied by simultaneous accumulation of RNF8 protein and the DNA repair protein NBS1 which bind to MDC1.[15] RNF8 mediates extensive chromatin decondensation through its subsequent interaction with CHD4 protein,[16] a component of the nucleosome remodeling and deacetylase complex NuRD. # RNF8 in Homologous Recombinational Repair DNA end resection is a pivotal step in HRR repair that produces 3’ overhangs that provide a platform to recruit proteins involved in HRR repair. The MRN complex, consisting of Mre11, Rad50 and NBS1, carries out the initial steps of this end resection.[17] RNF8 ubiquitinates NBS1 (both before and after DNA damage occurs), and this ubiquitination is required for effective homologous recombinational repair.[5] Ubiquitination of NBS1 by RNF8 is, however, not required for the role of NBS1 in another DNA repair process, the error-prone microhomology-mediated end joining DNA repair.[5] RNF8 appears to have other roles in HRR as well. RNF8, acting as a ubiquitin ligase, mono-ubiquitinates γH2AX to tether DNA repair molecules at DNA lesions.[18] In particular, RNF8 activity is required to recruit BRCA1 for homologous recombination repair.[19] # RNF8 in Non-Homologous End Joining Ku protein is a dimeric protein complex, a heterodimer of two polypeptides, Ku70 and Ku80. Ku protein forms a ring structure. An early step in non-homologous end joining DNA repair of a double-strand break is the slipping of a Ku protein (with its ring protein structure) over each end of the broken DNA. The two Ku proteins, one on each broken end, bind to each other and form a bridge.[20][21] This protects the DNA ends and forms a platform for further DNA repair enzymes to operate. After the broken ends are rejoined, the two Ku proteins still encircle the now intact DNA and can no longer slip off an end. The Ku proteins must be removed or they cause loss of cell viability.[22] The removal of Ku protein is performed either by RNF8 ubiquitination of Ku80, allowing it to be released from the Ku protein ring,[23] or else by NEDD8 promoted ubiquitination of Ku protein, causing its release from DNA.[22] # RNF8 in Nucleotide Excision Repair UV-induced formation of pyrimidine dimers in DNA can lead to cell death unless the lesions are repaired. Most repair of these lesions is by nucleotide excision repair.[24] After UV-irradiation, RNF8 is recruited to sites of UV-induced DNA damage and ubiquitinates chromatin component histone H2A. These responses provide partial protection against UV irradiation.[6][25] # Impaired spermatogenesis Spermatogenesis is the process in which spermatozoa are produced from spermatogonial stem cells by way of mitosis and meiosis. A major function of meiosis is homologous recombinational repair of this germline DNA.[26] RNF8 plays an essential role in signaling the presence of DNA double-strand breaks. Male mice with a gene knockout for RNF8 have impaired spermatogenesis, apparently due to a defect in homologous recombinational repair.[10] # Interactions RNF8 has been shown to interact with Retinoid X receptor alpha.[27]

https://www.wikidoc.org/index.php/RNF8

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ROMK

ROMK The renal outer medullary potassium channel (ROMK) is an ATP-dependent potassium channel (Kir1.1) that transports potassium out of cells. It plays an important role in potassium recycling in the thick ascending limb (TAL) and potassium secretion in the cortical collecting duct (CCD) of the nephron. In humans, ROMK is encoded by the KCNJ1 (potassium inwardly-rectifying channel, subfamily J, member 1) gene. Multiple transcript variants encoding different isoforms have been found for this gene. # Function Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. It is inhibited by internal ATP and probably plays an important role in potassium homeostasis. The encoded protein has a greater tendency to allow potassium to flow into a cell rather than out of a cell (hence the term "inwardly rectifying"). ROMK was identified as the pore-forming component of the mitochondrial ATP-sensitive potassium (mitoKATP) channel, known to play a critical role in cardioprotection against ischemic-reperfusion injury in the heart as well as in the protection against hypoxia-induced brain injury from stroke or other ischemic attacks. # Clinical significance Mutations in this gene have been associated with antenatal Bartter syndrome, which is characterized by salt wasting, hypokalemic alkalosis, hypercalciuria, and low blood pressure. # Role in hypokalemia and magnesium deficiency The ROMK channels are inhibited by magnesium in the nephron's normal physiologic state. In states of hypokalemia (a state of potassium deficiency), concurrent magnesium deficiency results in a state of hypokalemia that may be more difficult to correct with potassium replacement alone. This may be directly due to decreased inhibition of the outward potassium current in states where magnesium is low. Conversely, magnesium deficiency alone is not likely to cause a state of hypokalemia .

ROMK The renal outer medullary potassium channel (ROMK) is an ATP-dependent potassium channel (Kir1.1) that transports potassium out of cells. It plays an important role in potassium recycling in the thick ascending limb (TAL) and potassium secretion in the cortical collecting duct (CCD) of the nephron. In humans, ROMK is encoded by the KCNJ1 (potassium inwardly-rectifying channel, subfamily J, member 1) gene.[1][2][3] Multiple transcript variants encoding different isoforms have been found for this gene.[4] # Function Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. It is inhibited by internal ATP and probably plays an important role in potassium homeostasis. The encoded protein has a greater tendency to allow potassium to flow into a cell rather than out of a cell (hence the term "inwardly rectifying").[4] ROMK was identified as the pore-forming component of the mitochondrial ATP-sensitive potassium (mitoKATP) channel, known to play a critical role in cardioprotection against ischemic-reperfusion injury in the heart[5] as well as in the protection against hypoxia-induced brain injury from stroke or other ischemic attacks. # Clinical significance Mutations in this gene have been associated with antenatal Bartter syndrome, which is characterized by salt wasting, hypokalemic alkalosis, hypercalciuria, and low blood pressure.[4] # Role in hypokalemia and magnesium deficiency The ROMK channels are inhibited by magnesium in the nephron's normal physiologic state. In states of hypokalemia (a state of potassium deficiency), concurrent magnesium deficiency results in a state of hypokalemia that may be more difficult to correct with potassium replacement alone. This may be directly due to decreased inhibition of the outward potassium current in states where magnesium is low. Conversely, magnesium deficiency alone is not likely to cause a state of hypokalemia [6].

https://www.wikidoc.org/index.php/ROMK

459bc2b79ffd6491cbe80cabd617d24e90158c42

wikidoc

ROR1

ROR1 Tyrosine-protein kinase transmembrane receptor ROR1, also known as neurotrophic tyrosine kinase, receptor-related 1 (NTRKR1), is an enzyme that in humans is encoded by the ROR1 gene. ROR1 is a member of the receptor tyrosine kinase-like orphan receptor (ROR) family. # Function The protein encoded by this gene is a receptor tyrosine kinase that modulates neurite growth in the central nervous system. It is a type I membrane protein and belongs to the ROR subfamily of cell surface receptors. ROR1 is currently under investigation for its role in the metastasis of cancer cells. ROR1 has recently been shown to be expressed on ovarian cancer stem cell, on which it seems to play a functional role in promoting migration/invasion or spheroid formation in vitro and tumor engraftment in immune-deficient mice. Treatment with a humanized mAb specific for ROR1 (UC-961) could inhibit the capacity of ovarian cancer cells to migrate, form spheroids, or engraft immune-deficient mice. Moreover, such treatment inhibited the growth of tumor xenografts, which in turn had a reduced capacity to engraft immune-deficient mice and were relatively depleted of cells with features of CSC, suggesting that treatment with UC-961 could impair CSC renewal. Collectively, these studies indicate that ovarian CSCs express ROR1, which may be targeted for anti-CSC therapy.

ROR1 Tyrosine-protein kinase transmembrane receptor ROR1, also known as neurotrophic tyrosine kinase, receptor-related 1 (NTRKR1), is an enzyme that in humans is encoded by the ROR1 gene.[1][2][3] ROR1 is a member of the receptor tyrosine kinase-like orphan receptor (ROR) family. # Function The protein encoded by this gene is a receptor tyrosine kinase that modulates neurite growth in the central nervous system. It is a type I membrane protein and belongs to the ROR subfamily of cell surface receptors.[1] ROR1 is currently under investigation for its role in the metastasis of cancer cells.[4] ROR1 has recently been shown to be expressed on ovarian cancer stem cell, on which it seems to play a functional role in promoting migration/invasion or spheroid formation in vitro and tumor engraftment in immune-deficient mice. Treatment with a humanized mAb specific for ROR1 (UC-961) could inhibit the capacity of ovarian cancer cells to migrate, form spheroids, or engraft immune-deficient mice. Moreover, such treatment inhibited the growth of tumor xenografts, which in turn had a reduced capacity to engraft immune-deficient mice and were relatively depleted of cells with features of CSC, suggesting that treatment with UC-961 could impair CSC renewal. Collectively, these studies indicate that ovarian CSCs express ROR1, which may be targeted for anti-CSC therapy.[5]

https://www.wikidoc.org/index.php/ROR1

53e00492d0fe5cf258e70b6e43b49530df775596

wikidoc

ROR2

ROR2 Tyrosine-protein kinase transmembrane receptor ROR2 also known as neurotrophic tyrosine kinase, receptor-related 2, is a protein that in humans is encoded by the ROR2 gene located on position 9 of the long arm of chromosome 9. This protein is responsible for aspects of bone and cartilage growth. It is involved in Robinow syndrome and autosomal dominant brachydactyly type B. ROR2 is a member of the receptor tyrosine kinase-like orphan receptor (ROR) family. # Function The protein encoded by this gene is a receptor tyrosine kinase and type I transmembrane protein that belongs to the ROR subfamily of cell surface receptors. The protein may be involved in the early formation of the chondrocytes and may be required for cartilage and growth plate development. # Clinical significance Mutations in this gene can cause brachydactyly type B, a skeletal disorder characterized by hypoplasia/aplasia of distal phalanges and nails. In addition, mutations in this gene can cause the autosomal recessive form of Robinow syndrome, which is characterized by skeletal dysplasia with generalized limb bone shortening, segmental defects of the spine, brachydactyly, and a dysmorphic facial appearance.

ROR2 Tyrosine-protein kinase transmembrane receptor ROR2 also known as neurotrophic tyrosine kinase, receptor-related 2, is a protein that in humans is encoded by the ROR2 gene located on position 9 of the long arm of chromosome 9.[1][2][3] This protein is responsible for aspects of bone and cartilage growth. It is involved in Robinow syndrome and autosomal dominant brachydactyly type B. ROR2 is a member of the receptor tyrosine kinase-like orphan receptor (ROR) family. # Function The protein encoded by this gene is a receptor tyrosine kinase and type I transmembrane protein that belongs to the ROR subfamily of cell surface receptors. The protein may be involved in the early formation of the chondrocytes and may be required for cartilage and growth plate development.[1] # Clinical significance Mutations in this gene can cause brachydactyly type B, a skeletal disorder characterized by hypoplasia/aplasia of distal phalanges and nails. In addition, mutations in this gene can cause the autosomal recessive form of Robinow syndrome, which is characterized by skeletal dysplasia with generalized limb bone shortening, segmental defects of the spine, brachydactyly, and a dysmorphic facial appearance.[1]

https://www.wikidoc.org/index.php/ROR2

cc98e807eb1640d9420dfcdc95258ba487cf78bb

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ROS1

ROS1 Proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans is encoded by the ROS1 gene. # Function This proto-oncogene, highly expressed in a variety of tumor cell lines, belongs to the sevenless subfamily of tyrosine kinase insulin receptor genes. The protein encoded by this gene is a type I integral membrane protein with tyrosine kinase activity. The protein may function as a growth or differentiation factor receptor. # Role in cancer ROS1 is a receptor tyrosine kinase (encoded by the gene ROS1) with structural similarity to the anaplastic lymphoma kinase (ALK) protein; it is encoded by the c-ros oncogene and was first identified in 1986. The exact role of the ROS1 protein in normal development, as well as its normal physiologic ligand, have not been defined. Nonetheless, as gene rearrangement events involving ROS1 have been described in lung and other cancers, and since such tumors have been found to be remarkably responsive to small molecule tyrosine kinase inhibitors, interest in identifying ROS1 rearrangements as a therapeutic target in cancer has been increasing. Recently, the small molecule tyrosine kinase inhibitor, crizotinib, was approved for the treatment of patients with metastatic NSCLC whose tumors are ROS1 -positive. Gene rearrangements involving the ROS1 gene were first detected in glioblastoma tumors and cell lines. In 2007 a ROS1 rearrangement was identified in a cell line derived from a lung adenocarcinoma patient. Since that discovery, multiple studies have demonstrated an incidence of approximately 1% in lung cancers, demonstrated oncogenicity, and showed that inhibition of tumor cells bearing ROS1 gene fusions by crizotinib or other ROS1 tyrosine kinase inhibitors was effective in vitro. Clinical data supports the use of crizotinib in lung cancer patients with ROS1 gene fusions. Preclinical and clinical work suggests multiple potential mechanisms of drug resistance in ROS1 + lung cancer, including kinase domain mutations in ROS1 and bypass signaling via RAS and EGFR. Although the most preclinical and clinical studies of ROS1 gene fusions have been performed in lung cancer, ROS1 fusions have been detected in multiple other tumor histologies, including ovarian carcinoma, sarcoma, cholangiocarcinomas and others. Crizotinib or other ROS1 inhibitors may be effective in other tumor histologies beyond lung cancer as demonstrated by a patient with an inflammatory myofibroblastic tumor harboring a ROS1 fusion with a dramatic response to crizotinib. # Preclinical findings From a large-scale survey of tyrosine kinase activity in non-small cell lung cancer (NSCLC), and identified more than 50 distinct tyrosine kinases and over 2500 downstream substrates, with the goal of identifying candidate oncogenes. In a sampling of 96 tissue samples from NSCLC patients, approximately 30% displayed high levels of phosphotyrosine expression; further analysis was conducted to identify highly phosphorylated tyrosine kinases in NSCLC from a panel of 41 NSCLC cell lines, and 150 patient samples. Among the top 20 receptor tyrosine kinases identified in this analysis, 15 were identified in both cell lines and tumors, and among these were both ALK and These initial findings paved the way for more expansive analyses of ROS1 kinase fusions in NSCLC and other cancers. # Fusion prevalence In patients with NSCLC, approximately 2% are positive for a ROS1 gene rearrangement, and these rearrangements are mutually exclusive of ALK rearrangement. ROS1 fusion-positive patients tend to be younger, with a median age of 49.8 years, and never-smokers, with a diagnosis of adenocarcinoma. There is a higher representation of Asian ethnicity and patients with Stage IV disease. ROS1 rearrangements are estimated to be roughly half as common as ALK-rearranged NSCLCs. Similar to ALK-rearranged, ROS1-rearranged NSCLC have younger age of onset and a non-smoking history. A benefit of a small-molecule ALK, ROS1 , and cMET inhibitor, crizotinib, was also shown in this patient group. ROS1 expression was found in approximately 2% of NSCLC patients, and its expression was limited to those patients with ROS1 gene fusions. Similar findings were reported in a separate analysis of 447 NSCLC samples, of which 1.2% were found to be positive for ROS1 rearrangement; this study also confirmed the activity of the ALK/ROS1 /cMET inhibitor crizotinib in ROS1 -positive tumors. ROS1 fusions were also identified in approximately 2% of adenocarcinomas and 1% of glioblastoma samples in an assessment of kinase fusions across different cancers. Table 1: Sampling of ROS1 Rearrangements Observed in NSCLC and Other Cancers. All of the kinase fusions retain the tyrosine kinase domain of ROS1 . List is not exhaustive. (Adapted from Stumpfova 2012). - Multiple variant isoforms observed CD74; cluster of differentiation 74, long/short isoforms; EZR; ezrin; FIG; fused in glioblastoma; SDC4; LRIG3; leucine-rich repeats and immunoglobulin-like domains 3; SDC; syndecan 4; SLC34A2; solute carrier family 34 (sodium phosphate), member 2; TPM3; tropomyosin 3 # As a drug target Several drugs target ROS1 fusions in cancer, with varying levels of success; most of the drugs to date have been tested only for ROS1-positive non-small cell lung carcinoma (NSCLC). However, some clinical trials (like those for entrectinib, DS-6051b, and TPX-0005) accept patients with ROS1 cancer in any type of solid tumor. - Crizotinib is approved for treating metastatic ROS1-positive NSCLC in many countries. In clinical trials, crizotinib was shown to be effective for 70-80% of ROS1+ NSCLC patients, but it does not effectively treat the brain. Some patients have a response that lasts for years. Crizotinib is available to patients with solid tumors other than NSCLC through clinical trials. - Entrectinib (RXDX-101) is a selective tyrosine kinase inhibitor developed by Ignyta, Inc., with specificity, at low nanomolar concentrations, for all of three Trk proteins (encoded by the three NTRK genes, respectively) as well as the ROS1, and ALK receptor tyrosine kinases. An open label, multicenter, global phase 2 clinical trial called STARTRK-2 started in 2015 to test the drug in patients with ROS1/NTRK/ALK gene rearrangements. - Lorlatinib (also known as PF-06463922) was shown in an ongoing Phase 2 clinical trial to be effective in some ROS1+ NSCLC patients, and treats the cancer in the brain as well as the body. Lorlatinib has the potential to overcome certain resistance mutations that develop during treatment with crizotinib. - Ceritinib demonstrates clinical activity (including treating the brain) in ROS1+ NSCLC patients who had previously received platinum-based chemotherapy. In preclinical studies, ceritinib is unable to overcome most ROS1 resistance mutations, including ROS1 G2032R. It has more severe side effects than crizotinib for some patients. Ceritinib is US FDA approved for first line treatment of ALK+ metastatic non-small cell lung cancer. - TPX-0005 preclinical data suggests it is a potent inhibitor of ROS1+ cancer. A Phase I clinical trial opened in March 2017 for patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements. - DS-6051b preclinical data show it is active against ROS1-positive cancers. It is an ongoing clinical trial. - Cabozantinib preclinical data has shown the drug might overcome crizotinib resistance in ROS1+ cancer in early studies. However, the required dosage makes the drug difficult to tolerate for many patients. Cabozantinib is US FDA approved for metastatic medullary thyroid cancer (as Cometriq) and renal cell carcinoma (as Cabometyx). # Global ROS1 Initiative The Global ROS1 Initiative is a worldwide, multi-stakeholder collaboration with a goal of improving patient outcomes and accelerating research for any type of ROS1+ cancer. It is the first such collaboration focused on cancers driven by a single oncogene and was initiated by ROS1+ cancer patients and carers who call themselves "The ROS1ders."; their website tracks targeted therapies, clinical trials, world experts and new developments for ROS1+ cancers. Partners in the Initiative include patient-focused nonprofits Bonnie J. Addario Lung Cancer Foundation and Addario Lung Cancer Medical Institute, clinicians who treat ROS1+ patients, ROS1 researchers, pharmaceutical firms and biotech companies.

ROS1 Proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans is encoded by the ROS1 gene.[1][2] # Function This proto-oncogene, highly expressed in a variety of tumor cell lines, belongs to the sevenless subfamily of tyrosine kinase insulin receptor genes. The protein encoded by this gene is a type I integral membrane protein with tyrosine kinase activity. The protein may function as a growth or differentiation factor receptor.[2] # Role in cancer ROS1 is a receptor tyrosine kinase (encoded by the gene ROS1) with structural similarity to the anaplastic lymphoma kinase (ALK) protein; it is encoded by the c-ros oncogene and was first identified in 1986.[3][4][5][6] The exact role of the ROS1 protein in normal development, as well as its normal physiologic ligand, have not been defined.[4] Nonetheless, as gene rearrangement events involving ROS1 have been described in lung and other cancers, and since such tumors have been found to be remarkably responsive to small molecule tyrosine kinase inhibitors, interest in identifying ROS1 rearrangements as a therapeutic target in cancer has been increasing.[3][7] Recently, the small molecule tyrosine kinase inhibitor, crizotinib, was approved for the treatment of patients with metastatic NSCLC whose tumors are ROS1 -positive.[8] Gene rearrangements involving the ROS1 gene were first detected in glioblastoma tumors and cell lines.[9][10] In 2007 a ROS1 rearrangement was identified in a cell line derived from a lung adenocarcinoma patient.[11] Since that discovery, multiple studies have demonstrated an incidence of approximately 1% in lung cancers, demonstrated oncogenicity, and showed that inhibition of tumor cells bearing ROS1 gene fusions by crizotinib or other ROS1 tyrosine kinase inhibitors was effective in vitro.[12][13][14] Clinical data supports the use of crizotinib in lung cancer patients with ROS1 gene fusions.[15][16] Preclinical and clinical work suggests multiple potential mechanisms of drug resistance in ROS1 + lung cancer, including kinase domain mutations in ROS1 and bypass signaling via RAS and EGFR.[17][18][19] Although the most preclinical and clinical studies of ROS1 gene fusions have been performed in lung cancer, ROS1 fusions have been detected in multiple other tumor histologies, including ovarian carcinoma, sarcoma, cholangiocarcinomas and others.[20] Crizotinib or other ROS1 inhibitors may be effective in other tumor histologies beyond lung cancer as demonstrated by a patient with an inflammatory myofibroblastic tumor harboring a ROS1 fusion with a dramatic response to crizotinib.[21] # Preclinical findings From a large-scale survey of tyrosine kinase activity in non-small cell lung cancer (NSCLC), and identified more than 50 distinct tyrosine kinases and over 2500 downstream substrates, with the goal of identifying candidate oncogenes.[22] In a sampling of 96 tissue samples from NSCLC patients, approximately 30% displayed high levels of phosphotyrosine expression; further analysis was conducted to identify highly phosphorylated tyrosine kinases in NSCLC from a panel of 41 NSCLC cell lines, and 150 patient samples.[22] Among the top 20 receptor tyrosine kinases identified in this analysis, 15 were identified in both cell lines and tumors, and among these were both ALK and [22] These initial findings paved the way for more expansive analyses of ROS1 kinase fusions in NSCLC and other cancers. # Fusion prevalence In patients with NSCLC, approximately 2% are positive for a ROS1 gene rearrangement, and these rearrangements are mutually exclusive of ALK rearrangement.[23][unreliable medical source] ROS1 fusion-positive patients tend to be younger, with a median age of 49.8 years, and never-smokers, with a diagnosis of adenocarcinoma. There is a higher representation of Asian ethnicity and patients with Stage IV disease.[23] ROS1 rearrangements are estimated to be roughly half as common as ALK-rearranged NSCLCs. Similar to ALK-rearranged, ROS1-rearranged NSCLC have younger age of onset and a non-smoking history.[23] A benefit of a small-molecule ALK, ROS1 , and cMET inhibitor, crizotinib, was also shown in this patient group. ROS1 expression was found in approximately 2% of NSCLC patients, and its expression was limited to those patients with ROS1 gene fusions.[7][unreliable medical source] Similar findings were reported in a separate analysis of 447 NSCLC samples, of which 1.2% were found to be positive for ROS1 rearrangement; this study also confirmed the activity of the ALK/ROS1 /cMET inhibitor crizotinib in ROS1 -positive tumors.[4] ROS1 fusions were also identified in approximately 2% of adenocarcinomas and 1% of glioblastoma samples in an assessment of kinase fusions across different cancers.[24][unreliable medical source] Table 1: Sampling of ROS1 Rearrangements Observed in NSCLC and Other Cancers. All of the kinase fusions retain the tyrosine kinase domain of ROS1 . List is not exhaustive. (Adapted from Stumpfova 2012). * Multiple variant isoforms observed CD74; cluster of differentiation 74, long/short isoforms; EZR; ezrin; FIG; fused in glioblastoma; SDC4; LRIG3; leucine-rich repeats and immunoglobulin-like domains 3; SDC; syndecan 4; SLC34A2; solute carrier family 34 (sodium phosphate), member 2; TPM3; tropomyosin 3 # As a drug target Several drugs target ROS1 fusions in cancer, with varying levels of success; most of the drugs to date have been tested only for ROS1-positive non-small cell lung carcinoma (NSCLC).[25] However, some clinical trials (like those for entrectinib, DS-6051b, and TPX-0005) accept patients with ROS1 cancer in any type of solid tumor. - Crizotinib is approved for treating metastatic ROS1-positive NSCLC in many countries. In clinical trials, crizotinib was shown to be effective for 70-80% of ROS1+ NSCLC patients, but it does not effectively treat the brain. Some patients have a response that lasts for years.[26] Crizotinib is available to patients with solid tumors other than NSCLC through clinical trials.[27][28] - Entrectinib (RXDX-101) is a selective tyrosine kinase inhibitor developed by Ignyta, Inc., with specificity, at low nanomolar concentrations, for all of three Trk proteins (encoded by the three NTRK genes, respectively) as well as the ROS1, and ALK receptor tyrosine kinases. An open label, multicenter, global phase 2 clinical trial called STARTRK-2 started in 2015 to test the drug in patients with ROS1/NTRK/ALK gene rearrangements.[29] - Lorlatinib (also known as PF-06463922) was shown in an ongoing Phase 2 clinical trial to be effective in some ROS1+ NSCLC patients, and treats the cancer in the brain as well as the body. Lorlatinib has the potential to overcome certain resistance mutations that develop during treatment with crizotinib.[30] - Ceritinib demonstrates clinical activity (including treating the brain) in ROS1+ NSCLC patients who had previously received platinum-based chemotherapy. In preclinical studies, ceritinib is unable to overcome most ROS1 resistance mutations, including ROS1 G2032R. It has more severe side effects than crizotinib for some patients. Ceritinib is US FDA approved for first line treatment of ALK+ metastatic non-small cell lung cancer.[31][32] - TPX-0005 preclinical data suggests it is a potent inhibitor of ROS1+ cancer.[33] A Phase I clinical trial opened in March 2017 for patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements.[34] - DS-6051b preclinical data show it is active against ROS1-positive cancers.[30] It is an ongoing clinical trial.[35] - Cabozantinib preclinical data has shown the drug might overcome crizotinib resistance in ROS1+ cancer in early studies.[36] However, the required dosage makes the drug difficult to tolerate for many patients. Cabozantinib is US FDA approved for metastatic medullary thyroid cancer (as Cometriq) and renal cell carcinoma (as Cabometyx). # Global ROS1 Initiative The Global ROS1 Initiative is a worldwide, multi-stakeholder collaboration with a goal of improving patient outcomes and accelerating research for any type of ROS1+ cancer[37]. It is the first such collaboration focused on cancers driven by a single oncogene and was initiated by ROS1+ cancer patients and carers who call themselves "The ROS1ders.";[38] their website tracks targeted therapies, clinical trials, world experts and new developments for ROS1+ cancers[39]. Partners in the Initiative include patient-focused nonprofits Bonnie J. Addario Lung Cancer Foundation and Addario Lung Cancer Medical Institute, clinicians who treat ROS1+ patients, ROS1 researchers, pharmaceutical firms and biotech companies.

https://www.wikidoc.org/index.php/ROS1

8c07fe7965263c561a260be8ed16ac670554d809

wikidoc

RPN2

RPN2 Dolichyl-diphosphooligosaccharide—protein glycosyltransferase subunit 2, also called ribophorin ǁ is an enzyme that in humans is encoded by the RPN2 gene. # Function This gene encodes a type I integral ribophorin membrane protein found only in the rough endoplasmic reticulum. The encoded protein is part of an N-oligosaccharyl transferase complex that links high mannose oligosaccharides to asparagine residues found in the Asn-X-Ser/Thr consensus motif of nascent polypeptide chains. This protein is similar in sequence to the yeast oligosaccharyl transferase subunit SWP1. RPN2 has been demonstrated to be a prognostic marker of human cancer, and may be a potential target of clinical importance. # Structure ## Gene The RPN2 gene lies on the chromosome location of 20q11.23 and consists of 19 exons. ## Protein RPN2 consists of 631 amino acid residues and weighs 69284Da. # Function RPN2 is a unique integral glycoprotein in rough ER membrane that is involved in translocation and the maintenance of the structural uniqueness of the rough ER. It is also an essential subunit of N-oligosaccharyl transferase complex that conjugates high mannose oligosaccharides to asparagine residues in the N-X-S/T consensus motif of nascent polypeptide chains. RPN2 regulates the glycosylation of multi-drug resistance, and thus its interference could decrease the membrane localization of P-glycoprotein by reducing its glycosylation status and restored the sensitivity to docetaxel. # Clinical significance RPN2 has been demonstrated to be a prognostic marker of human cancer. RPN2 is highly expressed in breast cancer stem cells and is associated with tumor metastasis. Recent study has shown that its expression is correlated with clinically aggressive features of breast cancer, implying a possible application in personalized medicine. RPN2 silencing has been reported to repress tumorigenicity and to sensitize the tumors to cisplatin treatment, which led to the longer survival of NSCLC-bearing mice, suggesting that RPN2 may represent a promising new target for RNAi-based medicine against NSCLC. Similar potential application has also been shown in osteosarcoma, esophageal squamous cell carcinoma and colorectal cancer. RPN2 is also reported to be one of the prothrombin-binding proteins on monocyte surfaces, suggesting that its involvement in the pathophysiology of thrombosis in patients with APS. # Interactions P53 tetraspanin CD63 prothrombin # Model organisms Model organisms have been used in the study of RPN2 function. A conditional knockout mouse line, called Rpn2tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out on mutant mice and two significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.

RPN2 Dolichyl-diphosphooligosaccharide—protein glycosyltransferase subunit 2, also called ribophorin ǁ is an enzyme that in humans is encoded by the RPN2 gene.[1] # Function This gene encodes a type I integral ribophorin membrane protein found only in the rough endoplasmic reticulum. The encoded protein is part of an N-oligosaccharyl transferase complex that links high mannose oligosaccharides to asparagine residues found in the Asn-X-Ser/Thr consensus motif of nascent polypeptide chains. This protein is similar in sequence to the yeast oligosaccharyl transferase subunit SWP1.[1] RPN2 has been demonstrated to be a prognostic marker of human cancer, and may be a potential target of clinical importance. # Structure ## Gene The RPN2 gene lies on the chromosome location of 20q11.23 and consists of 19 exons. ## Protein RPN2 consists of 631 amino acid residues and weighs 69284Da. # Function RPN2 is a unique integral glycoprotein in rough ER membrane that is involved in translocation and the maintenance of the structural uniqueness of the rough ER. It is also an essential subunit of N-oligosaccharyl transferase complex that conjugates high mannose oligosaccharides to asparagine residues in the N-X-S/T consensus motif of nascent polypeptide chains.[2][3][4][5] RPN2 regulates the glycosylation of multi-drug resistance, and thus its interference could decrease the membrane localization of P-glycoprotein by reducing its glycosylation status and restored the sensitivity to docetaxel.[6] # Clinical significance RPN2 has been demonstrated to be a prognostic marker of human cancer. RPN2 is highly expressed in breast cancer stem cells and is associated with tumor metastasis. Recent study has shown that its expression is correlated with clinically aggressive features of breast cancer, implying a possible application in personalized medicine.[7] RPN2 silencing has been reported to repress tumorigenicity and to sensitize the tumors to cisplatin treatment, which led to the longer survival of NSCLC-bearing mice, suggesting that RPN2 may represent a promising new target for RNAi-based medicine against NSCLC.[6] Similar potential application has also been shown in osteosarcoma, esophageal squamous cell carcinoma and colorectal cancer.[8][9][10] RPN2 is also reported to be one of the prothrombin-binding proteins on monocyte surfaces, suggesting that its involvement in the pathophysiology of thrombosis in patients with APS.[11] # Interactions P53 [7] tetraspanin CD63 [12] prothrombin [11] # Model organisms Model organisms have been used in the study of RPN2 function. A conditional knockout mouse line, called Rpn2tm1a(EUCOMM)Wtsi[17][18] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[19][20][21] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[15][22] Twenty six tests were carried out on mutant mice and two significant abnormalities were observed.[15] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.[15]

https://www.wikidoc.org/index.php/RPN2

2c882c5071326104ed4ff7aff457f592567aaea1

wikidoc

RRM1

RRM1 Ribonucleoside-diphosphate reductase large subunit is an enzyme that in humans is encoded by the RRM1 gene. This gene encodes one of two non-identical subunits which constitute ribonucleoside-diphosphate reductase, an enzyme essential for the production of deoxyribonucleotides prior to DNA synthesis in S phase of dividing cells. It is one of several genes located in the imprinted gene domain of 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with the Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, and lung, ovarian, and breast cancer. This gene may play a role in malignancies and disease that involve this region. This gene is oriented in a head-to-tail configuration with the stromal interaction molecule 1 gene (STIM1), with the 3' end of STIM1 situated 1.6 kb from the 5' end of this gene. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

RRM1 Ribonucleoside-diphosphate reductase large subunit is an enzyme that in humans is encoded by the RRM1 gene.[1][2] This gene encodes one of two non-identical subunits which constitute ribonucleoside-diphosphate reductase, an enzyme essential for the production of deoxyribonucleotides prior to DNA synthesis in S phase of dividing cells. It is one of several genes located in the imprinted gene domain of 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with the Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, and lung, ovarian, and breast cancer. This gene may play a role in malignancies and disease that involve this region. This gene is oriented in a head-to-tail configuration with the stromal interaction molecule 1 gene (STIM1), with the 3' end of STIM1 situated 1.6 kb from the 5' end of this gene.[2] # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles.[§ 1] - ↑ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

https://www.wikidoc.org/index.php/RRM1

062bae1d21288588594f50a44a6b504ab5875141

wikidoc

RRM2

RRM2 Ribonucleoside-diphosphate reductase subunit M2, also known as ribonucleotide reductase small subunit, is an enzyme that in humans is encoded by the RRM2 gene. # Function This gene encodes one of two non-identical subunits for ribonucleotide reductase. This reductase catalyzes the formation of deoxyribonucleotides from ribonucleotides. Synthesis of the encoded protein (M2) is regulated in a cell-cycle dependent fashion. Transcription from this gene can initiate from alternative promoters, which results in two isoforms that differ in the lengths of their N-termini. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

RRM2 Ribonucleoside-diphosphate reductase subunit M2, also known as ribonucleotide reductase small subunit, is an enzyme that in humans is encoded by the RRM2 gene.[1][2] # Function This gene encodes one of two non-identical subunits for ribonucleotide reductase. This reductase catalyzes the formation of deoxyribonucleotides from ribonucleotides. Synthesis of the encoded protein (M2) is regulated in a cell-cycle dependent fashion. Transcription from this gene can initiate from alternative promoters, which results in two isoforms that differ in the lengths of their N-termini.[1] # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles.[§ 1] - ↑ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

https://www.wikidoc.org/index.php/RRM2

897fb0be467803813c5e7fd31c4e9b043c62c569

wikidoc

RSU1

RSU1 Ras suppressor protein 1 is a protein that in humans is encoded by the RSU1 gene. This gene encodes a protein that is involved in the Ras signal transduction pathway, growth inhibition, and nerve-growth factor induced differentiation processes, as determined in mouse and human cell line studies. In mouse, the encoded protein was initially isolated based on its ability to inhibit v-Ras transformation. Multiple alternatively spliced transcript variants for this gene have been reported; one of these variants was found only in glioma tumors. RSU-1 has also been seen to act as a structural protein in integrin-mediated focal-adhesion complexes. It bind strongly to the protein PINCH.

RSU1 Ras suppressor protein 1 is a protein that in humans is encoded by the RSU1 gene.[1][2] This gene encodes a protein that is involved in the Ras signal transduction pathway, growth inhibition, and nerve-growth factor induced differentiation processes, as determined in mouse and human cell line studies. In mouse, the encoded protein was initially isolated based on its ability to inhibit v-Ras transformation. Multiple alternatively spliced transcript variants for this gene have been reported; one of these variants was found only in glioma tumors.[2] RSU-1 has also been seen to act as a structural protein in integrin-mediated focal-adhesion complexes. It bind strongly to the protein PINCH.

https://www.wikidoc.org/index.php/RSU1

98e0a325496629ff0ca436089711d9619a163375

wikidoc

RTF1

RTF1 Rtf1, Paf1/RNA polymerase II complex component, homolog (S. cerevisiae) is a protein that in humans is encoded by the RTF1 gene. This locus may represent a gene involved in regulation of transcription elongation and chromatin remodeling, based on studies of similar proteins in other organisms. The encoded protein may bind single-stranded DNA. # Model organisms Model organisms have been used in the study of RTF1 function. A conditional knockout mouse line, called Rtf1tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on mutant mice and three significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; vertebral fusion was observed in male animals.

RTF1 Rtf1, Paf1/RNA polymerase II complex component, homolog (S. cerevisiae) is a protein that in humans is encoded by the RTF1 gene.[1] This locus may represent a gene involved in regulation of transcription elongation and chromatin remodeling, based on studies of similar proteins in other organisms. The encoded protein may bind single-stranded DNA.[1] # Model organisms Model organisms have been used in the study of RTF1 function. A conditional knockout mouse line, called Rtf1tm1a(KOMP)Wtsi[7][8] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[9][10][11] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[5][12] Twenty four tests were carried out on mutant mice and three significant abnormalities were observed.[5] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; vertebral fusion was observed in male animals.[5]

https://www.wikidoc.org/index.php/RTF1

ca3c4e1bca58b82f2691dedb4e7e4ef553cb3290

wikidoc

RTL6

RTL6 Retrotransposon Gag Like 6 is a protein encoded by the RTL6 gene in humans. RTL6 is a member of the Mart family of genes, which are related to Sushi-like retrotransposons and were derived from fish and amphibians. The RTL6 protein is localized to the nucleus and has a predicted leucine zipper motif that is known to bind nucleic acids in similar proteins, such as LDOC1. # Gene ## Locus The gene is on Chromosome 22 (human) at 22q13.31 on the minus strand from 44492570-44498125 nt on the GRCh38.p7 assembly of the human genome. Aliases for the gene include LDOC1L, MAR6, MART6, and SIRH3. RTL6 is made up of 2 exons and is encoded by 5556 base pairs of DNA . ## Origin RTL6 is a retrotransposon GAG related gene. It is one of eleven MART (Mammalian Retrotransposon Derived) genes in humans related to Sushi-like retrotransposons with long terminal repeats from fish and amphibians. Between 170-310 MYA, MART genes lost their ability to retrotranspose and concomitantly gained new, beneficial function for its host organism. # mRNA RTL6 has an alternate start of transcription 140 base pairs upstream of the normal transcribed region. The lengths of the primary mRNA and that with the upstream start of transcription are 5355 and 5495 base pairs respectively. # Protein ## Primary Information The primary amino acid sequence for RTL6 is made up of 239 residues. There are no known alternative splice variants of the protein. The molecular weight of the protein is 26.2 kDa and the isoelectric point is 11.58. RTL6 is a proline and arginine rich protein. ## Domains and Motifs RTL6 contains a predicted leucine zipper motif known to participate in nucleic acid binding in other proteins. RTL6 also contains a domain of unknown function from amino acid residues 98-177 . RTL6 is one of a number of genes belonging to the DUF4939 (domain of unknown function) superfamily. ## Secondary structure The secondary structure of RTL6 is made up of largely alpha helices. One region of RTL6 is also predicted to participate in a coiled-coil structure from amino acid residues 29-63. ## Post-translational modifications There are also two predicted phosphorylation sites for Protein Kinase C with high confidence scores at amino acid residues 6 and 45. There is also a predicted ubiquitination site with medium-confidence at amino acid residue 8. ## Cellular sublocation RTL6 is expected to be localized to the nucleus and cytosol based on the presence of a leucine zipper domain, the absence of signals indicating secretion or transmembrane domains, and immunohistochemical staining. # Expression RTL6 has been shown to be expressed at high levels during all stages of development and in a wide variety of tissues. RTL6 expression has been shown to fall in HeLa cervical cancer cells upon treatment with chemotherapeutic Casiopeinas and in A549 lung cancer cells upon treatment with Actinomycin D. # Interacting proteins RTL6 has been shown to interact with the following proteins: # Clinical Significance The RTL6 protein has been shown to interact with the UXAC protein from Yersinia pestis, the gram-negative bacterium responsible for the bubonic plague. # Homology/evolution ## Paralogs Eleven paralogs were identified for RTL6 in humans. The paralogs have diverse functions and expression patterns, although many are known to have zinc finger domains and bind nucleic acids: ## Orthologs RTL6 is highly conserved across mammals, including the leucine zipper motif and DUF4939. The gene is also conserved in marsupials such as the opossum but not in birds such as the chicken, suggesting the gene was likely formed after the divergence of mammals and birds but before the divergence of marsupials and mammals (170-310 MYA: The most distantly detectable organisms with homology in the gene are bony fishes including salmon and the common carp, but similarity to the human protein sequence is markedly less than that of mammals. No traces of the gene can be seen in intermediates between mammals and bony fishes such as reptiles or amphibians:

RTL6 Retrotransposon Gag Like 6 is a protein encoded by the RTL6 gene in humans.[1] RTL6 is a member of the Mart family of genes, which are related to Sushi-like retrotransposons and were derived from fish and amphibians.[2] The RTL6 protein is localized to the nucleus and has a predicted leucine zipper motif that is known to bind nucleic acids in similar proteins, such as LDOC1. # Gene ## Locus The gene is on Chromosome 22 (human) at 22q13.31 on the minus strand from 44492570-44498125 nt on the GRCh38.p7 assembly of the human genome. Aliases for the gene include LDOC1L, MAR6, MART6, and SIRH3. RTL6 is made up of 2 exons and is encoded by 5556 base pairs of DNA .[3] ## Origin RTL6 is a retrotransposon GAG related gene. It is one of eleven MART (Mammalian Retrotransposon Derived) genes in humans related to Sushi-like retrotransposons with long terminal repeats from fish and amphibians.[2] Between 170-310 MYA, MART genes lost their ability to retrotranspose and concomitantly gained new, beneficial function for its host organism.[4] # mRNA RTL6 has an alternate start of transcription 140 base pairs upstream of the normal transcribed region. The lengths of the primary mRNA and that with the upstream start of transcription are 5355 and 5495 base pairs respectively.[3] # Protein ## Primary Information The primary amino acid sequence for RTL6 is made up of 239 residues.[1] There are no known alternative splice variants of the protein. The molecular weight of the protein is 26.2 kDa and the isoelectric point is 11.58.[5] RTL6 is a proline and arginine rich protein.[5] ## Domains and Motifs RTL6 contains a predicted leucine zipper motif known to participate in nucleic acid binding in other proteins.[5] RTL6 also contains a domain of unknown function from amino acid residues 98-177 . RTL6 is one of a number of genes belonging to the DUF4939 (domain of unknown function) superfamily.[10] ## Secondary structure The secondary structure of RTL6 is made up of largely alpha helices.[11] One region of RTL6 is also predicted to participate in a coiled-coil structure from amino acid residues 29-63.[10] ## Post-translational modifications There are also two predicted phosphorylation sites for Protein Kinase C with high confidence scores at amino acid residues 6 and 45.[12][13] There is also a predicted ubiquitination site with medium-confidence at amino acid residue 8.[14] ## Cellular sublocation RTL6 is expected to be localized to the nucleus and cytosol based on the presence of a leucine zipper domain, the absence of signals indicating secretion or transmembrane domains, and immunohistochemical staining.[15][16][17] # Expression RTL6 has been shown to be expressed at high levels during all stages of development and in a wide variety of tissues.[18][19][9] RTL6 expression has been shown to fall in HeLa cervical cancer cells upon treatment with chemotherapeutic Casiopeinas and in A549 lung cancer cells upon treatment with Actinomycin D.[20][21] # Interacting proteins RTL6 has been shown to interact with the following proteins: # Clinical Significance The RTL6 protein has been shown to interact with the UXAC protein from Yersinia pestis, the gram-negative bacterium responsible for the bubonic plague.[26] # Homology/evolution ## Paralogs Eleven paralogs were identified for RTL6 in humans. The paralogs have diverse functions and expression patterns, although many are known to have zinc finger domains and bind nucleic acids: ## Orthologs RTL6 is highly conserved across mammals, including the leucine zipper motif and DUF4939. The gene is also conserved in marsupials such as the opossum but not in birds such as the chicken, suggesting the gene was likely formed after the divergence of mammals and birds but before the divergence of marsupials and mammals (170-310 MYA:[2] The most distantly detectable organisms with homology in the gene are bony fishes including salmon and the common carp, but similarity to the human protein sequence is markedly less than that of mammals. No traces of the gene can be seen in intermediates between mammals and bony fishes such as reptiles or amphibians:

https://www.wikidoc.org/index.php/RTL6

09de4357f99df32a6bbbfcd2b441c9de7968aa2e

wikidoc

RTN1

RTN1 Reticulon-1 also known as neuroendocrine-specific protein (NSP) is a protein that in humans is encoded by the RTN1 gene. This gene belongs to the family of reticulon-encoding genes. Reticulons are associated with the endoplasmic reticulum, and are involved in neuroendocrine secretion or in membrane trafficking in neuroendocrine cells. Alternatively spliced transcript variants encoding different isoforms have been identified. Multiple promoters rather than alternative splicing of internal exons seem to be involved in this diversity. # Interactions RTN1 has been shown to interact with BCL2-like 1 and UGCG.

RTN1 Reticulon-1 also known as neuroendocrine-specific protein (NSP) is a protein that in humans is encoded by the RTN1 gene.[1][2] This gene belongs to the family of reticulon-encoding genes. Reticulons are associated with the endoplasmic reticulum, and are involved in neuroendocrine secretion or in membrane trafficking in neuroendocrine cells. Alternatively spliced transcript variants encoding different isoforms have been identified. Multiple promoters rather than alternative splicing of internal exons seem to be involved in this diversity.[2] # Interactions RTN1 has been shown to interact with BCL2-like 1[3] and UGCG.[4]

https://www.wikidoc.org/index.php/RTN1

69d3972a08929669c1c01b93968db4fd05232c63

wikidoc

RYR1

RYR1 Ryanodine receptor 1 (RYR-1) also known as skeletal muscle calcium release channel or skeletal muscle-type ryanodine receptor is a protein found primarily in skeletal muscle. In humans, it is encoded by the RYR1 gene. # Function RYR1 functions as a calcium release channel in the sarcoplasmic reticulum, as well as a connection between the sarcoplasmic reticulum and the transverse tubule. RYR1 is associated with the dihydropyridine receptor (L-type calcium channels) within the sarcolemma of the T-tubule, which opens in response to depolarization, and thus effectively means that the RYR1 channel opens in response to depolarization of the cell. RYR1 plays a signaling role during embryonic skeletal myogenesis. A correlation exists between RYR1-mediated Ca2+ signaling and the expression of multiple molecules involved in key myogenic signaling pathways. Of these, more than 10 differentially expressed genes belong to the Wnt family which are essential for differentiation. This coincides with the observation that without RYR1 present, muscle cells appear in smaller groups, are underdeveloped, and lack organization. Fiber type composition is also affected, with less type 1 muscle fibers when there are decreased amounts of RYR1. These findings demonstrate RYR1 has a non-contractile role during muscle development. RYR1 is mechanically linked to neuromuscular junctions for the calcium release-calcium induced biological process. While nerve-derived signals are required for acetylcholine receptor cluster distribution, there is evidence to suggest RYR1 activity is an important mediator in the formation and patterning of these receptors during embryological development. The signals from the nerve and RYR1 activity appear to counterbalance each other. When RYR1 is eliminated, the acetylcholine receptor clusters appear in an abnormally narrow pattern, yet without signals from the nerve, the clusters are scattered and broad. Although their direct role is still unknown, RYR1 is required for proper distribution of acetylcholine receptor clusters. # Clinical significance Mutations in the RYR1 gene are associated with malignant hyperthermia susceptibility, central core disease, minicore myopathy with external ophthalmoplegia and samaritan myopathy, a benign congenital myopathy. Alternatively spliced transcripts encoding different isoforms have been demonstrated. Dantrolene may be the only known drug that is effective during cases of malignant hyperthermia. # Interactions RYR1 has been shown to interact with: - calmodulin - FKBP1A - HOMER1 - HOMER2 - HOMER3 and - TRDN.

RYR1 Ryanodine receptor 1 (RYR-1) also known as skeletal muscle calcium release channel or skeletal muscle-type ryanodine receptor is a protein found primarily in skeletal muscle. In humans, it is encoded by the RYR1 gene.[1][2] # Function RYR1 functions as a calcium release channel in the sarcoplasmic reticulum, as well as a connection between the sarcoplasmic reticulum and the transverse tubule.[3] RYR1 is associated with the dihydropyridine receptor (L-type calcium channels) within the sarcolemma of the T-tubule, which opens in response to depolarization, and thus effectively means that the RYR1 channel opens in response to depolarization of the cell. RYR1 plays a signaling role during embryonic skeletal myogenesis. A correlation exists between RYR1-mediated Ca2+ signaling and the expression of multiple molecules involved in key myogenic signaling pathways.[4] Of these, more than 10 differentially expressed genes belong to the Wnt family which are essential for differentiation. This coincides with the observation that without RYR1 present, muscle cells appear in smaller groups, are underdeveloped, and lack organization. Fiber type composition is also affected, with less type 1 muscle fibers when there are decreased amounts of RYR1.[5] These findings demonstrate RYR1 has a non-contractile role during muscle development. RYR1 is mechanically linked to neuromuscular junctions for the calcium release-calcium induced biological process. While nerve-derived signals are required for acetylcholine receptor cluster distribution, there is evidence to suggest RYR1 activity is an important mediator in the formation and patterning of these receptors during embryological development.[6] The signals from the nerve and RYR1 activity appear to counterbalance each other. When RYR1 is eliminated, the acetylcholine receptor clusters appear in an abnormally narrow pattern, yet without signals from the nerve, the clusters are scattered and broad. Although their direct role is still unknown, RYR1 is required for proper distribution of acetylcholine receptor clusters. # Clinical significance Mutations in the RYR1 gene are associated with malignant hyperthermia susceptibility, central core disease, minicore myopathy with external ophthalmoplegia and samaritan myopathy, a benign congenital myopathy.[7] Alternatively spliced transcripts encoding different isoforms have been demonstrated.[3] Dantrolene may be the only known drug that is effective during cases of malignant hyperthermia.[citation needed] # Interactions RYR1 has been shown to interact with: - calmodulin[8][9] - FKBP1A[10][11][12] - HOMER1[13][14] - HOMER2[14] - HOMER3[14] and - TRDN.[15][16][17][18]

https://www.wikidoc.org/index.php/RYR1

bfd92e5f026800756f36f951b89519281c3f859f

wikidoc

Rap1

Rap1 Rap1 (Ras-proximate-1 or Ras-related protein 1) is a small GTPase, which are small cytosolic proteins that act like cellular switches and are vital for effective signal transduction. There are two isoforms of the Rap1 protein, each encoded by a separate gene, RAP1A and RAP1B. Rap1 belongs to Ras-related protein family. GTPases are inactive when in their GDP-bound form, and become active when they bind to GTP. GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) regulate small GTPases, with GAPs promoting the GDP-bound (inactive) form, and GEFs promoting the GTP-bound (active) form. When bound to GTP, small GTPases regulate myriad cellular processes. These proteins are divided into families depending on their protein structure, and the most well studied is the Ras superfamily, of which Rap1 is a member. Whereas Ras is known for its role in cell proliferation and survival, Rap1 is predominantly involved in cell adhesion and cell junction formation. Ras and Rap are regulated by different sets of guanine nucleotide exchange factors and GTPase-activating proteins, thus providing one level of specificity. # Effectors ## RAPL The identification of Rap1 effector proteins has provided important insights into mechanisms by which Rap1 regulates T-cell receptor (TCR) signaling to integrins. A constitutively active Rap1 construct, Rap1G12V, was used as a bait in a yeast two-hybrid screen to identify RAPL as a Rap1-binding protein. Overexpression of RAPL enhances LFA-1 clustering and adhesion, and RAPL-deficient lymphocytes and dendritic cells exhibit impaired adhesion and migration. RAPL is also an integrin-associated protein as RAPL polarizes to the immunological synapse following antigen stimulation of T cells, colocalizes with LFA-1 following TCR or chemokine stimulation, and co-immunoprecipitates with LFA-1 in a Rap1-dependent manner (108). This interaction between RAPL and LFA-1 is dependent on lysine residues at positions 1097 and 1099 in the juxtamembrane region of the αL-subunit cytoplasmic domain. This is a functionally significant region of the αL cytoplasmic domain as deletion of the adjacent GFFKR motif results in a constitutively active LFA-1 integrin (124, 125). While lysines 1097 and 1099 are critical for Rap1-dependent activation of LFA-1, the β2-subunit cytoplasmic domain appears to be dispensable for activation of LFA-1 by Rap1 (126). Mutation of these lysine residues to alanine impairs the ability of LFA-1 to redistribute to the leading edge induced by Rap1 activation or overexpression of RAPL. Because RAPL localizes to the leading edge properly in cells expressing this mutant LFA-1, this finding suggests that RAPL may play a critical role in localizing LFA-1 to discrete regions of the plasma membrane. ## Mst1 The serine–threonine kinase Mst1, a member of a family of kinases homologous to the Ste20 kinase in yeast, has recently been identified as a RAPL effector. TCR-mediated activation of Mst1 is dependent on RAPL, and TCR-mediated adhesion to ICAM-1 and antigen-dependent conjugate formation are impaired following RNAi-mediated knockdown of Mst1 expression. Although Rap1 and RAPL have been shown to regulate both LFA-1 affinity and clustering, overexpression of Mst1 only enhances LFA-1 clustering. This finding suggests that LFA-1 clustering is critical for TCR signaling to integrins that is mediated by Rap1. It also implies the existence of Mst1-independent mechanisms by which Rap1 regulates LFA-1 affinity. ## PKD A striking feature of Rap1 and the Rap1-associated signaling proteins PKD, RAPL, and Mst1 is their localization to membranes where integrins are found. This provides a mechanism by which Rap1 can act directly on integrins and modulate integrin affinity and/or clustering. PKD, RAPL, and Mst1 have also all been proposed to play a role in movement of receptors to the plasma membrane. PKD-dependent regulation of vesicular transport requires PKD kinase activity, while PKD-dependent regulation of TCR signaling to integrins does not appear to require PKD kinase activity. Thus, PKD may play a distinct role in regulating Rap1-dependent integrin regulation. For example, the PKD-dependent association of Rap1 with C3G suggests that PKD may be critical for localizing Rap1 not only with integrins but also with Rap1 GEFs. The PKD–Rap1 interaction may thus be central to the subsequent activation of Rap1 and triggering of downstream effectors such as RAPL and Mst1. ## RIAM An additional Rap1 effector provides a link between Rap1 and the actin cytoskeleton. RIAM (Rap1–GTP-interacting adapter molecule) is a broadly expressed adaptor protein that contains an RA (Ras association)-like domain, a PH domain, and several proline-rich sequences. Like RAPL, RIAM interacts preferentially with active Rap1, and overexpression of RIAM enhances integrin-mediated adhesion. In addition, knockdown of RIAM inhibits adhesion induced by active Rap1 and inhibits the localization of active Rap1 at the plasma membrane. The ability of RIAM to associate with profilin, Ena/VASP proteins, and talin suggests that RIAM promotes Rap1-dependent integrin activation through effects on the actin cytoskeleton, particularly the interaction of talin with integrin cytoplasmic tails. Given the known role of talin in regulating integrin affinity, RIAM may provide an Mst1-independent mechanism by which Rap1 regulates integrin affinity.

Rap1 Rap1 (Ras-proximate-1 or Ras-related protein 1) is a small GTPase, which are small cytosolic proteins that act like cellular switches and are vital for effective signal transduction.[1] There are two isoforms of the Rap1 protein, each encoded by a separate gene, RAP1A and RAP1B. Rap1 belongs to Ras-related protein family. GTPases are inactive when in their GDP-bound form, and become active when they bind to GTP. GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) regulate small GTPases, with GAPs promoting the GDP-bound (inactive) form, and GEFs promoting the GTP-bound (active) form. When bound to GTP, small GTPases regulate myriad cellular processes. These proteins are divided into families depending on their protein structure, and the most well studied is the Ras superfamily, of which Rap1 is a member. Whereas Ras is known for its role in cell proliferation and survival, Rap1 is predominantly involved in cell adhesion and cell junction formation. Ras and Rap are regulated by different sets of guanine nucleotide exchange factors and GTPase-activating proteins, thus providing one level of specificity.[2] # Effectors ## RAPL The identification of Rap1 effector proteins has provided important insights into mechanisms by which Rap1 regulates T-cell receptor (TCR) signaling to integrins. A constitutively active Rap1 construct, Rap1G12V, was used as a bait in a yeast two-hybrid screen to identify RAPL as a Rap1-binding protein.[3] Overexpression of RAPL enhances LFA-1 clustering and adhesion, and RAPL-deficient lymphocytes and dendritic cells exhibit impaired adhesion and migration.[4] RAPL is also an integrin-associated protein as RAPL polarizes to the immunological synapse following antigen stimulation of T cells, colocalizes with LFA-1 following TCR or chemokine stimulation, and co-immunoprecipitates with LFA-1 in a Rap1-dependent manner (108). This interaction between RAPL and LFA-1 is dependent on lysine residues at positions 1097 and 1099 in the juxtamembrane region of the αL-subunit cytoplasmic domain. This is a functionally significant region of the αL cytoplasmic domain as deletion of the adjacent GFFKR motif results in a constitutively active LFA-1 integrin (124, 125). While lysines 1097 and 1099 are critical for Rap1-dependent activation of LFA-1, the β2-subunit cytoplasmic domain appears to be dispensable for activation of LFA-1 by Rap1 (126). Mutation of these lysine residues to alanine impairs the ability of LFA-1 to redistribute to the leading edge induced by Rap1 activation or overexpression of RAPL. Because RAPL localizes to the leading edge properly in cells expressing this mutant LFA-1, this finding suggests that RAPL may play a critical role in localizing LFA-1 to discrete regions of the plasma membrane. ## Mst1 The serine–threonine kinase Mst1, a member of a family of kinases homologous to the Ste20 kinase in yeast,[5] has recently been identified as a RAPL effector.[6] TCR-mediated activation of Mst1 is dependent on RAPL, and TCR-mediated adhesion to ICAM-1 and antigen-dependent conjugate formation are impaired following RNAi-mediated knockdown of Mst1 expression. Although Rap1 and RAPL have been shown to regulate both LFA-1 affinity and clustering, overexpression of Mst1 only enhances LFA-1 clustering. This finding suggests that LFA-1 clustering is critical for TCR signaling to integrins that is mediated by Rap1. It also implies the existence of Mst1-independent mechanisms by which Rap1 regulates LFA-1 affinity. ## PKD A striking feature of Rap1 and the Rap1-associated signaling proteins PKD, RAPL, and Mst1 is their localization to membranes where integrins are found. This provides a mechanism by which Rap1 can act directly on integrins and modulate integrin affinity and/or clustering. PKD, RAPL, and Mst1 have also all been proposed to play a role in movement of receptors to the plasma membrane. PKD-dependent regulation of vesicular transport requires PKD kinase activity, while PKD-dependent regulation of TCR signaling to integrins does not appear to require PKD kinase activity. Thus, PKD may play a distinct role in regulating Rap1-dependent integrin regulation. For example, the PKD-dependent association of Rap1 with C3G suggests that PKD may be critical for localizing Rap1 not only with integrins but also with Rap1 GEFs. The PKD–Rap1 interaction may thus be central to the subsequent activation of Rap1 and triggering of downstream effectors such as RAPL and Mst1. ## RIAM An additional Rap1 effector provides a link between Rap1 and the actin cytoskeleton. RIAM (Rap1–GTP-interacting adapter molecule) is a broadly expressed adaptor protein that contains an RA (Ras association)-like domain, a PH domain, and several proline-rich sequences. Like RAPL, RIAM interacts preferentially with active Rap1, and overexpression of RIAM enhances integrin-mediated adhesion. In addition, knockdown of RIAM inhibits adhesion induced by active Rap1 and inhibits the localization of active Rap1 at the plasma membrane. The ability of RIAM to associate with profilin, Ena/VASP proteins, and talin suggests that RIAM promotes Rap1-dependent integrin activation through effects on the actin cytoskeleton, particularly the interaction of talin with integrin cytoplasmic tails. Given the known role of talin in regulating integrin affinity, RIAM may provide an Mst1-independent mechanism by which Rap1 regulates integrin affinity.

https://www.wikidoc.org/index.php/Rap1

5618010a91681695a7c35f3e4a6c41c282654894

wikidoc

Rex1

Rex1 Rex1 (Zfp-42) is a known marker of pluripotency, and is usually found in undifferentiated embryonic stem cells. In addition to being a marker for pluripotency, its regulation is also critical in maintaining a pluripotent state. As the cells begin to differentiate, Rex1 is severely and abruptly downregulated. # Discovery Rex1 was discovered by Hosler, BA et al. in 1989 when studying F9 murine teratocarcinoma stem cells. They found that these teratocarcinoma stem cells expressed high levels of Rex1, and that they resembled pluripotent stem cells of the inner cell mass (ICM). Hosler, BA et al. found that these teratocarcinoma stem cells, when in the presence of retinoic acid (RA), differentiated into nontumorigenic cells resembling extraembryonic endoderm of early mouse embryos. They were able to isolate the nucleotide sequence for Rex1 using differential hybridization of an F9 cell. They named it Rex1 for reduced expression 1 because there was a steady decline of its mRNA levels within 12 hours of the addition of RA. # Structure Rex1 is a protein that in humans is encoded by the ZFP42 gene. The Rex1 protein is 310 amino acids long, and has four closely spaced zinc fingers at 188-212, 217-239, 245-269, and 275-299. # p38 MAPK & Mesenchymal Stem Cells Rex1 has been found to be critically important in maintaining proliferative state in mesenchymal stem cells (MSC), while simultaneously preventing differentiation. Both umbilical cord blood MSC and adipose MSC express high levels of Rex1, while bone marrow MSC expressed low levels of Rex1. Proliferation rates are highly correlated with Rex1 expression levels, meaning high Rex1 expression is correlated with high levels of proliferation. The MSCs with weak Rex1 expression, have activated p38 MAPK and high expression levels of MKK3. Thus, Rex1 expression is inversely correlated with p38 MAPK activation, and positively correlated with high proliferation rates. Rex1 was found to inhibit MKK3 expression, which activates p38 MAPK. Activated p38 MAPK, in turn, inhibits proliferation. Rex1 was also found to inhibit NOTCH and STAT3, two transcription factors which lead to differentiation. Therefore, Rex1 expression allows for high levels of proliferation, and prevents differentiation through a network of various transcription factors and protein kinases. # Embryo Development ## Tissue Derivation During embryogenesis, the inner cell mass (ICM) is separated from the trophoblast. The stem cells derived from the ICM and trophectoderm have been found to express high levels of Oct3/4 and Rex1. As the ICM matures and begins to form the epiblast, and primitive ectoderm, the cells in the ICM have been found to be a heterogenous population, with varying levels of Rex1 expression. Rex1−/Oct3/4− triggers trophectoderm differentiation, while Rex1+/Oct3/4+ cells predominantly differentiate into primitive endoderm and mesoderm. Also, Rex1−/Oct3/4+ cells differentiate into cells of primitive ectoderm, the somatic cell lineage. ## Gene Control Studies have shown that PEG3 and Nespas are downstream targets of Rex1. Rex1 can control the expression of Peg3 via epigenetic changes. YY1 has been shown to be involved in setting up DNA methylation on the maternal allele of PEG3 during oogenesis. Rex1 was found to protect the paternal allele from being methylated, and keep the PEG3 gene unmethylated during early embryogenesis. Rex1 exhibits gene control in developing embryos via its epigenetic control on genes such as PEG3, which has been identified as playing a key role in fetal growth rates # Expression in Adult Tissues The only adult tissue Rex1 has been identified in are the testicles. Using in situ hybridization it was determined that the spermatocytes in the more inner layers of the testicles are expressing Rex1. Thus, the male germ cells undergoing meiosis are the specific cells in the testicles that express Rex1. It has not been observed, however, that Rex1 is expressed in the female germ cells. # Rex1 Interactions with Other Transcription Factors Rex1 participates in a network of transcription factors that all work to regulate each other via varying expression levels. ## Nanog The Nanog protein has been found to be a transcriptional activator for the Rex-1 promoter, playing a key role in sustaining Rex1 expression. Knockdown of Nanog in embryonic stem cells results in a reduction of Rex-1 expression, while forced expression of Nanog stimulates Rex-1 expression. Nanog regulates the transcription of Rex1 through 2 strong transactivation domains on the C-terminus which are required to activate the Rex1 promoter. ## NOTCH Rex1 has been found to inhibit the expression of NOTCH, thus preventing differentiation. ## STAT3 Rex1 has been found to inhibit the expression of STAT3, thus preventing differentiation. ## Sox2 Cooperative regulation of Rex1 is seen with Sox2 and Nanog. ## Oct3/4 Oct3/4 can both repress and activate the Rex1 promoter. In cells that already express high level of Oct3/4, exogenously transfected Oct3/4 will lead to the repression of Rex1. However, in cells that are not actively expressing Oct3/4, an exogenous transfection of Oct3/4 will lead to the activation of Rex1. This implies a dual regulatory ability of Oct3/4 on Rex1. At low levels of the Oct3/4 protein, the Rex1 promoter is activated, while at high levels of the Oct3/4 protein, the Rex1 promoter is repressed.

Rex1 Rex1 (Zfp-42) is a known marker of pluripotency, and is usually found in undifferentiated embryonic stem cells. In addition to being a marker for pluripotency, its regulation is also critical in maintaining a pluripotent state.[1] As the cells begin to differentiate, Rex1 is severely and abruptly downregulated.[2] # Discovery Rex1 was discovered by Hosler, BA et al. in 1989 when studying F9 murine teratocarcinoma stem cells. They found that these teratocarcinoma stem cells expressed high levels of Rex1, and that they resembled pluripotent stem cells of the inner cell mass (ICM).[3] Hosler, BA et al. found that these teratocarcinoma stem cells, when in the presence of retinoic acid (RA), differentiated into nontumorigenic cells resembling extraembryonic endoderm of early mouse embryos.[4] They were able to isolate the nucleotide sequence for Rex1 using differential hybridization of an F9 cell. They named it Rex1 for reduced expression 1 because there was a steady decline of its mRNA levels within 12 hours of the addition of RA.[4] # Structure Rex1 is a protein that in humans is encoded by the ZFP42 gene.[5][6] The Rex1 protein is 310 amino acids long, and has four closely spaced zinc fingers at 188-212, 217-239, 245-269, and 275-299.[3] # p38 MAPK & Mesenchymal Stem Cells Rex1 has been found to be critically important in maintaining proliferative state in mesenchymal stem cells (MSC), while simultaneously preventing differentiation. Both umbilical cord blood MSC and adipose MSC express high levels of Rex1, while bone marrow MSC expressed low levels of Rex1. Proliferation rates are highly correlated with Rex1 expression levels, meaning high Rex1 expression is correlated with high levels of proliferation. The MSCs with weak Rex1 expression, have activated p38 MAPK and high expression levels of MKK3. Thus, Rex1 expression is inversely correlated with p38 MAPK activation, and positively correlated with high proliferation rates.[7] Rex1 was found to inhibit MKK3 expression, which activates p38 MAPK. Activated p38 MAPK, in turn, inhibits proliferation. Rex1 was also found to inhibit NOTCH and STAT3, two transcription factors which lead to differentiation.[7] Therefore, Rex1 expression allows for high levels of proliferation, and prevents differentiation through a network of various transcription factors and protein kinases. # Embryo Development ## Tissue Derivation During embryogenesis, the inner cell mass (ICM) is separated from the trophoblast. The stem cells derived from the ICM and trophectoderm have been found to express high levels of Oct3/4 and Rex1.[8] As the ICM matures and begins to form the epiblast, and primitive ectoderm, the cells in the ICM have been found to be a heterogenous population, with varying levels of Rex1 expression. Rex1−/Oct3/4− triggers trophectoderm differentiation, while Rex1+/Oct3/4+ cells predominantly differentiate into primitive endoderm and mesoderm.[9] Also, Rex1−/Oct3/4+ cells differentiate into cells of primitive ectoderm, the somatic cell lineage.[10] ## Gene Control Studies have shown that PEG3 and Nespas are downstream targets of Rex1.[11] Rex1 can control the expression of Peg3 via epigenetic changes. YY1 has been shown to be involved in setting up DNA methylation on the maternal allele of PEG3 during oogenesis.[12] Rex1 was found to protect the paternal allele from being methylated, and keep the PEG3 gene unmethylated during early embryogenesis.[11] Rex1 exhibits gene control in developing embryos via its epigenetic control on genes such as PEG3, which has been identified as playing a key role in fetal growth rates [13] # Expression in Adult Tissues The only adult tissue Rex1 has been identified in are the testicles. Using in situ hybridization it was determined that the spermatocytes in the more inner layers of the testicles are expressing Rex1.[14] Thus, the male germ cells undergoing meiosis are the specific cells in the testicles that express Rex1. It has not been observed, however, that Rex1 is expressed in the female germ cells. # Rex1 Interactions with Other Transcription Factors Rex1 participates in a network of transcription factors that all work to regulate each other via varying expression levels. ## Nanog The Nanog protein has been found to be a transcriptional activator for the Rex-1 promoter, playing a key role in sustaining Rex1 expression. Knockdown of Nanog in embryonic stem cells results in a reduction of Rex-1 expression, while forced expression of Nanog stimulates Rex-1 expression.[1] Nanog regulates the transcription of Rex1 through 2 strong transactivation domains on the C-terminus which are required to activate the Rex1 promoter.[1] ## NOTCH Rex1 has been found to inhibit the expression of NOTCH, thus preventing differentiation.[7] ## STAT3 Rex1 has been found to inhibit the expression of STAT3, thus preventing differentiation.[7] ## Sox2 Cooperative regulation of Rex1 is seen with Sox2 and Nanog.[1] ## Oct3/4 Oct3/4 can both repress and activate the Rex1 promoter. In cells that already express high level of Oct3/4, exogenously transfected Oct3/4 will lead to the repression of Rex1.[15] However, in cells that are not actively expressing Oct3/4, an exogenous transfection of Oct3/4 will lead to the activation of Rex1.[15] This implies a dual regulatory ability of Oct3/4 on Rex1. At low levels of the Oct3/4 protein, the Rex1 promoter is activated, while at high levels of the Oct3/4 protein, the Rex1 promoter is repressed.

https://www.wikidoc.org/index.php/Rex1

6c844aed92fa3a49e772e0b48cf09db0c925331d

wikidoc

SBDS

SBDS Ribosome maturation protein SBDS is a protein that in humans is encoded by the SBDS gene. An alternative transcript has been described, but its biological nature has not been determined. This gene has a closely linked pseudogene that is distally located. This gene encodes a member of a highly conserved protein family that exists from archaea to vertebrates and plants. # Function The encoded protein may function in RNA metabolism. The precise function of the SBDS protein is not known but it appears to play an important role in ribosome function or assembly. Knockdown of SBDS expression results in increased apoptosis in erythroid cells undergoing differentiation due to elevated ROS levels. Hence SBDS is critical for normal erythropoiesis. This family is highly conserved in species ranging from archaea to vertebrates and plants. The family contains several Shwachman-Bodian-Diamond syndrome (SBDS) proteins from both mouse and humans. Shwachman-Diamond syndrome is an autosomal recessive disorder with clinical features that include pancreatic exocrine insufficiency, haematological dysfunction and skeletal abnormalities. Members of this family play a role in RNA metabolism. A number of uncharacterised hydrophilic proteins of about 30 kDa share regions of similarity. These include, - Mouse protein 22A3. - Saccharomyces cerevisiae chromosome XII hypothetical protein YLR022c. - Caenorhabditis elegans hypothetical protein W06E11.4. - Methanococcus jannaschii hypothetical protein MJ0592. This particular protein sequence is highly conserved in species ranging from archaea to vertebrates and plants. # Structure The SBDS protein contains three domains, an N-terminal conserved FYSH domain, central helical domain and C-terminal domain containing an RNA-binding motif. # SBDS N-terminal domain ## Function This protein domain appears to be very important, since mutations in this domain are usually the cause of Shwachman-Bodian-Diamond syndrome. It shares distant structural and sequence homology to a protein named YHR087W found in the yeast Saccharomyces cerevisiae. The protein YHR087W is involved in RNA metabolism, so it is probable that the SBDS N-terminal domain has the same function. ## Structure The N-terminal domains contains a novel mixed alphabeta fold, four beta-strands, and four alpha-helices arranged as a three beta stranded anti-parallel-sheet. # SBDS central domain ## Function The function of this protein domain has been difficult to elucidate. It is possible that it has a role in binding to DNA or RNA. Protein binding to form a protein complex is also another possibility. It has been difficult to infer the function from the structure since this particular domain structure is found in archea. ## Structure This domain contains a very common structure, the winged helix-turn-helix. # SBDS C-terminal domain In molecular biology, the SBDS C-terminal protein domain is highly conserved in species ranging from archaea to vertebrates and plants. ## Function Members of this family are thought to play a role in RNA metabolism. However, its precise function remains to be elucidated. Furthermore, its structure makes it very difficult to predict the protein domain's function. ## Structure The structure of the C-terminal domain contains a ferredoxin-like fold This structure has a four-stranded beta-sheet with two helices on one side. # Clinical significance Mutations within this gene are associated with Shwachman-Bodian-Diamond syndrome . The two most common mutations associated with this syndrome are at positions 183–184 (TA→CT) resulting in a premature stop-codon (K62X) and a frameshift mutation at position 258 (2T→C) resulting in a stopcodon (C84fsX3).

SBDS Ribosome maturation protein SBDS is a protein that in humans is encoded by the SBDS gene.[1] An alternative transcript has been described, but its biological nature has not been determined. This gene has a closely linked pseudogene that is distally located.[2] This gene encodes a member of a highly conserved protein family that exists from archaea to vertebrates and plants. # Function The encoded protein may function in RNA metabolism.[2] The precise function of the SBDS protein is not known but it appears to play an important role in ribosome function or assembly.[3] Knockdown of SBDS expression results in increased apoptosis in erythroid cells undergoing differentiation due to elevated ROS levels. Hence SBDS is critical for normal erythropoiesis.[4] This family is highly conserved in species ranging from archaea to vertebrates and plants. The family contains several Shwachman-Bodian-Diamond syndrome (SBDS) proteins from both mouse and humans. Shwachman-Diamond syndrome is an autosomal recessive disorder with clinical features that include pancreatic exocrine insufficiency, haematological dysfunction and skeletal abnormalities. Members of this family play a role in RNA metabolism.[1][5] A number of uncharacterised hydrophilic proteins of about 30 kDa share regions of similarity. These include, - Mouse protein 22A3. - Saccharomyces cerevisiae chromosome XII hypothetical protein YLR022c. - Caenorhabditis elegans hypothetical protein W06E11.4. - Methanococcus jannaschii hypothetical protein MJ0592. This particular protein sequence is highly conserved in species ranging from archaea to vertebrates and plants.[1] # Structure The SBDS protein contains three domains, an N-terminal conserved FYSH domain, central helical domain and C-terminal domain containing an RNA-binding motif.[3] # SBDS N-terminal domain ## Function This protein domain appears to be very important, since mutations in this domain are usually the cause of Shwachman-Bodian-Diamond syndrome. It shares distant structural and sequence homology to a protein named YHR087W found in the yeast Saccharomyces cerevisiae. The protein YHR087W is involved in RNA metabolism, so it is probable that the SBDS N-terminal domain has the same function.[5] ## Structure The N-terminal domains contains a novel mixed alphabeta fold, four beta-strands, and four alpha-helices arranged as a three beta stranded anti-parallel-sheet.[5] # SBDS central domain ## Function The function of this protein domain has been difficult to elucidate. It is possible that it has a role in binding to DNA or RNA. Protein binding to form a protein complex is also another possibility. It has been difficult to infer the function from the structure since this particular domain structure is found in archea.[5] ## Structure This domain contains a very common structure, the winged helix-turn-helix.[5] # SBDS C-terminal domain In molecular biology, the SBDS C-terminal protein domain is highly conserved in species ranging from archaea to vertebrates and plants.[6] ## Function Members of this family are thought to play a role in RNA metabolism.[5] However, its precise function remains to be elucidated. Furthermore, its structure makes it very difficult to predict the protein domain's function.[5] ## Structure The structure of the C-terminal domain contains a ferredoxin-like fold[7] This structure has a four-stranded beta-sheet with two helices on one side.[5] # Clinical significance Mutations within this gene are associated with Shwachman-Bodian-Diamond syndrome .[2] The two most common mutations associated with this syndrome are at positions 183–184 (TA→CT) resulting in a premature stop-codon (K62X) and a frameshift mutation at position 258 (2T→C) resulting in a stopcodon (C84fsX3).[3]

https://www.wikidoc.org/index.php/SBDS

11c541e6f66362f73a08c11f4d7d9681bbf9d14b

wikidoc

SCO1

SCO1 Protein SCO1 homolog, mitochondrial, also known as SCO1, cytochrome c oxidase assembly protein, is a protein that in humans is encoded by the SCO1 gene. SCO1 localizes predominantly to blood vessels, whereas SCO2 is barely detectable, as well as to tissues with high levels of oxidative phosphorylation. Expression of SCO2 is also much higher than that of SCO1 in muscle tissue, while SCO1 is expressed at higher levels in liver tissue than SCO2. Mutations in both SCO1 and SCO2 are associated with distinct clinical phenotypes as well as tissue-specific cytochrome c oxidase (complex IV) deficiency. # Structure SCO1 is located on the p arm of chromosome 17 in position 13.1 and has 6 exons. The SCO1 gene produces a 33.8 kDa protein composed of 301 amino acids. The protein is a member of the SCO1/2 family. It contains 3 copper metal binding sites at positions 169, 173, and 260, a transit peptide, a 25 amino acid topological domain from positions 68-92, a 19 amino acid helical transmembrane domain from positions 93-111, and a 190 amino acid topological domain from positions 112-301 in the mitochondrial intermembrane. Additionally, SCO1 has been predicted to contain 10 beta strands, 7 helixes, and 2 turns and is a single-pass membrane protein. # Function Mammalian cytochrome c oxidase (COX) catalyzes the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane. In yeast, 2 related COX assembly genes, SCO1 and SCO2 (synthesis of cytochrome c oxidase), enable subunits 1 and 2 to be incorporated into the holoprotein. This gene is the human homolog to the yeast SCO1 gene. It is predominantly expressed in muscle, heart, and brain tissues, which are also known for their high rates of oxidative phosphorylation. SCO1 is a copper metallochaperone that is located in the inner mitochondrial membrane and is important for the maturation and stabilization of cytochrome c oxidase subunit II (MT-CO2/COX2). It plays a role in the regulation of copper homeostasis by controlling the localization and abundance of CTR1 and is responsible for the transportation of copper to the Cu(A) site on MT-CO2/COX2. # Clinical relevance Mutations in the SCO1 gene are associated with hepatic failure and encephalopathy resulting from mitochondrial complex IV deficiency also known as cytochrome c oxidase deficiency. This is a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Features include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development, mental retardation, and lactic acidosis. Some affected individuals manifest a fatal hypertrophic cardiomyopathy resulting in neonatal death. A subset of patients also suffer from Leigh syndrome. Specifically, cases of pathogenic SCO1 mutations have resulted in fatal infantile encephalopathy, neonatal-onset hepatic failure, and severe hepatopathy. The P174L and M294V mutations have been identified and implicated in these diseases and phenotypes. It has also been suggested that mutations in SCO1, as well as SCO2, can result in a cellular copper deficiency, which can occur separately from cytochrome c oxidase assembly defects. # Model organisms Model organisms have been used in the study of SCO1 function. A conditional knockout mouse line, called Sco1tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program—a high-throughput mutagenesis project to generate and distribute animal models of disease. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty two tests were carried out on mutant mice and two significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals. # Interactions SCO1 has been shown to have 127 binary protein-protein interactions including 120 co-complex interactions. SCO1 interacts with COA6, TMEM177, COX20, COX16, COX17, WDR19, CIDEB, and UBC7. It is also found in a complex with TMEM177, COX20, COA6, MT-CO2/COX2, COX18 and SCO2.

SCO1 Protein SCO1 homolog, mitochondrial, also known as SCO1, cytochrome c oxidase assembly protein, is a protein that in humans is encoded by the SCO1 gene.[1][2] SCO1 localizes predominantly to blood vessels, whereas SCO2 is barely detectable, as well as to tissues with high levels of oxidative phosphorylation. Expression of SCO2 is also much higher than that of SCO1 in muscle tissue, while SCO1 is expressed at higher levels in liver tissue than SCO2. Mutations in both SCO1 and SCO2 are associated with distinct clinical phenotypes as well as tissue-specific cytochrome c oxidase (complex IV) deficiency. [3][4][5] # Structure SCO1 is located on the p arm of chromosome 17 in position 13.1 and has 6 exons.[2] The SCO1 gene produces a 33.8 kDa protein composed of 301 amino acids.[6][7] The protein is a member of the SCO1/2 family. It contains 3 copper metal binding sites at positions 169, 173, and 260, a transit peptide, a 25 amino acid topological domain from positions 68-92, a 19 amino acid helical transmembrane domain from positions 93-111, and a 190 amino acid topological domain from positions 112-301 in the mitochondrial intermembrane. Additionally, SCO1 has been predicted to contain 10 beta strands, 7 helixes, and 2 turns and is a single-pass membrane protein.[4][5] # Function Mammalian cytochrome c oxidase (COX) catalyzes the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane. In yeast, 2 related COX assembly genes, SCO1 and SCO2 (synthesis of cytochrome c oxidase), enable subunits 1 and 2 to be incorporated into the holoprotein. This gene is the human homolog to the yeast SCO1 gene.[2] It is predominantly expressed in muscle, heart, and brain tissues, which are also known for their high rates of oxidative phosphorylation.[1] SCO1 is a copper metallochaperone that is located in the inner mitochondrial membrane and is important for the maturation and stabilization of cytochrome c oxidase subunit II (MT-CO2/COX2). It plays a role in the regulation of copper homeostasis by controlling the localization and abundance of CTR1 and is responsible for the transportation of copper to the Cu(A) site on MT-CO2/COX2.[8][4][5][9] # Clinical relevance Mutations in the SCO1 gene are associated with hepatic failure and encephalopathy resulting from mitochondrial complex IV deficiency also known as cytochrome c oxidase deficiency. This is a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Features include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development, mental retardation, and lactic acidosis. Some affected individuals manifest a fatal hypertrophic cardiomyopathy resulting in neonatal death. A subset of patients also suffer from Leigh syndrome.[9][10][4][5] Specifically, cases of pathogenic SCO1 mutations have resulted in fatal infantile encephalopathy, neonatal-onset hepatic failure, and severe hepatopathy. The P174L and M294V mutations have been identified and implicated in these diseases and phenotypes.[10][11][12] It has also been suggested that mutations in SCO1, as well as SCO2, can result in a cellular copper deficiency, which can occur separately from cytochrome c oxidase assembly defects.[9] # Model organisms Model organisms have been used in the study of SCO1 function. A conditional knockout mouse line, called Sco1tm1a(KOMP)Wtsi[16][17] was generated as part of the International Knockout Mouse Consortium program—a high-throughput mutagenesis project to generate and distribute animal models of disease.[18][19][20] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[14][21] Twenty two tests were carried out on mutant mice and two significant abnormalities were observed.[14] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.[14] # Interactions SCO1 has been shown to have 127 binary protein-protein interactions including 120 co-complex interactions. SCO1 interacts with COA6, TMEM177, COX20, COX16, COX17, WDR19, CIDEB, and UBC7. It is also found in a complex with TMEM177, COX20, COA6, MT-CO2/COX2, COX18 and SCO2.[22][4][5][23]

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8e031e5ecd55c9c837adfaf77fffb70892bfb15d

wikidoc

SCP2

SCP2 Non-specific lipid-transfer protein also known as sterol carrier protein 2 (SCP-2) or propanoyl-CoA C-acyltransferase is a protein that in humans is encoded by the SCP2 gene. # Function This gene encodes two proteins: sterol carrier protein X (SCPx) and sterol carrier protein 2 (SCP2), as a result of transcription initiation from 2 independently regulated promoters. The transcript initiated from the proximal promoter encodes the longer SCPx protein, and the transcript initiated from the distal promoter encodes the shorter SCP2 protein, with the 2 proteins sharing a common C-terminus. Evidence suggests that the SCPx protein is a peroxisome-associated thiolase that is involved in the oxidation of branched chain fatty acids, while the SCP2 protein is thought to be an intracellular lipid transfer protein. Alternative splicing of this gene produces multiple transcript variants, some encoding different isoforms. The full-length nature of all transcript variants has not been determined. # Clinical significance This gene is highly expressed in organs involved in lipid metabolism, and may play a role in Zellweger syndrome, in which cells are deficient in peroxisomes and have impaired bile acid synthesis. # Interactions SCP2 has been shown to interact with Caveolin 1 and peroxisomal receptor PEX5.

SCP2 Non-specific lipid-transfer protein also known as sterol carrier protein 2 (SCP-2) or propanoyl-CoA C-acyltransferase is a protein that in humans is encoded by the SCP2 gene.[1][2] # Function This gene encodes two proteins: sterol carrier protein X (SCPx) and sterol carrier protein 2 (SCP2), as a result of transcription initiation from 2 independently regulated promoters. The transcript initiated from the proximal promoter encodes the longer SCPx protein, and the transcript initiated from the distal promoter encodes the shorter SCP2 protein, with the 2 proteins sharing a common C-terminus. Evidence suggests that the SCPx protein is a peroxisome-associated thiolase that is involved in the oxidation of branched chain fatty acids, while the SCP2 protein is thought to be an intracellular lipid transfer protein. Alternative splicing of this gene produces multiple transcript variants, some encoding different isoforms. The full-length nature of all transcript variants has not been determined.[3] # Clinical significance This gene is highly expressed in organs involved in lipid metabolism, and may play a role in Zellweger syndrome, in which cells are deficient in peroxisomes and have impaired bile acid synthesis.[3] # Interactions SCP2 has been shown to interact with Caveolin 1[4] and peroxisomal receptor PEX5.[5]

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88045ead52e983dc549ae943e3580918e767c7b8

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SDHA

SDHA Succinate dehydrogenase complex, subunit A, flavoprotein variant is a protein that in humans is encoded by the SDHA gene. This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. SDHA contains the FAD binding site where succinate is deprotonated and converted to fumarate. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. # Structure The SDHA gene is located on the p arm of chromosome 5 at locus 15 and is composed of 16 exons. The SDHA protein encoded by this gene is 664 amino acids long and weighs 72.7 kDA. # Function The SDH complex is located on the inner membrane of the mitochondria and participates in both the citric acid cycle and the respiratory chain. The succinate dehydrogenase (SDH) protein complex catalyzes the oxidation of succinate (succinate + ubiquinone => fumarate + ubiquinol). Electrons removed from succinate transfer to SDHA, transfer across SDHB through iron sulphur clusters to the SDHC/SDHD subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane. Initially, SDHA oxidizes succinate via deprotonation at the FAD binding site, forming FADH2 and leaving fumarate, loosely bound to the active site, free to exit the protein. The electrons derived from succinate tunnel along the relay in the SDHB subunit until they reach the iron sulfur cluster. The electrons are then transferred to an awaiting ubiquinone molecule at the Q pool active site in the SDHC/SDHD dimer. The O1 carbonyl oxygen of ubiquinone is oriented at the active site (image 4) by hydrogen bond interactions with Tyr83 of SDHD. The presence of electrons in the iron sulphur cluster induces the movement of ubiquinone into a second orientation. This facilitates a second hydrogen bond interaction between the O4 carbonyl group of ubiquinone and Ser27 of SDHC. Following the first single electron reduction step, a semiquinone radical species is formed. The second electron arrives from the cluster to provide full reduction of the ubiquinone to ubiquinol. SDHA acts as an intermediate in the basic SDH enzyme action: - SDHA converts succinate to fumarate as part of the Citric Acid Cycle. This reaction also converts FAD to FADH2. - Electrons from the FADH2 are transferred to the SDHB subunit iron clusters ,,. This function is part of the Respiratory chain - Finally the electrons are transferred to the Ubiquinone (Q) pool via the SDHC/SDHD subunits. # Clinical significance Bi-allelic mutations (i.e. both copies of the gene are mutated) have been described in Leigh syndrome, a progressive brain disorder that typically appears in infancy or early childhood. Affected children may experience vomiting, seizures, delayed development, muscle weakness, and problems with movement. Heart disease, kidney problems, and difficulty breathing can also occur in people with this disorder. The SDHA gene mutations responsible for Leigh syndrome change single amino acids in the SDHA protein, such as a G555E mutation observed in multiple patients, or result in an abnormally short protein. These genetic changes disrupt the activity of the SDH enzyme, impairing the ability of mitochondria to produce energy. It is not known, however, how mutations in the SDHA gene are related to the specific features of Leigh syndrome. SDHA is a tumour suppressor gene, and heterozygous carriers have an increased risk of paragangliomas as well as pheochromocytomas and renal cancer. Risk management for heterozygous carriers of an SDHA mutation can involve annual urine tests for metanephrines and 3-methoxytyramine and MRIs. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

SDHA Succinate dehydrogenase complex, subunit A, flavoprotein variant is a protein that in humans is encoded by the SDHA gene.[1] This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. SDHA contains the FAD binding site where succinate is deprotonated and converted to fumarate. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[2] # Structure The SDHA gene is located on the p arm of chromosome 5 at locus 15 and is composed of 16 exons.[2] The SDHA protein encoded by this gene is 664 amino acids long and weighs 72.7 kDA.[3][4] # Function The SDH complex is located on the inner membrane of the mitochondria and participates in both the citric acid cycle and the respiratory chain. The succinate dehydrogenase (SDH) protein complex catalyzes the oxidation of succinate (succinate + ubiquinone => fumarate + ubiquinol). Electrons removed from succinate transfer to SDHA, transfer across SDHB through iron sulphur clusters to the SDHC/SDHD subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane. Initially, SDHA oxidizes succinate via deprotonation at the FAD binding site, forming FADH2 and leaving fumarate, loosely bound to the active site, free to exit the protein. The electrons derived from succinate tunnel along the [Fe-S] relay in the SDHB subunit until they reach the [3Fe-4S] iron sulfur cluster. The electrons are then transferred to an awaiting ubiquinone molecule at the Q pool active site in the SDHC/SDHD dimer. The O1 carbonyl oxygen of ubiquinone is oriented at the active site (image 4) by hydrogen bond interactions with Tyr83 of SDHD. The presence of electrons in the [3Fe-4S] iron sulphur cluster induces the movement of ubiquinone into a second orientation. This facilitates a second hydrogen bond interaction between the O4 carbonyl group of ubiquinone and Ser27 of SDHC. Following the first single electron reduction step, a semiquinone radical species is formed. The second electron arrives from the [3Fe-4S] cluster to provide full reduction of the ubiquinone to ubiquinol.[5] SDHA acts as an intermediate in the basic SDH enzyme action: - SDHA converts succinate to fumarate as part of the Citric Acid Cycle. This reaction also converts FAD to FADH2. - Electrons from the FADH2 are transferred to the SDHB subunit iron clusters [2Fe-2S],[4Fe-4S],[3Fe-4S]. This function is part of the Respiratory chain - Finally the electrons are transferred to the Ubiquinone (Q) pool via the SDHC/SDHD subunits. # Clinical significance Bi-allelic mutations (i.e. both copies of the gene are mutated) have been described in Leigh syndrome, a progressive brain disorder that typically appears in infancy or early childhood. Affected children may experience vomiting, seizures, delayed development, muscle weakness, and problems with movement. Heart disease, kidney problems, and difficulty breathing can also occur in people with this disorder.[6] The SDHA gene mutations responsible for Leigh syndrome change single amino acids in the SDHA protein, such as a G555E mutation observed in multiple patients,[7][8] or result in an abnormally short protein. These genetic changes disrupt the activity of the SDH enzyme, impairing the ability of mitochondria to produce energy. It is not known, however, how mutations in the SDHA gene are related to the specific features of Leigh syndrome. SDHA is a tumour suppressor gene, and heterozygous carriers have an increased risk of paragangliomas as well as pheochromocytomas and renal cancer.[9] Risk management for heterozygous carriers of an SDHA mutation can involve annual urine tests for metanephrines and 3-methoxytyramine and MRIs.[10] # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. [§ 1] - ↑ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

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de9936252f01675be0633602bc07721f92fe1382

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SDHB

SDHB Succinate dehydrogenase iron-sulfur subunit, mitochondrial (SDHB) also known as iron-sulfur subunit of complex II (Ip) is a protein that in humans is encoded by the SDHB gene. The succinate dehydrogenase (also called SDH or Complex II) protein complex catalyzes the oxidation of succinate (succinate + ubiquinone => fumarate + ubiquinol). SDHB is one of four protein subunits forming succinate dehydrogenase, the other three being SDHA, SDHC and SDHD. The SDHB subunit is connected to the SDHA subunit on the hydrophilic, catalytic end of the SDH complex. It is also connected to the SDHC/SDHD subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane. The subunit is an iron-sulfur protein with three iron-sulfur clusters. It weighs 30 kDa. # Structure The gene that codes for the SDHB protein is nuclear, not mitochondrial DNA. However, the expressed protein is located in the inner membrane of the mitochondria. The location of the gene in humans is on the first chromosome at locus p36.1-p35. The gene is coded in 1,162 base pairs, partitioned in 8 exons. The expressed protein weighs 31.6 kDa and is composed of 280 amino acids. SDHB contains the iron-sulphur clusters necessary for tunneling electrons through the complex. It is located between SDHA and the two transmembrane subunits SDHC and SDHD. # Function The SDH complex is located on the inner membrane of the mitochondria and participates in both the Citric Acid Cycle and Respiratory chain. SDHB acts as an intermediate in the basic SDH enzyme action shown in Figure 1: - SDHA converts succinate to fumarate as part of the Citric Acid Cycle. This reaction also converts FAD to FADH2. - Electrons from the FADH2 are transferred to the SDHB subunit iron clusters ,,. - Finally the electrons are transferred to the Ubiquinone (Q) pool via the SDHC/SDHD subunits. This function is part of the Respiratory chain. Initially, SDHA oxidizes succinate via deprotonation at the FAD binding site, forming FADH2 and leaving fumarate, loosely bound to the active site, free to exit the protein. Electrons from FADH2 are transferred to the SDHB subunit iron clusters ,, and tunnel along the relay until they reach the iron sulfur cluster. The electrons are then transferred to an awaiting ubiquinone molecule at the Q pool active site in the SDHC/SDHD dimer. The O1 carbonyl oxygen of ubiquinone is oriented at the active site (image 4) by hydrogen bond interactions with Tyr83 of SDHD. The presence of electrons in the iron sulphur cluster induces the movement of ubiquinone into a second orientation. This facilitates a second hydrogen bond interaction between the O4 carbonyl group of ubiquinone and Ser27 of SDHC. Following the first single electron reduction step, a semiquinone radical species is formed. The second electron arrives from the cluster to provide full reduction of the ubiquinone to ubiquinol. # Clinical significance Germline mutations in the gene can cause familial paraganglioma (in old nomenclature, Paraganglioma Type PGL4). The same condition is often called familial pheochromocytoma. Less frequently, renal cell carcinoma can be caused by this mutation. Paragangliomas related to SDHB mutations have a high rate of malignancy. When malignant, treatment is currently the same as for any malignant paraganglioma/pheochromocytoma. ## Cancer Paragangliomas caused by SDHB mutations have several distinguishing characteristics: - Malignancy is common, ranging from 38%-83% in carriers with disease. In contrast, tumors caused by SDHD mutations are almost always benign. Sporadic paragangliomas are malignant in less than 10% of cases. - Malignant paragangliomas caused by SDHB are usually (perhaps 92%) extra-adrenal. Sporadic pheochromocytomas/paragangliomas are extra-adrenal in less than 10% of cases. - The penetrance of the gene is often reported as 77% by age 50 (i.e. 77% of carriers will have at least one tumour by the age of 50). This is likely an overestimate. Currently (2011), families with silent SDHB mutations are being screened to determine the frequency of silent carriers. - The average age of onset is approximately the same for SDHB vs non-SDHB related disease (approximately 36 years). Mutations causing disease have been seen in exons 1 through 7, but not 8. As with the SDHC and SDHD genes, SDHB is a tumor suppressor gene. Tumor formation generally follows the Knudson "two hit" hypothesis. The first copy of the gene is mutated in all cells, however the second copy functions normally. When the second copy mutates in a certain cell due to a random event, Loss of Heterozygosity (LOH) occurs and the SDHB protein is no longer produced. Tumor formation then becomes possible. Given the fundamental nature of the SDH protein in all cellular function, it is not currently understood why only paraganglionic cells are affected. However, the sensitivity of these cells to oxygen levels may play a role. ## Disease pathways The precise pathway leading from SDHB mutation to tumorigenesis is not determined; there are several proposed mechanisms. ### Generation of reactive oxygen species When succinate-ubiquinone activity is inhibited, electrons that would normally transfer through the SDHB subunit to the Ubiquinone pool are instead transferred to O2 to create Reactive Oxygen Species (ROS) such as superoxide. The dashed red arrow in Figure 2 shows this. ROS accumulate and stabilize the production of HIF1-α. HIF1-α combines with HIF1-β to form the stable HIF heterodimeric complex, in turn leading to the induction of antiapoptotic genes in the cell nucleus. ### Succinate accumulation in the cytosol SDH inactivation can block the oxidation of succinate, starting a cascade of reactions: - The succinate accumulated in the mitochondrial matrix diffuses through the inner and outer mitochondrial membranes to the cytosol (purple dashed arrows in Figure 2). - Under normal cellular function, HIF1-α in the cytosol is quickly hydroxylated by prolyl hydroxylase (PHD), shown with the light blue arrow. This process is blocked by the accumulated succinate. - HIF1-α stabilizes and passes to the cell nucleus (orange arrow) where it combines with HIF1-β to form an active HIF complex that induces the expression of tumor causing genes. This pathway raises the possibility of a therapeutic treatment. The build-up of succinate inhibits PHD activity. PHD action normally requires oxygen and alpha-ketoglutarate as cosubstrates and ferrous iron and ascorbate as cofactors. Succinate competes with α-ketoglutarate in binding to the PHD enzyme. Therefore, increasing α-ketoglutarate levels can offset the effect of succinate accumulation. Normal α-ketoglutarate does not permeate cell walls efficiently, and it is necessary to create a cell permeating derivative (e.g. α-ketoglutarate esters). In-vitro trials show this supplementation approach can reduce HIF1-α levels, and may result in a therapeutic approach to tumours resulting from SDH deficiency. ### Impaired developmental apoptosis Paraganglionic tissue is derived from the neural crest cells present in an embryo. Abdominal extra-adrenal paraganglionic cells secrete catecholamines that play an important role in fetal development. After birth these cells usually die, a process that is triggered by a decline in nerve growth factor (NGF)which initiates apoptosis (cell death). This cell death process is mediated by an enzyme called prolyl hydroxylase EglN3. Succinate accumulation caused by SDH inactivation inhibits the prolyl hydroxylase EglN3. The net result is that paranglionic tissue that would normally die after birth remains, and this tissue may be able to trigger paraganglioma/pheochromocytoma later. ### Glycolysis upregulation Inhibition of the Citric Acid Cycle forces the cell to create ATP glycolytically in order to generate its required energy. The induced glycolytic enzymes could potentially block cell apoptosis. ## RNA editing The mRNA transcripts of the SDHB gene in human are edited through an unknown mechanism at ORF nucleotide position 136 causing the conversion of C to U and thus generating a stop codon resulting in the translation of the edited transcripts to a truncated SDHB protein with an R46X amino acid change. This editing has been shown in monocytes and some human lymphoid cell-lines, and is enhanced by hypoxia. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

SDHB Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial (SDHB) also known as iron-sulfur subunit of complex II (Ip) is a protein that in humans is encoded by the SDHB gene.[1][2][3] The succinate dehydrogenase (also called SDH or Complex II) protein complex catalyzes the oxidation of succinate (succinate + ubiquinone => fumarate + ubiquinol). SDHB is one of four protein subunits forming succinate dehydrogenase, the other three being SDHA, SDHC and SDHD. The SDHB subunit is connected to the SDHA subunit on the hydrophilic, catalytic end of the SDH complex. It is also connected to the SDHC/SDHD subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane. The subunit is an iron-sulfur protein with three iron-sulfur clusters. It weighs 30 kDa. # Structure The gene that codes for the SDHB protein is nuclear, not mitochondrial DNA. However, the expressed protein is located in the inner membrane of the mitochondria. The location of the gene in humans is on the first chromosome at locus p36.1-p35. The gene is coded in 1,162 base pairs, partitioned in 8 exons.[1] The expressed protein weighs 31.6 kDa and is composed of 280 amino acids.[4][5] SDHB contains the iron-sulphur clusters necessary for tunneling electrons through the complex. It is located between SDHA and the two transmembrane subunits SDHC and SDHD.[6] # Function The SDH complex is located on the inner membrane of the mitochondria and participates in both the Citric Acid Cycle and Respiratory chain. SDHB acts as an intermediate in the basic SDH enzyme action shown in Figure 1: - SDHA converts succinate to fumarate as part of the Citric Acid Cycle. This reaction also converts FAD to FADH2. - Electrons from the FADH2 are transferred to the SDHB subunit iron clusters [2Fe-2S],[4Fe-4S],[3Fe-4S]. - Finally the electrons are transferred to the Ubiquinone (Q) pool via the SDHC/SDHD subunits. This function is part of the Respiratory chain. Initially, SDHA oxidizes succinate via deprotonation at the FAD binding site, forming FADH2 and leaving fumarate, loosely bound to the active site, free to exit the protein. Electrons from FADH2 are transferred to the SDHB subunit iron clusters [2Fe-2S],[4Fe-4S],[3Fe-4S] and tunnel along the [Fe-S] relay until they reach the [3Fe-4S] iron sulfur cluster. The electrons are then transferred to an awaiting ubiquinone molecule at the Q pool active site in the SDHC/SDHD dimer. The O1 carbonyl oxygen of ubiquinone is oriented at the active site (image 4) by hydrogen bond interactions with Tyr83 of SDHD. The presence of electrons in the [3Fe-4S] iron sulphur cluster induces the movement of ubiquinone into a second orientation. This facilitates a second hydrogen bond interaction between the O4 carbonyl group of ubiquinone and Ser27 of SDHC. Following the first single electron reduction step, a semiquinone radical species is formed. The second electron arrives from the [3Fe-4S] cluster to provide full reduction of the ubiquinone to ubiquinol.[7] # Clinical significance Germline mutations in the gene can cause familial paraganglioma (in old nomenclature, Paraganglioma Type PGL4). The same condition is often called familial pheochromocytoma. Less frequently, renal cell carcinoma can be caused by this mutation. Paragangliomas related to SDHB mutations have a high rate of malignancy. When malignant, treatment is currently the same as for any malignant paraganglioma/pheochromocytoma. ## Cancer Paragangliomas caused by SDHB mutations have several distinguishing characteristics: - Malignancy is common, ranging from 38%-83%[8][9] in carriers with disease. In contrast, tumors caused by SDHD mutations are almost always benign. Sporadic paragangliomas are malignant in less than 10% of cases. - Malignant paragangliomas caused by SDHB are usually (perhaps 92%[9]) extra-adrenal. Sporadic pheochromocytomas/paragangliomas are extra-adrenal in less than 10% of cases. - The penetrance of the gene is often reported as 77% by age 50[8] (i.e. 77% of carriers will have at least one tumour by the age of 50). This is likely an overestimate. Currently (2011), families with silent SDHB mutations are being screened[10] to determine the frequency of silent carriers. - The average age of onset is approximately the same for SDHB vs non-SDHB related disease (approximately 36 years). Mutations causing disease have been seen in exons 1 through 7, but not 8. As with the SDHC and SDHD genes, SDHB is a tumor suppressor gene. Tumor formation generally follows the Knudson "two hit" hypothesis. The first copy of the gene is mutated in all cells, however the second copy functions normally. When the second copy mutates in a certain cell due to a random event, Loss of Heterozygosity (LOH) occurs and the SDHB protein is no longer produced. Tumor formation then becomes possible. Given the fundamental nature of the SDH protein in all cellular function, it is not currently understood why only paraganglionic cells are affected. However, the sensitivity of these cells to oxygen levels may play a role. ## Disease pathways The precise pathway leading from SDHB mutation to tumorigenesis is not determined; there are several proposed mechanisms.[11] ### Generation of reactive oxygen species When succinate-ubiquinone activity is inhibited, electrons that would normally transfer through the SDHB subunit to the Ubiquinone pool are instead transferred to O2 to create Reactive Oxygen Species (ROS) such as superoxide. The dashed red arrow in Figure 2 shows this. ROS accumulate and stabilize the production of HIF1-α. HIF1-α combines with HIF1-β to form the stable HIF heterodimeric complex, in turn leading to the induction of antiapoptotic genes in the cell nucleus. ### Succinate accumulation in the cytosol SDH inactivation can block the oxidation of succinate, starting a cascade of reactions: - The succinate accumulated in the mitochondrial matrix diffuses through the inner and outer mitochondrial membranes to the cytosol (purple dashed arrows in Figure 2). - Under normal cellular function, HIF1-α in the cytosol is quickly hydroxylated by prolyl hydroxylase (PHD), shown with the light blue arrow. This process is blocked by the accumulated succinate. - HIF1-α stabilizes and passes to the cell nucleus (orange arrow) where it combines with HIF1-β to form an active HIF complex that induces the expression of tumor causing genes.[12] This pathway raises the possibility of a therapeutic treatment. The build-up of succinate inhibits PHD activity. PHD action normally requires oxygen and alpha-ketoglutarate as cosubstrates and ferrous iron and ascorbate as cofactors. Succinate competes with α-ketoglutarate in binding to the PHD enzyme. Therefore, increasing α-ketoglutarate levels can offset the effect of succinate accumulation. Normal α-ketoglutarate does not permeate cell walls efficiently, and it is necessary to create a cell permeating derivative (e.g. α-ketoglutarate esters). In-vitro trials show this supplementation approach can reduce HIF1-α levels, and may result in a therapeutic approach to tumours resulting from SDH deficiency.[13] ### Impaired developmental apoptosis Paraganglionic tissue is derived from the neural crest cells present in an embryo. Abdominal extra-adrenal paraganglionic cells secrete catecholamines that play an important role in fetal development. After birth these cells usually die, a process that is triggered by a decline in nerve growth factor (NGF)which initiates apoptosis (cell death). This cell death process is mediated by an enzyme called prolyl hydroxylase EglN3. Succinate accumulation caused by SDH inactivation inhibits the prolyl hydroxylase EglN3.[14] The net result is that paranglionic tissue that would normally die after birth remains, and this tissue may be able to trigger paraganglioma/pheochromocytoma later. ### Glycolysis upregulation Inhibition of the Citric Acid Cycle forces the cell to create ATP glycolytically in order to generate its required energy. The induced glycolytic enzymes could potentially block cell apoptosis. ## RNA editing The mRNA transcripts of the SDHB gene in human are edited through an unknown mechanism at ORF nucleotide position 136 causing the conversion of C to U and thus generating a stop codon resulting in the translation of the edited transcripts to a truncated SDHB protein with an R46X amino acid change. This editing has been shown in monocytes and some human lymphoid cell-lines,[15] and is enhanced by hypoxia.[16] # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. [§ 1] - ↑ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

https://www.wikidoc.org/index.php/SDHB

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SDHC

SDHC SDHC is an abbrevation for succinate dehydrogenase complex subunit C. The term SDHC can refer to; - The protein subunit itself. - The gene that codes for this protein. The succinate dehydrogenase (SDH) protein complex catalyzes the oxidation of succinate (succinate + ubiquinone => fumarate + ubiquinol). The SDHA subunit is connected to the SDHB subunit on the hydrophilic, catalytic end of the complex. Electrons removed from succinate transfer SDHA, to SDHB and further to the SDHC/SDHD subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane. # Function of the SDHC protein The SDH complex is located on the inner membrane of the mitochondria and participates in both the Citric Acid Cycle and Respiratory chain. SDHC acts as an intermediate in the basic SDH enzyme action: - SDHA converts succinate to fumarate as part of the Citric Acid Cycle. This reaction also converts FAD to FADH2. - Electrons from the FADH2 are transferred to the SDHB subunit iron clusters ,,. This function is part of the Respiratory chain - Finally the electrons are transferred to the Ubiquinone (Q) pool via the SDHC/SDHD subunits. # Gene that codes for SDHC The gene that codes for the SDHC protein is nuclear, even though the protein is located in the inner membrane of the mitochondria. The location of the gene in humans is on the first chromosome at q21. The gene is partitioned in 6 exons. The expressed protein has 170 amino acids. SDHC was previously called PGL3.

SDHC SDHC is an abbrevation for succinate dehydrogenase complex subunit C. The term SDHC can refer to; - The protein subunit itself. - The gene that codes for this protein. The succinate dehydrogenase (SDH) protein complex catalyzes the oxidation of succinate (succinate + ubiquinone => fumarate + ubiquinol). The SDHA subunit is connected to the SDHB subunit on the hydrophilic, catalytic end of the complex. Electrons removed from succinate transfer SDHA, to SDHB and further to the SDHC/SDHD subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane. # Function of the SDHC protein The SDH complex is located on the inner membrane of the mitochondria and participates in both the Citric Acid Cycle and Respiratory chain. SDHC acts as an intermediate in the basic SDH enzyme action: - SDHA converts succinate to fumarate as part of the Citric Acid Cycle. This reaction also converts FAD to FADH2. - Electrons from the FADH2 are transferred to the SDHB subunit iron clusters [2Fe-2S],[4Fe-4S],[3Fe-4S]. This function is part of the Respiratory chain - Finally the electrons are transferred to the Ubiquinone (Q) pool via the SDHC/SDHD subunits. # Gene that codes for SDHC The gene that codes for the SDHC protein is nuclear, even though the protein is located in the inner membrane of the mitochondria. The location of the gene in humans is on the first chromosome at q21. The gene is partitioned in 6 exons. The expressed protein has 170 amino acids. SDHC was previously called PGL3. Template:WH Template:WS

https://www.wikidoc.org/index.php/SDHC