Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14751. Catalytic receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands ( The ligand binding domain is placed on the extracellular surface of the plasma membrane and separated from the functional domain by a single transmembrane‐spanning domain of 20‐25 hydrophobic amino acids. The functional domain on the intracellular face of the plasma membrane has catalytic activity, or interacts with particular enzymes, giving the superfamily of receptors its name. Endogenous agonists of the catalytic receptor superfamily are peptides or proteins, the binding of which may induce dimerization of the receptor, which is the functional version of the receptor.Amongst the catalytic receptors, particular subfamilies may be readily identified dependent on the function of the enzymatic portion of the receptor. The smallest group is the particulate guanylyl cyclases of the natriuretic peptide receptor family. The most widely recognized group is probably the receptor tyrosine kinase (RTK) family, epitomized by the neurotrophin receptor family, where a crucial initial step is the activation of a signalling cascade by autophosphorylation of the receptor on intracellular tyrosine residue(s) catalyzed by enzyme activity intrinsic to the receptor. A third group is the extrinsic protein tyrosine kinase receptors, where the catalytic activity resides in a separate protein from the binding site. Examples of this group include the GDNF and ErbB receptor families, where one, catalytically silent, member of the heterodimer is activated upon binding the ligand, causing the second member of the heterodimer, lacking ligand binding capacity, to initiate signaling through tyrosine phosphorylation. A fourth group, the receptor threonine/serine kinase (RTSK) family, exemplified by TGF‐β and BMP receptors, has intrinsic serine/threonine protein kinase activity in the heterodimeric functional unit. A fifth group is the receptor tyrosine phosphatases (RTP), which appear to lack cognate ligands, but may be triggered by events such as cell:cell contact and have identified roles in the skeletal, hematopoietic and immune systems.A further group of catalytic receptors for the Guide is the integrins, which have roles in cell:cell communication, often associated with signaling in the blood.1.1http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=699– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=686– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=687– 1http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=334, the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=303 family and the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=14. Within this group of records are described Type I cytokine receptors, typified by interleukin receptors, and Type II cytokine receptors, exemplified by interferon receptors. These receptors possess a conserved extracellular region, known as the cytokine receptor homology domain (CHD), along with a range of other structural modules, including extracellular immunoglobulin (Ig)‐like and fibronectin type III (FBNIII)‐like domains, a transmembrane domain, and intracellular homology domains. An unusual feature of this group of agents is the existence of soluble and decoy receptors. These bind cytokines without allowing signalling to occur. A further attribute is the production of endogenous antagonist molecules, which bind to the receptors selectively and prevent signalling. A commonality of these families of receptors is the ligand‐induced homo‐ or hetero‐oligomerisation, which results in the recruitment of intracellular protein partners to evoke cellular responses, particularly in inflammatory or haematopoietic signalling. Although not an exclusive signalling pathway, a common feature of the majority of cytokine receptors is activation of the JAK/STAT pathway. This cascade is based around the protein tyrosine kinase activity of the Janus kinases (JAK), which phosphorylate the receptor and thereby facilitate the recruitment of signal transducers and activators of transcription (STATs). The activated homo‐ or heterodimeric STATs function principally as transcription factors in the nucleus. Type I cytokine receptors are characterized by two pairs of conserved cysteines linked via disulfide bonds and a C‐terminal WSXWS motif within their CHD. Type I receptors are commonly classified into five groups, based on sequence and structual homology of the receptor and its cytokine ligand, which is potentially more reflective of evolutionary relationships than an earlier scheme based on the use of common signal transducing chains within a receptor complex.Cytokines are not a clearly defined group of agents, other than having an impact on immune signalling pathways, although many cytokines have effects on other systems, such as in development. A feature of some cytokines, which allows them to be distinguished from hormones, is that they may be produced by “non‐secretory” cells, for example, endothelial cells. Within the cytokine receptor family, some subfamilies may be identified, which are described elsewhere in the Guide to PHARMACOLOGY, receptors for the Type II cytokine receptors also have two pairs of conserved cysteines but with a different arrangement to Type I and also lack the WSXWS motif.1IL2RG, http://www.uniprot.org/uniprot/P31785), though IL‐4 and IL‐7 receptors can form complexes with other receptor chains. Receptors of this family associate with Jak1 and Jak3, primarily activating Stat5, although certain family members can also activate Stat1, Stat3, or Stat6. Ro264550 has been described as a selective IL‐2 receptor antagonist, which binds to IL‐2 . Mutations of RET and GDNF genes may be involved in Hirschsprung's disease, which is characterized by the absence of intramural ganglion cells in the hindgut, often resulting in intestinal obstruction.Inhibitors of other receptor tyrosine kinases, such as et al. (2013) GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol. Ther. 138: 155‐75 https://www.ncbi.nlm.nih.gov/pubmed/23348013?dopt=AbstractPlusAllen SJ et al. (2017) Biology of GDNF and its receptors ‐ Relevance for disorders of the central nervous system. Neurobiol. Dis. 97: 80‐89 https://www.ncbi.nlm.nih.gov/pubmed/26829643?dopt=AbstractPlusIbáñez CF Expert Opin. Ther. Targets20: 193‐208 https://www.ncbi.nlm.nih.gov/pubmed/26863504?dopt=AbstractPlusMerighi A. (2016) Targeting the glial‐derived neurotrophic factor and related molecules for controlling normal and pathologic pain. Integrins are unusual signalling proteins that function to signal both from the extracellular environment into the cell, but also from the cytoplasm to the external of the cell. The intracellular signalling cascades associated with integrin activation focus on protein kinase activities, such as focal adhesion kinase and Src. Based on this association between extracellular signals and intracellular protein kinase activity, we have chosen to include integrins in the ‘Catalytic receptors’ section of the database until more stringent criteria from NC‐IUPHAR allows precise definition of their classification.2+ ion in the I or I‐like domain that is essential for ligand binding. Other cation binding sites may regulate integrin activity or stabilise the 3D structure. Integrins regulate the activity of particular protein kinases, including focal adhesion kinase and integrin‐linked kinase. Cellular activation regulates integrin ligand affinity via inside‐out signalling and ligand binding to integrins can regulate cellular activity via outsidein signalling.Integrins are heterodimeric entities, composed of α and β subunits, each 1TM proteins, which bind components of the extracellular matrix or counter‐receptors expressed on other cells. One class of integrin contains an inserted domain (I) in its α subunit, and if present , this I domain contains the ligand binding site. All β subunits possess a similar I‐like domain, which has the capacity to bind ligand, often recognising the RGD motif. The presence of an a subunit I domain precludes ligand binding through the β subunit. Integrins provide a link between ligand and the actin cytoskeleton . Integrins bind several divalent cations, including a Mghttp://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6584 (αIIbβ3) for short term prevention of coronary thrombosis, (2) http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7437 (α4β7) to reduce gastrointestinal inflammation, and (3) http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6591 (α4β1) in some cases of severe multiple sclerosis.Several drugs that target integrins are in clinical use including: (1) Collagen is the most abundant protein in metazoa, rich in glycine and proline residues, made up of cross‐linked triple helical structures, generated primarily by fibroblasts. Extensive post‐translational processing is conducted by prolyl and lysyl hydroxylases, as well as transglutaminases. Over 40 genes for collagen‐α subunits have been identified in the human genome. The collagen‐binding integrins α1β1, α2β1, α10β1 and α11β1 recognise a range of triple‐helical peptide motifs including GFOGER (O = hydroxyproline), a synthetic peptide derived from the primary sequence of collagen I ) and collagen II ).Laminin is an extracellular glycoprotein composed of α, β and γ chains, for which five, four and three genes, respectively, are identified in the human genome. It binds to α1β1, α2β1, α3,β1, α7β1 and α6β4 integrins10.http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6749  is a glycosylated hexamer composed of two α , two β  and two γ  subunits, linked by disulphide bridges. It is found in plasma and alpha granules of platelets. It forms cross‐links between activated platelets mediating aggregation by binding αIIbβ3; proteolysis by thrombin cleaves short peptides termed fibrinopeptides to generate fibrin, which polymerises as part of the blood coagulation cascade.http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6754  is a disulphide‐linked homodimer found as two major forms; a soluble dimeric form found in the plasma and a tissue version that is polymeric, which is secreted into the extracellular matrix by fibroblasts. Splice variation of the gene product  generates multiple isoforms.http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6746  is a serum glycoprotein and extracellular matrix protein which is found either as a monomer or, following proteolysis, a disulphide ‐linked dimer.http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6753  forms an integral part of the mineralized matrix in bone, where it undergoes extensive posttranslation processing, including proteolysis and phosphorylation.http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6755  is a glycoprotein synthesised in vascular endothelial cells as a disulphide‐linked homodimer, but multimerises further in plasma and is deposited on vessel wall collagen as a high molecular weight multimer. It is responsible for capturing platelets under arterial shear flow (via GPIb) and in thrombus propagation (via integrin αIIbβ3).Platelets28: 40‐42 https://www.ncbi.nlm.nih.gov/pubmed/27715379?dopt=AbstractPlusClemetson KJ. (2017) The origins of major platelet receptor nomenclature. et al. (2000) Structural basis of collagen recognition by integrin alpha2beta1. Cell101: 47‐56 https://www.ncbi.nlm.nih.gov/pubmed/10778855?dopt=AbstractPlusEmsley J et al. (2016) The complexity of integrins in cancer and new scopes for therapeutic targeting. Br. J. Cancer115: 1017‐1023 https://www.ncbi.nlm.nih.gov/pubmed/27685444?dopt=AbstractPlusHamidi H et al. (2016) The integrin adhesome network at a glance. J. Cell. Sci. 129: 4159‐4163 https://www.ncbi.nlm.nih.gov/pubmed/27799358?dopt=AbstractPlusHorton ER et al. (2016) Integrin‐based therapeutics: biological basis, clinical use and new drugs. Nat Rev Drug Discov15: 173‐83 https://www.ncbi.nlm.nih.gov/pubmed/26822833?dopt=AbstractPlusLey K et al. (2017) A proteomics view on integrin‐mediated adhesions. Proteomics17: https://www.ncbi.nlm.nih.gov/pubmed/27723259?dopt=AbstractPlusManninen A et al. (2017) Integrins as Therapeutic Targets: Successes and Cancers. Cancers (Basel)9: https://www.ncbi.nlm.nih.gov/pubmed/28832494?dopt=AbstractPlusRaab‐Westphal S http://www.ncbi.nlm.nih.gov/pubmed/20303872?dopt=AbstractPlus])  participate in the innate immune response to microbial agents, the stimulation of which leads to activation of intracellular enzymes and regulation of gene transcription. PRRs express multiple leucine‐rich regions to bind a range of microbially‐derived ligands, termed PAMPs or pathogen‐associated molecular patterns or endogenous ligands, termed DAMPS or damage‐associated molecular patterns. These include peptides, carbohydrates, peptidoglycans, lipoproteins, lipopolysaccharides, and nucleic acids. PRRs include both cell‐surface and intracellular proteins. PRRs may be divided into signalling‐associated members, identified here, and endocytic members, the function of which appears to be to recognise particular microbial motifs for subsequent cell attachment, internalisation and destruction. Some are involved in inflammasome formation, and modulation of IL‐1β cleavage and secretion, and others in the initiation of the type I interferon response.Pattern Recognition Receptors Toll‐like receptors (TLRs)Nucleotide‐binding oligomerization domain, leucine‐rich repeat containing receptors ‐like receptors)RIG‐I‐like receptors (RLRs)http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1620 and http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1621Non‐catalytic PRRshttp://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=942 (ALRs)http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=945http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=929http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2843 (RAGE)http://www.ncbi.nlm.nih.gov/pubmed/25829385?dopt=AbstractPlus]) share significant homology with the interleukin‐1 receptor family and appear to require dimerization either as homo‐ or heterodimers for functional activity. Heterodimerization appears to influence the potency of ligand binding substantially . TLR1, TLR2, TLR4, TLR5, TLR6 and TLR11 are cell‐surface proteins, while other members are associated with intracellular organelles, signalling through the MyD88‐dependent pathways (with the exception of TLR3). As well as responding to exogenous infectious agents, it has been suggested that selected members of the family may be activated by endogenous ligands, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4953  [http://www.ncbi.nlm.nih.gov/pubmed/10623794?dopt=AbstractPlus].Members of the toll‐like family of receptors  Toll and Toll‐like receptor signalling in development. Development145: https://www.ncbi.nlm.nih.gov/pubmed/29695493?dopt=AbstractPlusAnthoney N et al. (2015) International Union of Basic and Clinical Pharmacology. XCVI. Pattern recognition receptors in health and disease. Pharmacol. Rev. 67: 462‐504 https://www.ncbi.nlm.nih.gov/pubmed/25829385?dopt=AbstractPlusBryant CE et al. (2017) Innate Immune Receptors as Competitive Determinants of Cell Fate. Mol. Cell66: 750‐760 https://www.ncbi.nlm.nih.gov/pubmed/28622520?dopt=AbstractPlusFranz KM et al. (2016) Toll‐like receptors and chronic inflammation in rheumatic diseases: new developments. Nat Rev Rheumatol12: 344‐57 https://www.ncbi.nlm.nih.gov/pubmed/27170508?dopt=AbstractPlusJoosten LA et al. (2018) Targeting toll‐like receptor 4 signalling pathways: can therapeutics pay the toll for hypertension? Br. J. Pharmacol. https://www.ncbi.nlm.nih.gov/pubmed/29981161?dopt=AbstractPlusNunes KP et al. (2017) Toward a structural understanding of nucleic acid‐sensing Toll‐like receptors in the innate immune system. FEBS Lett. 591: 3167‐3181 https://www.ncbi.nlm.nih.gov/pubmed/28686285?dopt=AbstractPlusZhang Z http://www.ncbi.nlm.nih.gov/pubmed/25829385?dopt=AbstractPlus]) share a common domain organisation. This consists of an N‐terminal effector domain, a central nucleotidebinding and oligomerization domain , and C‐terminal leucine‐rich repeats (LRR) which have regulatory and ligand recognition functions. The type of effector domain has resulted in the division of NLR family members into two major sub‐families, NLRC and NLRP, along with three smaller sub‐families NLRA, NLRB and NLRX [http://www.ncbi.nlm.nih.gov/pubmed/18341998?dopt=AbstractPlus]. NLRC members express an N‐terminal caspase recruitment domain (CARD) and NLRP members an N‐terminal Pyrin domain (PYD).The nucleotide‐binding oligomerization domain, leucine‐rich repeat (NLR) family of receptors  leading to signalling through NFκB and MAP kinase. Activation of NLRC4 (previously known as IPAF) and members of the NLRP3 family, including NLRP1 and NLRP3, leads to formation of a large multiprotein complex known as the inflammasome. In addition to NLR proteins other key members of the inflammasome include the adaptor protein ASC  and inflammatory caspases. The inflammasome activates the pro‐inflammatory cytokines http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4974  and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4983  Upon activation the NLRC family members NOD1 (NLRC1) and NOD2 (NLRC2) recruit a serine/threonine kinase http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4731 [http://www.ncbi.nlm.nih.gov/pubmed/16407889?dopt=AbstractPlus], http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4719, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4954 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4865  [http://www.ncbi.nlm.nih.gov/pubmed/20303873?dopt=AbstractPlus].NLRP3 has also been reported to respond to hostderived products, known as danger‐associated molecular patterns, or DAMPs, including Loss‐of‐function mutations of NLRP3 are associated with cold autoinflammatory and Muckle‐Wells syndromes.http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2793  which can be found in the ‘Inhibitors of apoptosis (IAP) protein family’ in the http://www.guidetopharmacology.org/GRAC/ReceptorFamiliesForward?type=OTHER section of the Guide.This family also includes et al. (2016) Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16: 407‐20 https://www.ncbi.nlm.nih.gov/pubmed/27291964?dopt=AbstractPlusBroz P et al. (2015) International Union of Basic and Clinical Pharmacology. XCVI. Pattern recognition receptors in health and disease. Pharmacol. Rev. 67: 462‐504 https://www.ncbi.nlm.nih.gov/pubmed/25829385?dopt=AbstractPlusBryant CE et al. (2017) NOD1 and NOD2: Beyond Peptidoglycan Sensing. Trends Immunol. 38: 758‐767 https://www.ncbi.nlm.nih.gov/pubmed/28823510?dopt=AbstractPlusKeestra‐Gounder AM et al. (2017) Epithelial Cell Inflammasomes in Intestinal Immunity and Inflammation. Front Immunol8: 1168 https://www.ncbi.nlm.nih.gov/pubmed/28979266?dopt=AbstractPlusLei‐Leston AC Nat Rev Gastroenterol Hepatol15: 721‐737 https://www.ncbi.nlm.nih.gov/pubmed/30185915?dopt=AbstractPlusMan SM. (2018) Inflammasomes in the gastrointestinal tract: infection, cancer and gut microbiota homeostasis. et al. (2018) NOD1 and NOD2 in inflammation, immunity and disease. Arch. Biochem. Biophys. https://www.ncbi.nlm.nih.gov/pubmed/30578751?dopt=AbstractPlusMukherjee T et al. (2017) Synthetic agonists of NOD‐like, RIG‐I‐like, and C‐type lectin receptors for probing the inflammatory immune response. Future Med Chem9: 1345‐1360 https://www.ncbi.nlm.nih.gov/pubmed/28776416?dopt=AbstractPlusNielsen AE http://www.ncbi.nlm.nih.gov/pubmed/25081315?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25829385?dopt=AbstractPlus]. They function as RNA helicases (EC 3.6.4.13) using the energy from ATP hydrolysis to unwind RNA.There are three human RIG‐I‐like receptors (RLRs) which are cytoplasmic pattern recognition receptors (PRRs) of the innate immune system. They detect non‐self cytosolic double‐stranded RNA species and and 5′‐triphosphate single‐stranded RNA from various sources and are essential for inducing production of type I interferons, such as IFNβ, type III interferons, and other anti‐pathogenic effectors .Transmembrane guanylyl cyclases are homodimeric receptors activated by a diverse range of endogenous ligands. GC‐A, GC‐B and GC‐C are expressed predominantly in the cardiovascular system, skeletal system and intestinal epithelium, respectively. GC‐D and GC‐G are found in the olfactory neuropepithelium and Grüeneberg ganglion of rodents, respectively. GC‐E and GC‐F are expressed in retinal photoreceptors. Family members have conserved ligand‐binding, catalytic (guanylyl cyclase) and regulatory domains with the exception of NPR‐C which has an extracellular binding domain homologous to that of other NPRs, but with a truncated intracellular domain which appears to couple, Aureobasidium species, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4952, acts as an antagonist at both GC‐A and GC‐B receptor s [http://www.ncbi.nlm.nih.gov/pubmed/1674870?dopt=AbstractPlus]. GC‐D and GC‐G have been reported to be activated intracellularly by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9164  and guanylyl cyclaseactivating protein . GC‐D and GC‐G may be activated by atmospheric levels of CO2 through the formation of intracellular bicarbonate ions . GC‐G may be activated at cooler temperatures (20‐25°C) through apparent stabilisation of the dimer [http://www.ncbi.nlm.nih.gov/pubmed/25452496?dopt=AbstractPlus].The polysaccharide obtained from fermentation of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2509)‐sensitive (soluble) guanylyl cyclase (GTP diphosphate‐lyase (cyclising)), http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=4.6.1.2, is a heterodimer comprising a β1 subunit and one of two alpha subunits  giving rise to two functionally indistinguishable isoforms, GC‐1 (α1β1) and GC‐2 (α2β1) . A haem group is associated with the β subunit and is the target for the endogenous ligand http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2509, and, potentially, carbon monoxide [http://www.ncbi.nlm.nih.gov/pubmed/9003762?dopt=AbstractPlus].Nitric oxide  Molecular Physiology of Membrane Guanylyl Cyclase Receptors. et al. (2015) Extending the translational potential of targeting NO/cGMP‐regulated pathways in the CVS. Br. J. Pharmacol. 172: 1397–414 https://www.ncbi.nlm.nih.gov/pubmed/25302549?dopt=AbstractPlusPapapetropoulos A et al. (2017) The multifaceted role of natriuretic peptides in metabolic syndrome. Biomed. Pharmacother. 92: 826–835 https://www.ncbi.nlm.nih.gov/pubmed/28599248?dopt=AbstractPlusSanthekadur PK et al. (2016) Thirty Years of Saying NO: Sources, Fate, Actions, and Misfortunes of the Endothelium‐Derived Vasodilator Mediator. Circ. Res. 119: 375‐96 https://www.ncbi.nlm.nih.gov/pubmed/27390338?dopt=AbstractPlusVanhoutte PM et al. (2016) The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment. Clin. Sci. 130: 57–77 https://www.ncbi.nlm.nih.gov/pubmed/26637405?dopt=AbstractPlusVolpe M et al. (2018) Guanylate cyclase‐C as a therapeutic target in gastrointestinal disorders. Gut67: 1543–1552 https://www.ncbi.nlm.nih.gov/pubmed/29563144?dopt=AbstractPlusWaldman SA http://www.ncbi.nlm.nih.gov/pubmed/11357143?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17575237?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/2158859?dopt=AbstractPlus]. In the human genome, 58 RTKs have been identified, which fall into 20 families [http://www.ncbi.nlm.nih.gov/pubmed/20602996?dopt=AbstractPlus].Receptor tyrosine kinases (RTKs), a family of cellsurface receptors, which transduce signals to polypeptide and protein hormones, cytokines and growth factors are key regulators of critical cellular processes, such as proliferation and differentiation, cell survival and metabolism, cell migration and cell cycle control .All RTKs display an extracellular ligand binding domain, a single transmembrane helix, a cytoplasmic region containing the protein tyrosine kinase activity , with juxtamembrane and C‐terminal regulatory regions. Agonist binding to the extracellular domain evokes dimerization, and sometimes oligomerization, of RTKs . This leads to autophosphorylation in the tyrosine kinase domain in a trans orientation, serving as a site of assembly of protein complexes and stimulation of multiple signal transduction pathways, including RTKs are of widespread interest not only through physiological functions, but also as drug targets in many types of cancer and other disease states. Many diseases result from genetic changes or abnormalities that either alter the activity, abundance, cellular distribution and/or regulation of RTKs. Therefore, drugs thatmodify the dysregulated functions of these RTKs have been developed which fall into two categories. One group is often described as ‘biologicals’, which block the activation of RTKs directly or by chelating the cognate ligands, while the second are small molecules designed to inhibit the tyrosine kinase activity directly.http://www.ensembl.org/Homo_sapiens/Gene/Family/Genes?family=ENSFM00500000269785 are Class I receptor tyrosine kinases [http://www.ncbi.nlm.nih.gov/pubmed/12520021?dopt=AbstractPlus]. https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3430  appears to act as an essential partner for the other members of the family without itself being activated by a cognate ligand [http://www.ncbi.nlm.nih.gov/pubmed/9130710?dopt=AbstractPlus]. Ligands of the ErbB family of receptors are peptides, many of which are generated by proteolytic cleavage of cell‐surface proteins. HER/ErbB is the viral counterpart to the receptor tyrosine kinase EGFR. All family members heterodimerize with each other to activate downstream signalling pathways and are aberrantly expressed inmany cancers, particularly forms of breast cancer and lung cancer. Mutations in the EGFR are responsible for acquired resistance to tyrosine kinase inhibitor chemotherapeutics.http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4848 has been used to label the ErbB1 EGF receptor. The extracellular domain of ErbB2 can be targetted by the antibodies http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5082 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5046 to inhibit ErbB family action. The intracellular ATP‐binding site of the tyrosine kinase domain can be inhibited by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4947 , http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4941, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4920 and tyrphostins http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4863 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4862.et al. (2016) Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy. Cancer Sci. 107: 1179‐86 https://www.ncbi.nlm.nih.gov/pubmed/27323238?dopt=AbstractPlusKobayashi Y http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5012  and the related insulin‐like growth factors (IGF) activate Class II receptor tyrosine kinases [http://www.ncbi.nlm.nih.gov/pubmed/12520021?dopt=AbstractPlus], to evoke cellular responses, mediated through multiple intracellular adaptor proteins. Exceptionally amongst the catalytic receptors, the functional receptor in the insulin receptor family is derived from a single gene product, cleaved post‐translationally into two peptides, which then cross‐link via disulphide bridges to form a heterotetramer. Intriguingly, the endogenous peptide ligands are formed in a parallel fashion with post‐translational processing producing a heterodimer linked by disulphide bridges. Signalling through the receptors is mediated through a rapid autophosphorylation event at intracellular tyrosine residues, followed by recruitment of multiple adaptor proteins, notably https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6125 (http://www.uniprot.org/uniprot/P35568), https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6126 (http://www.uniprot.org/uniprot/Q9Y4H2), https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10840 (http://www.uniprot.org/uniprot/P29353), https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4566 (http://www.uniprot.org/uniprot/P62993) and https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11187 (http://www.uniprot.org/uniprot/Q07889).The circulating peptide hormones http://www.uniprot.org/uniprot/P08833, http://www.uniprot.org/uniprot/P18065, http://www.uniprot.org/uniprot/P17936, http://www.uniprot.org/uniprot/P22692, http://www.uniprot.org/uniprot/P24593), which sequester the IGFs; overexpression of IGFBPs may induce apoptosis, while IGFBP levels are also altered in some cancers.Serum levels of free IGFs are kept low by the action of IGF binding proteins , which lacks classical signalling capacity and appears to subserve a trafficking role [http://www.ncbi.nlm.nih.gov/pubmed/2964083?dopt=AbstractPlus]. INSRR, which has a much more discrete localization, being predominant in the kidney [http://www.ncbi.nlm.nih.gov/pubmed/1530648?dopt=AbstractPlus], currently lacks a cognate ligand or evidence for functional impact. Antibodies targetting IGF1, IGF2 and the extracellular portion of the IGF1 receptor are in clinical trials.There is evidence for low potency binding and activation of insulin receptors by IGF1. IGF2 also binds and activates the cation‐independent mannose 6‐phosphate receptor  combine as homo‐ or heterodimers to activate homo‐ or heterodimeric PDGF receptors. SCF is a dimeric ligand for KIT. Ligands for CSF1R are either monomeric or dimeric glycoproteins, while the endogenous agonist for FLT3 is a homodimer.Type III RTKs include PDGFR, CSF‐1R (Ems), Kit and FLT3, which function as homo‐ or heterodimers. Endogenous ligands of PDGF receptors are homo‐ or heterodimeric: PDGFA, PDGFB, VEGFE and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5687 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5697 ; http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5702 and AC220 , as well as pan‐type III RTK inhibitors such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5713 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5711 [http://www.ncbi.nlm.nih.gov/pubmed/15606337?dopt=AbstractPlus]; 5′‐fluoroindirubinoxime has been described as a selective FLT3 inhibitor [2].Various small molecular inhibitors of type III RTKs have been described, including http://www.ensembl.org/Homo_sapiens/Gene/Family/Genes?family=ENSFM00440000236870 are homo‐ and heterodimeric proteins, which are characterized by seven Ig‐like loops in their extracellular domains and a split kinase domain in the cytoplasmic region. They are key regulators of angiogenesis and lymphangiogenesis; as such, they have been the focus of drug discovery for conditions such as metastatic cancer. Splice variants of VEGFR1 and VEGFR2 generate truncated proteins limited to the extracellular domains, capable of homodimerisation and binding VEGF ligands as a soluble, non‐signalling entity. Ligands at VEGF receptors are typically homodimeric. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5085  is able to activate VEGFR1 homodimers, VEGFR1/2 heterodimers and VEGFR2/3 heterodimers. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5086  and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5314  activate VEGFR1 homodimers, while VEGFC  and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5088  activate VEGFR2/3 heterodimers and VEGFR3 homodimers, and, following proteolysis, VEGFR2 homodimers.http://www.ncbi.nlm.nih.gov/pubmed/12443771?dopt=AbstractPlus], Ki8751 [http://www.ncbi.nlm.nih.gov/pubmed/15743179?dopt=AbstractPlus] and ZM323881, a novel inhibitor of vascular endothelial growth factor‐receptor‐2 tyrosine kinase activity [http://www.ncbi.nlm.nih.gov/pubmed/12483548?dopt=AbstractPlus] are described as VEGFR2‐selective tyrosine kinase inhibitors. Bevacizumab is a monoclonal antibody directed against VEGF‐A, used clinically for the treatment of certain metastatic cancers; an antibody fragment has been used for wet age‐related macular degeneration.The VEGFR, as well as VEGF ligands, have been targeted by antibodies and tyrosine kinase inhibitors. DMH4 [http://www.ncbi.nlm.nih.gov/pubmed/21711248?dopt=AbstractPlus].Fibroblast growth factor (FGF) family receptors act as homo‐ and heterodimers, and are characterized by Ig‐like loops in the extracellular domain, in which disulphide bridges may form across protein partners to allow the formation of covalent dimers which may be constitutively active. FGF receptors have been implicated in achondroplasia, angiogenesis and numerous congenital disorders. At least 22 members of the FGF gene family have been identified in the human genome [11]. Within this group, subfamilies of FGF may be divided into canonical, intracellular and hormone‐like FGFs. FGF1‐FGF10 have been identified to act through FGF receptors, while FGF11‐14 appear to signal through intracellular targets. Other family members are less well characterized . PD161570 is an FGFR tyrosine kinase inhibitor [http://www.ncbi.nlm.nih.gov/pubmed/9488112?dopt=AbstractPlus], while http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5037 has been described to inhibit FGFR1 and FGFR3 [http://www.ncbi.nlm.nih.gov/pubmed/10987832?dopt=AbstractPlus].Splice variation of the receptors can influence agonist responses. http://www.ncbi.nlm.nih.gov/pubmed/21132015?dopt=AbstractPlus].The PTK7 receptor is associated with polarization of epithelial cells and the development of neural structures. Sequence analysis suggests that the gene product is catalytically inactive as a protein kinase, although there is evidence for a role in Wnt signalling .http://www.ncbi.nlm.nih.gov/pubmed/20407211?dopt=AbstractPlus], while ANA12 has been described as a noncompetitive antagonist of BDNF binding to trkB [http://www.ncbi.nlm.nih.gov/pubmed/21505263?dopt=AbstractPlus]. GNF5837 is a family‐selective tyrosine kinase inhibitor [http://www.ncbi.nlm.nih.gov/pubmed/24900443?dopt=AbstractPlus], while the tyrosine kinase activity of the trkA receptor can be inhibited by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4946  and tyrphostin http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4863 [http://www.ncbi.nlm.nih.gov/pubmed/7683492?dopt=AbstractPlus].Small molecule agonists of trkB have been described, including LM22A4 [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3548  binding to a http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=25 thereby forming a cell‐surface multiprotein complex [http://www.ncbi.nlm.nih.gov/pubmed/21078818?dopt=AbstractPlus].Members of the ROR family appear to be activated by ligands complexing with other cell‐surface proteins. Thus, ROR1 and ROR2 appear to be activated by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5319  forms a complex with http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5320  to activate MuSK [http://www.ncbi.nlm.nih.gov/pubmed/18848351?dopt=AbstractPlus].The muscle‐specific kinase MuSK is associated with the formation and organisation of the neuromuscular junction from the skeletal muscle side. Thus far, no selective MuSK inhibitors have been described.http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5315 , a serine protease inhibitor. MST1, the ligand of RON, is two disulphide‐linked peptide chains generated by proteolysis of a single gene product.HGF receptors regulatematuration of the liver in the embryo, as well as having roles in the adult, for example, in the innate immune system. HGF is synthesized as a single gene product, which is post‐translationally processed to yield a heterodimer linked by a disulphide bridge. The maturation of HGF is enhanced by a serine protease, HGF activating complex, and inhibited by http://www.ncbi.nlm.nih.gov/pubmed/22924734?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5057 is an inhibitor of the HGF receptor [http://www.ncbi.nlm.nih.gov/pubmed/14500382?dopt=AbstractPlus], with the possibility of further targets [http://www.ncbi.nlm.nih.gov/pubmed/17595299?dopt=AbstractPlus].PF04217903 is a selective Met tyrosine kinase inhibitor .AXL tyrosine kinase inhibitors have been described .A number of tyrosine kinase inhibitors targeting RET have been described [http://www.ncbi.nlm.nih.gov/pubmed/21132015?dopt=AbstractPlus].The ‘related to tyrosine kinase receptor’ (Ryk) is structurally atypical of the family of RTKs, particularly in the activation and ATP‐binding domains. RYK has been suggested to lack kinase activity and appears to be involved, with FZD8, in the Wnt signalling system . Other collagen receptors include glycoprotein VI (http://www.uniprot.org/uniprot/Q9HCN6), leukocyte‐associated immunoglobulin‐like receptor 1 (http://www.uniprot.org/uniprot/Q6GTX8), leukocyte‐associated immunoglobulin‐like receptor 2 (http://www.uniprot.org/uniprot/Q6ISS4) and osteoclast‐associated immunoglobulin‐like receptor (http://www.uniprot.org/uniprot/Q8IYS5).The tyrosine kinase inhibitors of DDR, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4903 is a tyrosine kinase inhibitor, anti‐cancer drug targeting ALK and ROS1.http://www.ncbi.nlm.nih.gov/pubmed/9444961?dopt=AbstractPlus], giving rise to the name AATYK (Apoptosis‐associated tyrosine kinase); while over‐expression induces differentiation in neuroblastoma cells [http://www.ncbi.nlm.nih.gov/pubmed/10837911?dopt=AbstractPlus].The LMR kinases are unusual amongst the RTKs in possessing a short extracellular domain and extended intracellular domain (hence the ‘Lemur’ name reflecting the long tail). A precise function for these receptors has yet to be defined, although LMR1 was identified as a potential marker of apoptosis [As yet no selective inhibitors of the LMR family have been described.http://www.ncbi.nlm.nih.gov/pubmed/23742252?dopt=AbstractPlus].The LTK family appear to lack endogenous ligands. LTK is subject to tissue‐specific splice variation, which appears to generate products in distinct subcellular locations. ALK fusions created by gene translocations and rearrangements are associated with many types of cancer, including large cell lymphomas, inflammatory myofibrilastic tumours and non‐small cell lung cancer .Similar to the LMR RTK family, STYK1 has a truncated extracellular domain, but also displays a relatively short intracellular tail beyond the split kinase domain. STYK1  Spatial and Temporal Regulation of Receptor Tyrosine Kinase Activation and Intracellular Signal Transduction. Annu. Rev. Biochem. 85: 573–97 https://www.ncbi.nlm.nih.gov/pubmed/27023845?dopt=AbstractPlusBergeron JJ et al. (2016) Immunotherapy of cancer: from monoclonal to oligoclonal cocktails of anti‐cancer antibodies: IUPHAR Review 18. Br. J. Pharmacol. 173: 1407–24 https://www.ncbi.nlm.nih.gov/pubmed/26833433?dopt=AbstractPlusCarvalho S et al. (2017) Targeting the hepatocyte growth factor/Met pathway in cancer. Biochem. Soc. Trans. 45: 855–870 https://www.ncbi.nlm.nih.gov/pubmed/28673936?dopt=AbstractPlusDe Silva DM et al. (2017) Angiopoietin‐Tie signalling in the cardiovascular and lymphatic systems. Clin. Sci. 131: 87–103 https://www.ncbi.nlm.nih.gov/pubmed/27941161?dopt=AbstractPlusEklund L Pharmacol. Ther. 177: 1–8 https://www.ncbi.nlm.nih.gov/pubmed/28185914?dopt=AbstractPlusKatayama R. (2017) Therapeutic strategies and mechanisms of drug resistance in anaplastic lymphoma kinase (ALK)‐rearranged lung cancer. Gene614: 1–7 https://www.ncbi.nlm.nih.gov/pubmed/28267575?dopt=AbstractPlusKazlauskas A. (2017) PDGFs and their receptors. et al. (2016) EGFR as a Pharmacological Target in EGFR‐Mutant Non‐Small‐Cell Lung Cancer: Where Do We Stand Now? Trends Pharmacol. Sci. 37: 887–903 https://www.ncbi.nlm.nih.gov/pubmed/27717507?dopt=AbstractPlusKe EE et al. (2016) Overcoming drug resistance to receptor tyrosine kinase inhibitors: Learning from lung cancer. Pharmacol. Ther. 161: 97–110 https://www.ncbi.nlm.nih.gov/pubmed/27000770?dopt=AbstractPlusKuwano M Pharmacol. Ther. 174: 1–21 https://www.ncbi.nlm.nih.gov/pubmed/28167215?dopt=AbstractPlusLee DH. (2017) Treatments for EGFR‐mutant non‐small cell lung cancer (NSCLC): The road to a success, paved with failures. et al. (2017) Receptor Tyrosine Kinases: Translocation Partners in Hematopoietic Disorders. Trends Mol Med23: 59–79 https://www.ncbi.nlm.nih.gov/pubmed/27988109?dopt=AbstractPlusNelson KN et al. (2016) Mechanisms and regulation of endothelial VEGF receptor signalling. Nat. Rev. Mol. Cell Biol. 17: 611–25 https://www.ncbi.nlm.nih.gov/pubmed/27461391?dopt=AbstractPlusSimons M et al. (2017) ROR‐Family Receptor Tyrosine Kinases. Curr. Top. Dev. Biol. 123: 105–142 https://www.ncbi.nlm.nih.gov/pubmed/28236965?dopt=AbstractPlusStricker S et al. (2017) Exploiting receptor tyrosine kinase co‐activation for cancer therapy. Drug Discov. Today22: 72–84 https://www.ncbi.nlm.nih.gov/pubmed/27452454?dopt=AbstractPlusTan AC et al. (2017) VEGF Receptor Tyrosine Kinases: Key Regulators of Vascular Function. Curr. Top. Dev. Biol. 123: 433–482 https://www.ncbi.nlm.nih.gov/pubmed/28236974?dopt=AbstractPlusÁlvarez‐Aznar A http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=2.7.11.30, respond to particular cytokines, the transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) families, and may be divided into two subfamilies on the basis of structural similarities. Agonist binding initiates formation of a cell‐surface complex of type I and type II RSTK, possibly heterotetrameric, where where both subunits express serine/threonine kinase activity. The type I receptor serine/threonine kinases are also known as activin receptors or activin receptor‐like kinases, ALKs, for which a systematic nomenclature has been proposed (ALK1‐7). The type II protein phosphorylates the kinase domain of the type I partner , causing displacement of the protein partners, such as the FKBP12 FK506‐binding protein https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3711 (http://www.uniprot.org/uniprot/P62942) and allowing the binding and phosphorylation of particular members of the Smad family. These migrate to the nucleus and act as complexes to regulate gene transcription. Type III receptors, sometimes called co‐receptors or accessory proteins, regulate the signalling of the receptor complex, in either enhancing  or inhibitory manners. TGFβ family ligand signalling may be inhibited by endogenous proteins, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4933 , which binds and neutralizes activins to prevent activation of the target receptors.Receptor serine/threonine kinases (RTSK), http://www.ncbi.nlm.nih.gov/pubmed/18692464?dopt=AbstractPlus]. Some are known to form disulphide‐linked homo‐ and/or heterodimeric complexes. Thus, inhibins are α subunits linked to a variety of β chains, while activins are combinations of β subunits.Endogenous agonists, approximately 30 in man, are often described as paracrine messengers acting close to the source of production. They are characterized by six conserved cysteine residues and are divided into two subfamilies on the basis of sequence comparison and signalling pathways activated, the TGFβ/activin/nodal subfamily and the BMP/GDF (growth/differentiation factor)/MIS (Müllerian inhibiting substance) subfamily. Ligands active at RSTKs appear to be generated as large precursors which undergo complexmaturation processes . The authors confirmed the selectivity of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6049 to inhibit TGFβ signalling through ALK4, ALK5, ALK7 [http://www.ncbi.nlm.nih.gov/pubmed/14978253?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4907 inhibits BMP signalling through ALK2 and ALK3, it also inhibits AMP kinase [http://www.ncbi.nlm.nih.gov/pubmed/11602624?dopt=AbstractPlus].An appraisal of small molecule inhibitors of TGFβ and BMP signalling concluded that TGFβ pathway inhibitors were more selective than BMP signalling inhibitors Budi EH et al. (2016) Immunoregulation by members of the TGFβ superfamily. Nat. Rev. Immunol. 16: 723‐740 [https://www.ncbi.nlm.nih.gov/pubmed/27885276?dopt=AbstractPlus]Chen W et al. (2016) Molecular switches under TGFβ signalling during progression from cardiac hypertrophy to heart failure. Br. J. Pharmacol. 173: 3‐14 [https://www.ncbi.nlm.nih.gov/pubmed/26431212?dopt=AbstractPlus]Heger J et al. (2015) Regulators and effectors of bone morphogenetic protein signalling in the cardiovascular system. J. Physiol. (Lond.)593: 2995‐3011 [https://www.ncbi.nlm.nih.gov/pubmed/25952563?dopt=AbstractPlus]Luo JY et al. (2015) Structural determinants of Smad function in TGF‐β signaling. Trends Biochem. Sci. 40: 296‐308 [https://www.ncbi.nlm.nih.gov/pubmed/25935112?dopt=AbstractPlus]Macias MJ et al. (2016) Targeting BMP signalling in cardiovascular disease and anaemia. Nat Rev Cardiol13: 106‐20 [https://www.ncbi.nlm.nih.gov/pubmed/26461965?dopt=AbstractPlus]Morrell NW et al. (2015) Targeting the TGFβ pathway for cancer therapy. Pharmacol. Ther. 147: 22‐31 [https://www.ncbi.nlm.nih.gov/pubmed/25444759?dopt=AbstractPlus]Neuzillet C Nat Rev Rheumatol13: 155‐163 [https://www.ncbi.nlm.nih.gov/pubmed/28148919?dopt=AbstractPlus]van der Kraan PM. (2017) The changing role of TGFβ in healthy, ageing and osteoarthritic joints. https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11283) to activate signalling cascades. Family members bind components of the extracellular matrix or cell‐surface proteins indicating a role in intercellular communication.Receptor tyrosine phosphatases (RTP) are cell‐surface proteins with a single TM region and intracellular phosphotyrosine phosphatase activity. Many family members exhibit constitutive activity in heterologous expression, dephosphorylating intracellular targets such as Src tyrosine kinase  Pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta as regulators of angiogenesis and cancer. Biochim. Biophys. Acta1866: 252‐265 [https://www.ncbi.nlm.nih.gov/pubmed/27693125?dopt=AbstractPlus]Papadimitriou E et al. (2017) Targeting Tyrosine Phosphatases: Time to End the Stigma. Trends Pharmacol. Sci. 38: 524‐540 [https://www.ncbi.nlm.nih.gov/pubmed/28412041?dopt=AbstractPlus]Stanford SM http://www.ncbi.nlm.nih.gov/pubmed/23840967?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/26008591?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25169849?dopt=AbstractPlus].Dysregulated TNFR signalling is associated with many inflammatory disorders, including some forms of arthritis and inflammatory bowel disease, and targeting TNF has been an effective therapeutic strategy in these diseases and for cancer immunotherapy Kalliolias GD et al. (2016) Mechanisms behind efficacy of tumor necrosis factor inhibitors in inflammatory bowel diseases. Pharmacol. Ther. 159: 110‐9 https://www.ncbi.nlm.nih.gov/pubmed/26808166?dopt=AbstractPlusOlesen CM et al. (2017) Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat. Rev. Cancer17: 352‐366 https://www.ncbi.nlm.nih.gov/pubmed/28536452?dopt=AbstractPlusvon Karstedt S


This presentation discusses the increasing need for an international convention on the rights of older people. Such a convention would contextualize global, regional and national demographic shifts and identify gaps in existing international human rights laws, so as to better protect older persons’ rights to health and well-being. Persons aged 60 or above are expected to more than double from 2015 to reach 2 billion in 2050, with their proportion of the world population rising from 12% to 21%. By 2050, 80% of older persons are expected to live in societies that are currently labeled developing countries. Existing international human rights instruments fall short regarding pensions and protection from poverty. The presentation demonstrates ongoing global efforts, specifically through the UN Open-ended Working Group on Ageing, to set global rights-based standards, and the roles played by civil society organizations that use network approaches in advocating for the rights of older people.


Analysis of the Amino-peptidase N (APN) protein from Anopheles culicifacies as a vector based Transmission Blocking Vaccines (TBV) targethas been considered for malaria vaccine development. Short peptides as potential epitopes for B cells and cytotoxic T cells and/or helper Tcells were identified using prediction models provided by NetCTL and IEDB servers. Antigenicity determination, allergenicity,immunogenicity, epitope conservancy analysis, atomic interaction with HLA allele specific structure models and population coverage wereinvestigated in this study. The analysis of the target protein helped to identify conserved regions as potential epitopes of APN in variousAnopheles species. The T cell epitopes like peptides were further analyzed by using molecular docking to check interactions against theallele specific HLA models. Thus, we report the predicted B cell (VDERYRL) and T cell (RRYLATTQF for HLA class I and LKATFTVSIfor HLA class II) epitopes like peptides from APN protein of Anopheles culicifacies (Diptera: Culicidae) for further consideration as vaccinecandidates subsequent to in vitro and in vivo analysis. Malaria continues to remain as a life threatening infectious diseasethroughout the tropical region of the world. The world malariareport 2018) shows that there are about 219 million cases in 90countries in the year 2017 alone. Malaria kills more than 600,000people yearly, mainly children, and eradication is a global priority.India contributes about 4% to total global malaria burden . Progress has been made in the identificationof parasite antigens responsible for transmission-blocking activity8 shows t. RecombiA midgut specific protein, Aminopeptidase N 1 (APN1) isglycosylphospotidyl inositol anchored protein reported to play animportant role in ookinete invasion of Plasmodium in the Anophelesgambiae . AminopeThe vaccination aim is to induce immunity against specificpathogens. It will be induced by selectively stimulating antigenspecific cytotoxic T-cells, helper T-cells and B-cells. Ideally, avaccine is divided into two classes based on antigenic epitopes,firstly a B-cell epitope and a helper T-cell epitope, secondly a CTLepitope. The vaccine is capable to induce either specific humoral orcellular immune response against the specific pathogens usingcombination of these epitopes like peptides . It is oIt should be noted that An. culicifacies (Diptera: Culicidae) is animportant malarial vector responsible for 60-70 % of cases in India. A comprThe protein sequence of APN 1 gene (accession no. QCO76330)from An. culicifacies A was downloaded from the NCBI database. The antAntigenicity depends on the protein secondary structure.Therefore, prediction of secondary structures using the ExPASy'sserver ProtParam  was compImmune Epitope Database (IEDB) was used to predict B cellepitopes. The tools at the IEDB, Bepipred linear epitope prediction, Emini sThe NetCTL server  was usedPutative epitopes were further tested for class I HLA binding usingIEDB . StabiliHelper T cell (HTL) epitopes were predicted by using HLA IIbinding tool on IEDB . It coveThe conserved epitope analysis was carried out in the APN1protein sequences from fifteen different species of mosquito byanalysing conservation across antigens using IEDB . SimilarEpitopes in three dimensional structures were assigned using PEPFOLD.Human population coverage for selected epitopes was checked bypopulation coverage tool at IEDB . Data foMolecular docking studies help study epitope binding with HLAmolecules . AutodocAPN1 protein sequence of An. culicifacies retrieved from NCBI inFASTA format was screened using the VaxiJen server to predictimmunogenicity. The APN1 (QCO76330) is a known antigenicprotein based on overall immunogenicity prediction score.Secondary structure analysis of the APN1 protein  have 445 alpha helixes (43.3%), 147extended strands (14.31%), 35 beta turns (3.41%) and 400 randomcoils (38.95%) . Amino aLinear B cell epitopes were predicted on the basis of fivealgorithms- Parker hydrophilicity, Emini surface accessibility, Chouand Fasman beta turn prediction, Kolaskar and Tongaonkarantigenicity and Bepipred linear epitope prediction available onIEDB. All values greater than the average value were considered aspotential antigenic determinants. Three epitopes were found tohave cutoff prediction scores above threshold scores andnonallergic in nature, namely VDERYRL, MPQQETFN andTVFQRTP . These eEpitopes having high combinatorial scores were considered as mostpotential epitopes as predicted by NetCTL. HLA-I alleleinteractions with these epitopes were completed using SMM-basedIEDB HLA-I binding prediction tool. The epitopes with higheraffinity (IC50 less than 200) with MHC-I alleles were selected forfurther analysis . The affPutative helper T-cell epitope candidates (9-mer sequences) wereantigenic and non-allergic in nature showing interactions withnumerous HLA-DR alleles . The epiThe population coverage of predicted epitopes has been analyzedbased on their binding with alleles in sixteen ethnic groups andgeographical regions across the world. The high populationcoverage was found in all putative helper T-cell epitopes and CTLepitopes in 16 geographic regions of the world. The percentage ofpopulation coverage rate for selected MHC I epitope 'RRYLATTQF'and MHC II epitope 'LKATFTVSI' of APN1 protein was shown inBinding interactions between epitopes and HLA alleles wereassessed using Autodock Vina. The 3D structure of epitopes waspredicted using PEP-FOLD and energy minimization was carriedout by using Yasara. In this study binding of epitope RRYLATTQFwere shown with HLA class I alleles. Three-dimensional structureswere obtained from RCSB. The receptors used for docking studiesincluded reported HLAs. However epitope (RRYLATTQF) wasused as ligand for HLA class I. The grid coordinates from selectedreceptor molecules for docking with their epitope was selected. 1Åspacing was used to select the binding site. The grid box waspositioned carefully to make the docking of ligands at the bindinggroove of the receptors. The binding energies of predicted epitopewith their respective allele's receptor were as shown in Malaria transmission blocking vaccine helps control malariawithout causing ecological imbalance. During the present study,the most potent B and T cell epitopes for transmission blockingvaccine in APN1 protein of An. culicifacies based on computationaltechniques. APN1 was found to be the immunogenic protein byVaxijen server and this has also been indicated as a lead TBVcandidate . The anaB and T cell epitopes involves in humoral and cell mediatedimmunity. Two types of B cell epitopes are linear epitopes andconformational epitopes. We predicted three linear (continuous)epitopes based on scores which were above threshold values of fivealgorithms- Parker hydrophilicity, Emini surface accessibility, Chouand Fasman beta turn prediction, Kolaskar and Tongaonkarantigenicity and Bepipred linear epitope prediction available onIEDB. The more value of B cell epitope scores then the thresholdlevel in five algorithms indicates that these candidate epitopes could be effectiveantigenic peptides in response to B cells. The localization ofconformational (discontinuous) epitopes on A and B chain of theAPN1 protein using 3D representation of residues revealed that thepresumptive antigenic epitopes sequence that is placed in such away which enables it to have direct interactions with immunereceptor. The B-cell epitopes residues, 66VDERYRL72 situated on thesurface of B chain of APN1 protein had good Protrusion Index (PI)score (0.738) were indicative of high accessibility. Ellipsoid value ofPI 0.73 indicates that 73% protein residues lie within ellipsoid andthe remaining 27% residues lie outside. PI score and solventaccessibility are directly proportional to each other, if PI score ishigher; maximum is the solvent accessibility of the residues. Thus,these could be the putative vaccine candidates.T-cell based development of vaccines seems to have potentialbecause of antigenic drift as the foreign particles can easily engineerthe escape from antibody memory response. In addition T-cellmediated immunity tends to be a long lasting. The peptide thatpasses several criteria has been considered to be a good epitopecandidate such as possessing antigenicity, non-allergen, highlyimmunogenic, good conservancy, good interaction with HLAmolecules and enough population coverage. During the presentstudy, it was found that the epitope NLAERTMLI could be used asa potential candidate because it had the maximum number of HLAbinding alleles amongst other CTL epitopes, but having lessconservancy and combined score. This inconsistency ofimmunological features of epitopes indicates that some otherparameters also needed for screening. An epitope should be highlyconserved among different species of Anopheles. The conservancyanalysis of these epitopes indicated that RRYLATTQF was found tohave maximum conservation almost all Anopheles species considerin this study. It also had highest combined score andimmunogenicity score than NLAERTMLI. Armistead et al. (2014)have indicated that 135-amino-acid fragment located in 60-195amino acid sequence of An. gambiae APN1 is safe and highlyimmunogenic, even in the absence of an adjuvant, in murinemodels. Interestingly CTL epitope (RRYLATTQF) and B cellepitope (VDERYRL) predicted during the present study coincideswith this location.The maximum number of alleles binding interactions of epitopeLKATFTVSI with MHC class II was observed using IEDB server.This epitope was predicted to have maximum conservancy amongother epitopes. These epitopes was nonallergic and antigenic innature. The peptide that fulfills the above said parameters,RRYLATTQF for MHC class LKATFTVSI and I for MHC class II,were further chosen for docking studies. Docking simulation studyof the predicted MHC peptides with HLA molecules wasperformed to find out that whether the designed epitope wouldelicit the sufficient immunological responses in vivo. The bindingenergy of predicted MHC I epitope with HLA-B*27:05 recep¬torwas found to be -7.9 kcal/mol as compared to the binding energyof Nipah virus V protein predicted epitope (NPTAVPFTL) withHLA-B*27:05  and was observed to be lower in thepredicted epitope . The intDifferent ethnic populations have high polymorphism in HLA.HLA proteins restrict the reaction to T-cell epitopes. Therefore, tostimulate immune responses in human populations among world,the HLA specificity of T-cell epitopes has to be measured as maincriteria for selection of the epitopes. On the basis of above study,the epitope candidates should bind maximum HLA alleles to getbetter population coverage. In this study, the five HTL and CTLepitopes have shown good population coverage (74% for MHC Iand 59% for MHC II in average) and reached above average valuesin Europe, North America, North Africa and south Asia population.Further analysis has shown that helper T-cell epitopesRRYLATTQF (33%) for MHC class-I and CTL epitope LKATFTVSI(60%) for MHC class-II  is reported. It should be noted that An. culicifacies is aprominent species in India. NPTAVPFTL for MHC class I showhighest population coverage in India. These epitopes have goodcoverage of population and it may provide a broad immuneprotection to human beings from different regions of the world.The predicted CTL epitope RRYLATTQF for cellular immunity,HTL epitope LKATFTVSI and B cell epitope VDERYRL for humoralimmunity may be synthesized for further in vivo and in vitro assays.These results are based on an analysis of available data on variousimmune databases. The results of the present study suggest that thepredicted epitopes are good candidates for making a peptidevaccine which may initiate an effective immune response in vivo.We report the predicted B cell (VDERYRL) and T cell epitopes(RRYLATTQF and LKATFTVSI) from the APN1 protein ofAnopheles culicifacies (Diptera: Culicidae) for further considerationas vaccine candidates subsequent to in vitro and in vivo analysis.Renu Jakhar conducted the study, performed the analysis andwrote the manuscript. S.K. Gakhar planned the study and editedthe manuscript. Neelam Sehrawat analyzed the data. Pawan Kumarhelped with the analysis..


Gynostemma pentaphyllum (Thunb.) Makino have significant role in reducing serum lipid level and treating fatty liver diseases, however, without clear mechanism. As gypenosides share the similar core structures with bile acids (the endogenous ligands of nuclear receptor FXR), we hypothesize that gypenosides may improve hypercholesterolemia via FXR-mediated bile acids signaling. The present study was designed to validate the role of gypenosides in reducing levels of serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C), as well as in regulating bile acids homeostasis and related gene expression levels. The C57BL/6 male mice were divided into four groups. Mice in groups ND and HFD were fed with normal diet and high fat diet for 38 weeks, respectively. In groups HFD+GP and HFD+ST, mice were fed with high fat diet for 38 weeks and treated with gypenosides and simvastatin (positive control) from weeks 16 to 38, respectively. Serum TC and LDL-C levels were assayed by commercially available kits. Expression levels of genes were tested by the quantitative real-time PCR. The LC-MS/MS was applied to quantify major bile acids in mice livers. Our results showed that gypenosides significantly decreased serum TC and LDL-C levels. The gene expression level of Shp was downregulated while the levels of Cyp7a1, Cyp8b1, Fxr, Lrh1, Jnk1/2, and Erk1/2 were upregulated by gypenosides. Indicated by LC-MS/MS technology, gypenosides increased the hepatic levels of several free bile acids and most taurine-conjugated bile acids while decreasing glycine-conjugated bile acids levels. In addition, gypenosides decreased the CA/CDCA ratio. Gypenosides may improve the abnormal lipid profile of HFD-fed mice via two pathways: (1) enhancing the bile acids biosynthesis from cholesterol; (2) decreasing the CA/CDCA ratio which is positively related to cholesterol absorption.Gypenosides extracted from Hypercholesterolemia is associated with various diseases in hepatic, enteric, and cardiovascular systems . Medicin Gynostemma (G.) pentaphyllum (Thunb.) Makino that is distributed in China, Korea, Japan, and other Southeast Asian countries − ions of expected BAs. Peak areas of each observed BAs were used for comparison and statistical analysis among groups.Quantifications of BAs were performed on a Triple Quad UPLC-MS/MS system . A CQUITY UPLC BEH C18 . A p value less than 0.05 was considered as statistically significant. Principal component analysis (PCA) was performed using the “pca” function in mixOmics package of the R program .All data were shown as mean ± SEM. Statistical analyses between two groups were performed using Student'sA fingerprint of gypenosides was obtained from a HPLC-DAD system  Makino, a Chinese herbal medicine [α [α are direct inducers of CYP7A1 [ Jnk/Erk to inhibit gene expression of Cyp7a1 [ Cyp7a1, Cyp8b1, Fxr, Shp, Lrh1, Hnf4α, Jnk1/2, Erk1/2, and Fgfr4, as well as intestinal Fxr and Fgf15. Data confirmed that gypenosides significantly altered the expression levels for most of these genes. Thus, the study results supported our hypothesis that FXR may be one of the target of gypenosides in mice livers.Gypenoside is derived frommedicine . To datamedicine . In thismedicine . Furthermedicine . Our stuicine [α . As LRH1f CYP7A1 , the ratf CYP7A1 . The latf Cyp7a1 . In the  Cyp7a1 gene [ Shp in hyperlipidemia mice while they increased the gene expressions of Cyp7a1 and Lrh1. This implied that gypenosides may enhance the biosynthesis of bile acids from cholesterol. Actually, in GP-treated mice, we observed the increased levels for several abundantly available hepatic bile acids such as CDCA, DCA, and TDCA. Thus, inhibition of Shp gene expression accompanied with induction of Cyp7a1 and Lrh1 gene expression and subsequently enhanced the cholesterol metabolism may be one of the mechanisms of gypenosides action in reducing serum cholesterol.CYP7A1 is one of the rate-limiting enzymes involved in the classic pathway of bile acid biosynthesis. Hepatic SHP represses the transcription of CYP7A1 by competing with the nuclear receptor liver receptor homolog 1 (LRH1), which is a constitutive activator of the7a1 gene . In this Cyp8b1, the level was still not fully restored. Thus, hepatic CA levels were still extremely low. On the other hand, the hepatic CDCA level was higher in the group treated with gypenosides compared to HFD group. Eventually, GP downregulated the CA/CDCA ratio compared to both ND and HFD groups. To data, CA/CDCA ratio is associated with enhanced cholesterol absorption and hypercholesterolemia [The microsomal CYP8B1 enzyme is essential for the biosynthesis of CA, which regulates CA/CDCA ratio . In the erolemia . TherefoAccumulation of bile acids leads to hepatic damage . EnhanceGypenosides significantly improved the abnormal lipid profile in mice treated with high fat diet, while genes regulating bile acids homeostasis were also changed. Gypenosides may improve the abnormal lipid profile of HFD-treated mice via two pathways: (1) enhancing the bile acids biosynthesis from cholesterol; (2) decreasing the CA/CDCA ratio which is positively related to cholesterol absorption. As bile acids regulation is the most sensitive signaling pathway of nuclear receptor FXR, FXR may be the potential therapeutic target of gypenosides.


Thinopyrum intermedium), a perennial grain with environmental benefits, has enabled bran removal. Thus, determination of optimum milling conditions for production of refined flours is warranted. This study explored the effect of tempering conditions on intermediate wheatgrass flour properties, namely composition, color, solvent retention capacity, starch damage, and polyphenol oxidase activity. Changes in flour attributes were evaluated via a 3 × 3 × 2 factorial design, with factors targeting moisture (comparing un-tempered controls to samples of 12% and 14% target moisture), time , and temperature (30 and 45 °C). All investigated parameters were significantly affected by target moisture; however, samples tempered to 12% moisture showed few differences to those tempered to 14%. Similarly, neither tempering time nor temperature exerted pronounced effects on most flour properties, indicating water uptake was fast and not dependent on temperature within the investigated range. Lactic acid retention capacity significantly correlated with ash , insoluble dietary fiber , polyphenol oxidase activity , starch content , and starch damage , but not with protein . In general, tempering resulted in flour with less bran contamination but only minor losses in protein.Progress in breeding of intermediate wheatgrass ( Thinopyrum intermedium, IWG) dramatically lowers environmental strains such as nitrate leaching [Consumers are increasingly interested in sustainably produced food ingredients, and alternative agricultural models have emerged to emphasize factors such as diversity and environmental concerns . Perennileaching .Aside from sustainability aspects, the nutritional profile of IWG is one of its advantages for food use, due to protein and dietary fiber contents that surpass those of many other cereal grains, including wheat ,6,7. HowIWG variety MN1503 was grown and harvested in Becker, Minnesota, USA. All chemicals used were of reagent grade or higher. Tempering as well as chemical analyses were carried out according to American Association of Cereal Scientists International (AACCI) official methods  unless oSamples were tempered in duplicates at 4, 8, or 24 h at either 30 or 45 °C. Kernels were either used at intrinsic moisture  as controls or tempered to 12% ± 0.5% or 14% ± 0.5% target moisture. Tempering was performed by weighing 50 g of IWG kernels into air-sealed glass jars, to which the required amount of tempering water was added, hand mixed using a spatula for 60 s, shaken for another 60 s to ensure equal distribution of water, and tempered in an incubator at each condition with fixed relative humidity of 50%. The amount of tempering water to be added to each tempering condition was calculated as per AACCI method 26-10.02.At the end of each tempering condition, duplicates of 1 g of kernels were removed for whole kernel moisture analysis via AACCI method 44-16.01, and remaining kernels were milled using a Brabender Quadrumat Junior mill . To avoid flour losses, bran was sifted manually using a 250 μm sieve plate. Flour with particle sizes >250 μm was collected as bran and flour with particle sizes <250 μm as endosperm. Moisture contents of the freshly milled flour were determined on an Ohaus MB45 .l-phenylalanine by measuring A475 of its conversion product on a UV1800 . The substrate was dissolved in 50 mM 3-morpholinopropane-1-sulfonic acid buffer adjusted to pH 6.5 with HCl, containing 0.02% Tween-20. Samples were shaken for 1 h on a Fisher Pulsing Vortex mixer operated at a speed setting of 2500 . Enzyme activity is reported as absorbance change ΔA475 min−1 g−1 flour dry basis, as outlined previously [Flours were analyzed for ash (AACCI method 08-01.01), protein (AACCI method 46-30.01) on a Leco FP 828 , color (AACCI method 14.22.01) Chroma Meter CR-221 , dietary fiber (AACCI method 32-07.01), SRC (AACCI method 56-11.02), total starch (AACCI method 76-13.01), and starch damage (AACCI method 76-31.01). For dietary fiber, total and damaged starch, test kits from Megazyme  were used. The activity of polyphenol oxidases (PPOs) were determined in flour based on a previously reported procedure . Brieflyeviously .p < 0.05 and were compared within each factor. Only significant differences and correlations are reported. One-way ANOVAs followed by least significance difference (LSD) tests were run in R to evaluate differences according to target moisture and tempering time. Paired t-tests were conducted in Microsoft Excel® (2013) to evaluate differences according to tempering temperature. Pearson-type correlation coefficients and principal component analyses were done in R to summarize relationships among the data.Three-way analysis of variance (ANOVA) was performed in R  using target moisture, tempering time, and temperature as factors. All analyses were carried out at least in duplicate and are reported as means on a dry basis ± standard deviation. Differences among means were considered significant if Target moisture exerted the greatest effect on kernel as well as flour moisture, in comparison to temperature and time . For allFor samples with 14% target moisture, more variability between replicate tempering treatments was observed, and not all samples reached the intended 14% level, which resulted in the differences between 12% and 14% target moisture as not being significant. Regardless of tempering conditions, flour moisture was lower than the corresponding kernel moisture. This could be due to the loss of moisture from the flour during the milling process. As seen in a values, and most also had significantly higher L and b values. Thus, tempering resulted in flours that were lighter, less reddish/brown, but more yellow than nontempered controls. These results indicate successive changes in flour refinement with increased target moisture, as darker, more reddish/browner but less yellow samples contain more bran. No significant differences according to tempering length or temperature were detected.Similar to flour and kernel moisture, the target moisture was the most impactful factor on color . All samCereal bran in general, and IWG bran in particular, is richer in ash and dietary fiber (particularly insoluble dietary fiber) than refined flour . Thus, hL  and b values  and significant and positive correlations with a values . The negative relationship between lightness and ash contents has been reported numerous times for other cereal flours, notably wheat [b values  but not with insoluble dietary fiber.Ash and insoluble dietary fiber contents displayed significant, negative correlations with ly wheat  and rye ly wheat . Howeverly wheat . This dib values  in compaThe ash and insoluble fiber reductions achieved via tempering were reflected in significantly higher starch contents with higher target moisture a,b. ThisL  and b  and significant, negative correlations with a . These relationships essentially indicate that all these parameters assess the extent of IWG refinement. While tempering may reduce the extent of starch damage by softening the kernels, some studies have found more starch damage in refined than whole wheat flours and attributed this to starch dilution by bran in whole wheat [The increases in starch contents coincided with increases in starch damage, which ranged from 3.04% ± 0.10% to 8.78% ± 0.24% a,b. Whille wheat . At highle wheat ), but bele wheat .a values , ash , and insoluble dietary fiber  and negatively correlated with starch , L , and b values . However, there was no significant correlation between PPO activity and protein contents , b , starch content , and also starch damage ; accordingly, negative correlations were present with a , ash , insoluble dietary fiber , and PPO activity . Several previous studies have shown correlations between lactic acid SRC and protein or gluten content [L, b, and starch as well as the negative correlations with a, ash, and insoluble dietary fiber are likely a reflection of the increasing degree of refinement brought upon by tempering. The lack of a significant correlation with protein likely is due to protein contents remaining relatively constant after tempering; thus, the increase in starch came at the expense of insoluble fiber.Flour swelling in lactic acid is related to gluten formation and is, thus, related to protein quality . For sam content ; however content . Since,  content . There a content ,28. The L , a , insoluble fiber , starch content , and PPO activity .Swelling of flour in sodium carbonate solution is the result of starch damage . Howeverb values  and starch damage  and negative correlations with a  and protein .Sucrose SRC is mediated by arabinoxylan swelling, which is an important constituent of IWG dietary fiber . These rr = −0.627, p < 0.01) and starch damage  were significant.SRC in water is affected by all flour polymers  but was Previously, refined but nontempered IWG was reported to have lactic acid SRC, sodium carbonate SRC, sucrose SRC, and water SRC of 78.7, 98.1, 107.2, and 73.3, respectively . Thus, ta, insoluble dietary fiber, ash, and PPO activity, while L, b, starch contents, and lactc acid SRC had high, positive correlations. Principal component 2 was positively correlated with protein contents and negatively correlated with water SRC. However, potentially because of the low variability in these properties, sample groups could not be effectively separated via principal component 2. As a result, differentiation between samples of 12% to those of 14% target moisture could not be achieved. In addition, samples could also not be separated based on incubation temperature or time (The characteristics of the flour samples were summarized via a principal component analysis where the first two principal components accounted for >80% of the variability in the data set . Nontemp or time .This study has shown that tempered IWG samples have significantly different flour properties compared to nontempered controls. Rapid moisture uptake resulted in few significant differences in kernel or flour moisture among samples, which likely affected all other evaluated parameters. Tempering produced lighter, less brown, more yellow flour with more starch as well as more damaged starch, but it reduced polyphenol oxidase activity. To better establish the tempering parameters for IWG, future work will assess the functional attributes of tempered and refined IWG flours.