Normal cells In unstressed cells,<unk>  plays a number of important roles, which include assisting folding, intracellular transport, maintenance, and degradation of proteins as well as facilitating cell signaling. Protein folding and role as chaperone<unk>  is known to associate with the non-native structures of many proteins, which has led to the proposal that<unk>  is involved in protein folding in general. Furthermore,<unk>  has been shown to suppress the aggregation of a wide range of "client" or "substrate" proteins and hence acts as a general protective chaperone. However<unk>  is somewhat more selective than other chaperones. Protein degradation Eukaryotic proteins that are no longer needed or are misfolded or otherwise damaged are usually marked for destruction by the polyubiquitation pathway. These ubiquitinated proteins are recognized and degraded by the 26S proteasome. Hence the 26S proteasome is an integral part of the cell's mechanism to degrade proteins. Furthermore, a constant supply of functional<unk>  is needed to maintain the tertiary structure of the proteasome. Finally experiments done with heat sensitive<unk>  mutants and the 26S proteasome suggest that<unk>  is responsible for most, if not all, of the ATPase activity of the proteasome. Interaction with steroid receptors Schematic diagram of the translocation of the glucocorticoid receptor (GR) from the cytoplasm into the nucleus assisted by<unk>  (90). In the cytoplasm, GR is complexed with<unk>  and the immunophilin FKBP51 (51). Binding of hormone to GR causes a conformational change in the complex, which results in exchange of FKBP51 for FKBP52 (52). FKBP52 in turn binds the dynein (dyn) motor protein that attaches to the cytoskeleton and transports the GR complex into the nucleus. Once in the nucleus, the complex disassembles releasing GR, which dimerizes and binds to DNA where it facilitates transcription of DNA into mRNA. steroid hormone receptor (SHR) activation. The minimal complex for SHR activation include<unk> ,<unk> , HOP (Hsp organizing protein),<unk>  and p23 protein. Just after translation the steroid hormone receptor binds to<unk>  and<unk>  (top, left). Next, HOP protein (composed from TPR domains) deliver it to<unk> . HOP mediates interaction between<unk>  and<unk>  through their C-terminal domains. This transfer takes place only if ADP is bound to<unk> . The exchange of ADP to ATP inside N-terminal pocket induces dissociation of<unk>  and its co-chaperones from the complex that associate then with p23 (via N-terminal side of<unk>  dimer) which prevents ATP hydrolysis, and immunophilins, which replaces HOP (right). At this point, if the chaperone binds geldanamycin, which mimics ADP binding, proteins p23 and HOP dissociate and CHIP, an E3 ubiquitin ligase, is attached to the complex and SHR receptor is being degraded through the proteasome-mediateted pathway (bottom, right). Immunophilins, FKBP51 and FKBP52, are responsible for transportation of<unk> -SHR-ligand complexes along the microtubule fibers (additionally, dynamitin and dynein, the microtubule-associated proteins are involved in this process). Therefore, a translocation of hormones, p53 and probably other<unk>  substrate proteins within cytoplasm is fast and tightly controlled. ATP hydrolysis inside<unk>  nucleotide-binding pocket leads to the dissociation of the complex. Next, steroid hormone receptors dimerize and are translocated to the nucleus (bottom, left). Subsequently, SHR-hormone complexes bind to particular DNA sequences in the promoters of hormone-responsive genes to control their transcription. It should be stressed, that the movement of SHRs inside the nucleus is also<unk> - and ATP-dependent. But it is not known whether<unk> -HSP70-SHR complexes can be transmitted through the nuclear envelope pores as a whole or could shuttle between separate<unk>  molecular complexes on both sides of the nuclear envelope The glucocorticoid receptor (GR) is the most thoroughly studied example of a steroid receptor whose function is crucially dependent on interactions with<unk> . In the absence of the steroid hormone cortisol, GR resides in the cytosol complexed with several chaperone proteins including<unk>  (see figure to the right). These chaperones maintain the GR in a state capable of binding hormone. A second role of<unk>  is to bind immunophilins (e.g., FKBP52) that attach the GR complex to the dynein protein trafficking pathway, which translocates the activated receptor from the cytoplasm into the nucleus. Once in the nucleus, the GR dimerizes and binds to specific sequences of DNA and thereby upregulates the expression of GR responsive genes.<unk>  is also required for the proper functioning of several other steroid receptors, including those responsible for the binding of aldosterone, androgen, estrogen, and progesterone. Cancerous cells Cancerous cells overexpress a number of proteins, including growth factor receptors, such as EGFR, or signal transduction proteins such as PI3K and AKT (Inhibition of these proteins may trigger apoptosis).<unk>  stabilizes various growth factor receptors and some signaling molecules including PI3K and AKT proteins. Hence inhibition of<unk>  downregulates the PI3K/AKT pathway leading to downregulation of the anti-apoptotic protein Bcl-w resulting in apoptosis of cancerous and senescent cells. Interestingly, the disruption of<unk>  with nano-therapeutics has been implicated in targeting drug-induced resistance and relieves the suppression of Natural Killer (NK) immune cells in breast cancer. Another important role of<unk>  in cancer is the stabilization of mutant proteins such as v-Src, the fusion oncogene Bcr/Abl, and mutant forms of p53 that appear during cell transformation. It appears that<unk>  can act as a "protector" of less stable proteins produced by DNA mutations.<unk>  is also required for induction of vascular endothelial growth factor (VEGF) and nitric oxide synthase (NOS). Both are important for de novo angiogenesis that is required for tumour growth beyond the limit of diffusion distance of oxygen in tissues. It also promotes the invasion step of metastasis by assisting the matrix metalloproteinase MMP2. Together with its co-chaperones,<unk>  modulates tumour cell apoptosis "mediated through effects on AKT, tumor necrosis factor receptors (TNFR) and nuclear factor-κB (NF-κB) function." . Also,<unk>  participates in many key processes in oncogenesis such as self-sufficiency in growth signals, stabilization of mutant proteins, angiogenesis, and metastasis.
Hsp90
HspE7
Bcl-xL
Bcl-2
Caspase-9
Mad2
IKK2
NLRP3