Melanoma Molecular Maps Projects



Title: HSP90 and protein chaperoning
Legend: HSP90 exerts its chaperone function to ensure the correct conformation, activity, intracellular localization and proteolytic turnover of a range of proteins involved in cell growth, differentiation and survival. In particular HSP90 is essential for the stability and the function of many oncogenic client proteins such as ErbB2, Bcr-Abl, AKT, CRAF, CDK4, PLK1, c-Met, mutant p53 and BRAF, HIF1, steroid hormone receptors, survivin and telomerase hTERT. HSP90 activity depends on its transient N-terminal dimerization, which stimulates the intrinsic ATPase activity. This process is controlled by an orchestrated set of interactions with a range of accessory proteins (co-chaperones). Initially client proteins interact with the HSP70 / HSP40 / HIP (HSP interacting protein) complex. HSP70 and HSP90 are then linked by the adaptor protein HOP (HSP organizing protein). HOP can only bind to ADP-bound HSP90; when HSP90 exchanges ADP for ATP, it undergoes a conformational change, which includes the transient dimerization of the N-terminal domains, which leads to the dissociation of HSP70/HSP40/HIP/HOP and the ATP-dependent association of other co-chaperones (e.g. CDC37, p23, immunophilin CYP40) to form the mature complex. It is while the HSP90 chaperone cycle is in the mature state that the associated client protein is biologically active. Inhibition of ATP binding to HSP90 prevents the formation of the mature complex and results in the recruitment of E3 ligase and proteasome-dependent degradation of client proteins. Although it is not usually subject to mutation or amplification in cancer, HSP90 is over-expressed in a range of human malignancies. Since inhibition of HSP90 function results in the simultaneous depletion of multiple oncoproteins, several inhibitors have been developed (e.g. geldanamycin derivatives), some being under clinical investigation. REFERENCES: [1] Whitesell L et al, Nat Rev Cancer 2005, 5:761-72. [2] Bishop SC et al, Curr Cancer Drug Targets 2007, 7:369-88. Figure #40
Author: The MMMP Team (updated: January 2008)

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