POST-TRANSLATIONAL REGULATION OFCO-CHAPERONES AFFECTS HSP90 DRUG SENSITIVTY IN CANCER
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AbstractHeat Shock Protein-90 (Hsp90) is a molecular chaperone critical to thestability and activity of over 200 proteins known as “clients” including many oncogenes. Hsp90 chaperone function is linked to its ability to hydrolyze ATP and Hsp90 drugs inhibit its activity leading to the degradation of clients, thus making Hsp90 an attractive target for cancer therapy. The Hsp90 chaperone cycle is fine-tuned by another group of proteins called co-chaperones. They modifythe cycle, allowing Hsp90 to chaperone different pools of clients. Post-translational modifications (PTM) of Hsp90 and its co-chaperones can also regulate the chaperone cycle, and affect Hsp90 drug sensitivity. Here it is shownthat c-Abl kinase phosphorylates Y223in the co-chaperoneAha1, promotingits interaction with and stimulation of Hsp90 ATPase activity. Pharmacologic inhibition of c-Abl prevents the Aha1-Hsp90 interaction thereby, hypersensitizing cancer cells to Hsp90 inhibitors.Another co-chaperone of Hsp90, protein phosphatase-5 (PP5), mediates thede-phosphorylation of the co-chaperone Cdc37which is an essentialprocessfor the activation of kinase clients. The crystal structure of phospho-Cdc37 bound to the catalytic domain of PP5revealed elements of substrate specificity within the phosphatase cleft. Hyperactivityandhypoactivity of PP5 increasedHsp90 binding to its inhibitor, providing insight into increasingthe efficacy of Hsp90 inhibitors by regulation of PP5 activity in tumors.PP5 is autoinhibited by intramolecular interactions that can be activated by anumber of cellular factors, includingHsp90. Casein kinase-1δ (CK1δ)-mediated phosphorylation of T362-PP5, was identified as an integral step for PP5 activation, independent of binding to Hsp90. Additionally, the tumor suppressor von Hippel-Lindau (VHL), the substrate recognition component of the VCB-E3-ubiquitin ligase, was found to interact with and multi-monoubiquitinate K185/K199-PP5 for proteasomal degradationin an oxygen-independent manner. Furthermore, VHL-deficient clear cell renal cell carcinoma (ccRCC) cell lines or patient tumors exhibit elevated PP5 levels. Down-regulation of PP5 caused apoptosis inccRCC cells, suggesting a prosurvival role for PP5 in ccRCC.Thisevidence suggests that inhibition of the enzymes that target and catalyze the PTM of Hsp90 and co-chaperones can act synergistically with Hsp90 inhibitors, providingnovel therapeutic strategiesto enhance the efficacy of Hsp90 inhibitors in cancer cells.
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