Abstract
Recruitment of client kinases to HSP90 by CDC37 is blocked by ATP-competitive kinase inhibitors.
Major finding: Recruitment of client kinases to HSP90 by CDC37 is blocked by ATP-competitive kinase inhibitors.
Concept: CDC37 recruits client kinases to HSP90 and inhibits their activity by antagonizing ATP binding.
Impact: ATP-competitive kinase inhibitors may also induce kinase degradation by blocking chaperone access.
The molecular chaperone HSP90 stabilizes client proteins and protects them from proteasomal degradation. The cochaperone CDC37 specifically recruits kinases to HSP90, but the basis for this specificity is unknown. Because CDC37 interacts with a wide range of kinases, Polier and colleagues hypothesized that CDC37 would interact with a universal feature of client kinases. The authors formed a complex of HSP90, CDC37, and BRAF, an HSP90 client kinase, by mixing the individually purified proteins and showed not only that CDC37 was essential for the interaction between BRAF and HSP90 but also that binding of a fluorescently labeled ADP analogue to the BRAF ATP-binding site and BRAF-dependent phosphorylation were reduced in the presence of CDC37. These findings show that CDC37 inhibits the activity of client kinases stabilized by HSP90 by interacting with their ATP-binding clefts and suggest that ATP-competitive kinase inhibitors might disrupt this interaction. Indeed, treatment of cancer cells with ATP-competitive kinase inhibitors such as vemurafenib, lapatinib, and erlotinib led to a time- and concentration-dependent loss of association between CDC37 and its cognate kinases as well as decreased phosphorylation of downstream targets. Interestingly, at higher inhibitor concentrations where the kinase no longer bound CDC37 or HSP90, total kinase amounts decreased, consistent with increased proteasomal degradation due to chaperone deprivation. These findings raise the possibility that the activity of ATP-competitive inhibitors is not only attributable to inhibition of kinase activity but is also related to promotion of kinase degradation through antagonism of CDC37-mediated recruitment to HSP90. Consistent with this possibility, a significantly higher concentration of vemurafenib was required to inhibit the growth of CDC37-overexpressing cells than cells in which CDC37 was knocked down. This additional role in chaperone deprivation may factor into clinical responses to ATP-competitive inhibitors that target HSP90 client kinases.
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