LB4
CDC37 and HARC are two structurally related HSP90 co-chaperones with distinct biological functions
Jennifer Smith, Emmanuel de Billy, Paul Clarke, Paul Workman
The Institute of Cancer Research, Surrey, UK
Background
HSP90 is a chaperone protein involved in the stability and the activation of specific proteins. Through this function, HSP90 is involved in an array of biological functions including tumourigenesis. Several associated proteins called co-chaperones regulate its activity and its substrate specificity. Our laboratory is interested in studying the function of specific HSP90 co-chaperones. One of them, CDC37, is involved in the stabilization and activation of specific oncogenic kinases including AKT, RAF and CDK4 kinases. HARC is a more recently identified HSP90 co-chaperone structurally related to CDC37. HARC and CDC37 are highly homologous in a central region required for HSP90 binding. We are now investigating the biological function of HARC and its role in the regulation of the HSP90 chaperone machinery.
Results
We have demonstrated that silencing the co-chaperone CDC37 destabilises kinase clients, decreases cell signalling through kinase clients and sensitises cancer cells to HSP90 inhibitors, promoting apoptosis. We show that CDC37 and HARC both bind to HSP90. However, unlike CDC37, HARC does not appear to bind kinases. Early studies indicate that HARC/HSP90 and CDC37/HSP90 constitute two different complexes. By protein overexpression or by using the siRNA approach we demonstrate that HARC and CDC37 have opposite effects on CDK4 protein expression.
Conclusion
Our results support an essential role for CDC37 in concert with HSP90 in maintaining oncogenic protein kinase clients and endorse the therapeutic potential of targeting CDC37 in cancer as an alternative to pharmacological HSP90 inhibitors. Our preliminary studies of HARC indicate that HARC/HSP90 and CDC37/HSP90 constitute two distinct HSP90 complexes with likely different biological functions. Our working hypothesis is that HARC and CDC37 may have antagonistic functions regarding the stabilisation/degradation of HSP90 clients.
