It is believed that the stability and activity of client proteins are passively regulated by the Hsp90 (heat-shock protein 90) chaperone machinery, which is known to be modulated by its intrinsic ATPase activity, co-chaperones and post-translational modifications. However, it is unclear whether client proteins themselves participate in regulation of the chaperoning process. The present study is the first example to show that a client kinase directly regulates Hsp90 activity, which is a novel level of regulation for the Hsp90 chaperone machinery. First, we prove that PKCγ (protein kinase Cγ) is a client protein of Hsp90α, and, that by interacting with PKCγ , Hsp90a prevents PKC? degradation and facilitates its cytosol-to-membrane translocation and activation. A threonine residue set, Thr115/ Thr425/Thr603, of Hsp90a is specifically phosphorylated by PKCγ , and, more interestingly, this threonine residue set serves as a 'phosphorylation switch' for Hsp90a binding or release of PKCγ . Moreover, phosphorylation of Hsp90a by PKCγ decreases the binding affinity of Hsp90α towardsATP and co-chaperones such as Cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity. Further investigation demonstrated that the reciprocal regulation of Hsp90α and PKCγ plays a critical role in cancer cells, and that simultaneous inhibition of PKCγ and Hsp90α synergistically prevents cell migration and promotes apoptosis in cancer cells. © The Authors Journal compilation.
CITATION STYLE
Lu, X. A., Wang, X., Zhuo, W., Jia, L., Jiang, Y., Fu, Y., & Luo, Y. (2014). The regulatory mechanism of a client kinase controlling its own release from Hsp90 chaperone machinery through phosphorylation. Biochemical Journal, 457(1), 171–183. https://doi.org/10.1042/BJ20130963
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