The regulatory mechanism of a client kinase controlling its own release from Hsp90 chaperone machinery through phosphorylation

This study is the first example showing that a client kinase directly regulates Hsp90 activity, which is a novel regulatory level for the Hsp90 chaperone machinery. We first prove that PKCγ is a client protein of Hsp90α, and that through interacting with PKCγ, Hsp90α prevents PKCγ degradation and facilitates its cytosol-to-membrane translocation and activation. Interestingly, a threonine cluster, Thr-115/425/603, of Hsp90α is specifically phosphorylated by PKCγ, and what is more interesting is this threonine cluster serves as a “phosphorylation switch” for Hsp90α binding or release of PKCγ. Moreover, phosphorylation of Hsp90α by PKCγ decreases the binding affinity of Hsp90α towards ATP and cochaperones such as Cdc37, thereby decreasing its chaperone activity. Further study demonstrates 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.
Source: BJ Cell - Category: Biochemistry Authors: Tags: BJ Cell Source Type: research