Coordinated Regulation of Serum- and Glucocorticoid-Inducible Kinase 3 by a C-terminal Hydrophobic Motif and Hsp90-Cdc37 Chaperone Complex [Signal Transduction]

December 30th, 2013 by Wang, Y., Xu, W., Zhou, D., Neckers, L., Chen, S.

Serum- and glucocorticoid-inducible kinase 3 (SGK3) mediates a variety of cellular processes including membrane transport, cell proliferation and survival, and it has been implicated in Akt-independent signaling downstream of oncogenic PIK3CA mutations in human cancers. However, the regulation of SGK3 is poorly understood. Here we report that SGK3 stability and kinase activation are regulated by the Hsp90-Cdc37 chaperone complex. Hsp90-Cdc37 associates with the kinase domain of SGK3 and acts in concert with a C-terminal hydrophobic motif (HM) of SGK3 to prevent Hsp70 association and ubiquitin ligase CHIP-mediated degradation. Phosphorylation of HM triggers release of Cdc37 and concomitant association of 3-phosphoinositide dependent kinase 1 (PDK1) to activate SGK3. Our study provides new insights into regulation of SGK3 stability and activation, and the rationale for application of Hsp90 inhibitors in treating SGK3-dependent cancers.
  • Posted in Journal of Biological Chemistry, Publications
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