title: The regulatory mechanism of a client kinase controlling its own release from Hsp90 chaperone machinery through phosphorylation.
abstract: 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, Hsp90α prevents PKCγ degradation and facilitates its cytosol-to-membrane translocation and activation. A threonine residue set, Thr(115)/Thr(425)/Thr(603), of Hsp90α is specifically phosphorylated by PKCγ, and, more interestingly, this threonine residue set 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 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.
authors.forename: Xin-an
authors.initials: XA
authors.lastname: Lu
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhuo
authors.forename: Lin
authors.initials: L
authors.lastname: Jia
authors.forename: Yushan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Yan
authors.initials: Y
authors.lastname: Fu
authors.forename: Yongzhang
authors.initials: Y
authors.lastname: Luo
mesh_terms: D017209:Apoptosis / Q000502:physiology; D018797:Cell Cycle Proteins / Q000502:physiology; D002465:Cell Movement; D018833:Chaperonins / Q000502:physiology; D004789:Enzyme Activation; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology
chemical_list: C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; C533585:HSP90AA2P protein, human; D018832:Molecular Chaperones; C087857:protein kinase C gamma; D011493:Protein Kinase C; D018833:Chaperonins