Hsp90-Dependent Activation of Protein Kinases Is Regulated by Chaperone-Targeted Dephosphorylation of Cdc37

Section of Structural Biology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK.
Molecular cell (Impact Factor: 14.02). 10/2008; 31(6):886-95. DOI: 10.1016/j.molcel.2008.07.021
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Activation of protein kinase clients by the Hsp90 system is mediated by the cochaperone protein Cdc37. Cdc37 requires phosphorylation at Ser13, but little is known about the regulation of this essential posttranslational modification. We show that Ser13 of uncomplexed Cdc37 is phosphorylated in vivo, as well as in binary complex with a kinase (C-K), or in ternary complex with Hsp90 and kinase (H-C-K). Whereas pSer13-Cdc37 in the H-C-K complex is resistant to nonspecific phosphatases, it is efficiently dephosphorylated by the chaperone-targeted protein phosphatase 5 (PP5/Ppt1), which does not affect isolated Cdc37. We show that Cdc37 and PP5/Ppt1 associate in Hsp90 complexes in yeast and in human tumor cells, and that PP5/Ppt1 regulates phosphorylation of Ser13-Cdc37 in vivo, directly affecting activation of protein kinase clients by Hsp90-Cdc37. These data reveal a cyclic regulatory mechanism for Cdc37, in which its constitutive phosphorylation is reversed by targeted dephosphorylation in Hsp90 complexes.

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    • "So far, two kinases, Snf1 and Yak1, have been shown to activate Hsf1 in response to glucose starvation (Hahn and Thiele, 2004; Lee et al., 2008), but no repressive kinase has been identified. Although Ppt1 might counteract several protein kinases, we focused on the fact that Ppt1 dephosphorylates CK2-dependent phosphorylation site in Cdc37 (Vaughan et al., 2008). Additionally, Hsp90 phosphorylated by CK2 was dephosphorylated by Ppt1 in vitro (Wandinger et al., 2006). "
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    • "FKBP and Cyp40 are prolyl isomerases and are part of the Hsp90 multichaperone complex. Sgt1 participates in kinetochore assembly and PP5 helps regulates posttranslational modifications of Hsp90 and its co-chaperone Cdc37 [18]. The role of Pih1 and Tah1 is implicated in chromatin remodeling complexes and small nucleolar RNP maturation [19]. "
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