Hsp90-dependent activation of protein kinases is regulated by chaperone-targeted dephosphorylation of Cdc37.
Hsp90-dependent activation of protein kinases is regulated by chaperone-targeted dephosphorylation of Cdc37.
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DOI：
10.1016/j.molcel.2008.07.021
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发表时间：
2008-09-26
期刊：
影响因子：
16
通讯作者：
Pearl, Laurence H.
中科院分区：
文献类型：
--
作者：
Vaughan, Cara K.;Mollapour, Mehdi;Smith, Jennifer R.;Truman, Andrew;Hu, Bin;Good, Valerie M.;Panaretou, Barry;Neckers, Len;Clarke, Paul A.;Workman, Paul;Piper, Peter W.;Prodrornou, Chrisostolmos;Pearl, Laurence H.
通过热休克蛋白90系统激活蛋白激酶客户是由辅伴侣蛋白Cdc37介导的。Cdc37需要在Ser13磷酸化，但很少有人知道这个重要的翻译后修饰的调节。我们发现，Ser13的未复合Cdc37在体内磷酸化，以及在二元复合物与激酶（C-K），或在三元复合物与热休克蛋白90和激酶（H-C-K）。而pSer13-Cdc37在H-C-K复合物是抵抗非特异性磷酸酶，它是有效地去磷酸化的伴侣靶向蛋白磷酸酶5（PP5/Ppt1），这不会影响分离的Cdc37。我们发现Cdc37和PP5/Ppt1在酵母和人类肿瘤细胞中与Hsp90复合物相关，并且PP5/Ppt1在体内调节Ser13-Cdc37的磷酸化，直接影响Hsp90-Cdc37对蛋白激酶客户的激活。这些数据揭示了Cdc37的循环调节机制，其中Cdc37的组成性磷酸化通过Hsp90复合物中的靶向去磷酸化来逆转。
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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