CK2 binds, phosphorylates, and regulates its pivotal substrate Cdc37, an Hsp90-cochaperone
CK2 binds, phosphorylates, and regulates its pivotal substrate Cdc37, an Hsp90-cochaperone
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DOI：
10.1007/s11010-005-2949-8
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发表时间：
2005-06-01
影响因子：
4.3
通讯作者：
Nishida, E
中科院分区：
文献类型：
--
作者：
Miyata, Y;Nishida, E
蛋白激酶CK2可磷酸化和调节大量底物，但CK2在蛋白激酶介导的信号转导系统中的作用在很大程度上仍不确定。CDC37是一种蛋白激酶靶向的分子伴侣，它与Hsp90的协同作用是多种信号转导途径所必需的。本文描述了CK2与CDC37之间的相互作用。我们的证据表明，在N端保守的Ser13中，CK2对CDC37的磷酸化是CDC37与包括Akt、CDK4、Mok和Raf1在内的蛋白激酶有效结合的先决条件。此外，CK2对CDC37的磷酸化是Hsp90重新聚集到蛋白激酶-CDC37复合体中的关键。我们观察到CK2的一个子集与细胞中的Hsp90和CDC37相关。Hsp90和CDC37仅定位于胞浆，CK2α和CK2β主要定位于胞核，但也以不同方式定位于胞浆。此外，在大肠杆菌系统中观察到了CDC37与CK2α的直接结合。综上所述，这些发现表明，CK2的一个亚群在细胞质中与Hsp90和CDC37形成复合物，并磷酸化CDC37，从而调节CDC37的分子伴侣活性。由于CK2的活性依赖于CDC37，CK2和CDC37构成了一个正反馈机制来控制多个依赖于CDC37的信号蛋白激酶。讨论了CDC37的结构和CK2-CDC37相互作用的生理意义。
Protein kinase CK2 phosphorylates and regulates a large number of substrates but roles of CK2 in protein kinase-mediated signal transduction systems remain largely uncertain. Cdc37 is a protein kinase-targeting molecular chaperone and its function in cooperation with Hsp90 is required for various signaling kinases. In this article, interaction between CK2 and Cdc37 is described. We present evidence indicating that phosphorylation of Cdc37 by CK2 in conserved Ser13 in the N-terminal extremity was prerequisite for the efficient binding activity of Cdc37 to protein kinases including Akt, Cdk4, MOK, and Raf1. In addition, the phosphorylation of Cdc37 by CK2 was crucial for the recruitment of Hsp90 to the protein kinase-Cdc37 complexes. We observed that a subset of CK2 was associated with Hsp90 and Cdc37 in cells. Whereas Hsp90 and Cdc37 were exclusively distributed in the cytoplasm, CK2 alpha and CK2 beta were localized mainly in the nucleus but also in the cytoplasm with different patterns. Moreover, direct association of Cdc37 with CK2 alpha was observed in an E. coli system. Collectively, these findings indicated that a subpopulation of CK2 forms complexes with Hsp90 and Cdc37 in the cytoplasm and phosphorylates Cdc37, thus regulates the molecular chaperone activity of Cdc37. Since CK2 activity depends on Cdc37, CK2 and Cdc37 constitute a positive feedback machinery to control multiple Cdc37-dependent signaling protein kinases. The structure of Cdc37 and physiological importance of the CK2-Cdc37 interaction are discussed.