CK2 controls multiple protein kinases by phosphorylating a kinase-targeting molecular chaperone, Cdc37
CK2 controls multiple protein kinases by phosphorylating a kinase-targeting molecular chaperone, Cdc37
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DOI：
10.1128/mcb.24.9.4065-4074.2004
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发表时间：
2004-05-01
影响因子：
5.3
通讯作者：
Nishida, E
中科院分区：
文献类型：
--
作者：
Miyata, Y;Nishida, E
Cdc 37是一种激酶相关的分子伴侣，其功能与Hsp 90一致，是许多信号蛋白激酶所必需的。在这里，我们报告，哺乳动物Cdc 37是一个关键的底物的CK 2（酪蛋白激酶11）。纯化的Cdc 37磷酸化在体外的一个保守的丝氨酸残基，Ser 13，由CK 2。此外，Ser 13是体内Cdc 37唯一的磷酸化位点。重要的是，Cdc 37在Ser 13上的CK 2磷酸化对于Cdc 37对所检测的各种激酶的最佳结合活性是必不可少的，所述激酶包括Raf 1、Akt、Aurora-B、Cdk 4、Src、MOK、MAK和MRK。此外，nonphosphorylatable突变体的Cdc 37显着抑制协会的热休克蛋白90与蛋白激酶，而热休克蛋白90结合活性的突变体是不变的。用特异性CK 2抑制剂处理细胞抑制体内Cdc 37的磷酸化，并降低Cdc 37靶激酶的水平。这些结果揭示了Cdc 37的调节机制，确定了CK 2和许多关键蛋白激酶之间通过Cdc 37的一种新的分子连接，并揭示了CK 2调节多效性细胞功能的分子基础。
Cdc37 is a kinase-associated molecular chaperone whose function in concert with Hsp90 is essential for many signaling protein kinases. Here, we report that mammalian Cdc37 is a pivotal substrate of CK2 (casein kinase 11). Purified Cdc37 was phosphorylated in vitro on a conserved serine residue, Ser13, by CK2. Moreover, Ser13 was the unique phosphorylation site of Cdc37 in vivo. Crucially, the CK2 phosphorylation of Cdc37 on Ser13 was essential for the optimal binding activity of Cdc37 toward various kinases examined, including Raf1, Akt, Aurora-B, Cdk4, Src, MOK, MAK, and MRK. In addition, nonphosphorylatable mutants of Cdc37 significantly suppressed the association of Hsp90 with protein kinases, while the Hsp90-binding activity of the mutants was unchanged. The treatment of cells with a specific CK2 inhibitor suppressed the phosphorylation of Cdc37 in vivo and reduced the levels of Cdc37 target kinases. These results unveil a regulatory mechanism of Cdc37, identify a novel molecular link between CK2 and many crucial protein kinases via Cdc37, and reveal the molecular basis for the ability of CK2 to regulate pleiotropic cellular functions.