Casein kinase 1 functions as both penultimate and ultimate kinase in regulating Cdc25A destruction.
Casein kinase 1 functions as both penultimate and ultimate kinase in regulating Cdc25A destruction.
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DOI：
10.1038/onc.2010.96
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发表时间：
2010-06-10
期刊：
影响因子：
8
通讯作者：
Piwnica-Worms, H.
中科院分区：
文献类型：
--
作者：
Honaker, Y.;Piwnica-Worms, H.
Cdc 25 A蛋白磷酸酶通过激活细胞周期蛋白依赖性蛋白激酶来驱动细胞周期转换。未能调节Cdc 25 A导致细胞周期进程失调，绕过细胞周期检查点和基因组不稳定性。泛素介导的蛋白水解在平衡Cdc 25 A水平中起重要作用。Cdc 25 A含有DS 82 G基序，其磷酸化在间期被β-TrCP E3连接酶靶向。β-TrCP靶向Cdc 25 A需要丝氨酸79（S79）和82（S82）的磷酸化。在这里，我们报告了酪蛋白激酶1 α（CK 1 α）以分级方式磷酸化S79和S82上的Cdc 25 A，需要先通过Chk 1或GSK-3β磷酸化丝氨酸76。这有助于β-TrCP结合和泛素介导的Cdc 25 A在整个间期和暴露于遗传毒性应激后的蛋白水解。Cdc 25 A被至少三种激酶（Chk 1、GSK-3β、CK 1 α）引发，其中一些也需要引发，确保了不同的细胞外和细胞内信号与Cdc 25 A相互作用，以精确控制细胞分裂。
The Cdc25A protein phosphatase drives cell cycle transitions by activating cyclin-dependent protein kinases. Failure to regulate Cdc25A leads to deregulated cell cycle progression, bypass of cell cycle checkpoints and genome instability. Ubiquitin-mediated proteolysis plays an important role in balancing Cdc25A levels. Cdc25A contains a DS82G motif whose phosphorylation is targeted by β-TrCP E3 ligase during interphase. Targeting of β-TrCP to Cdc25A requires phosphorylation of serines 79 (S79) and 82 (S82). Here, we report that casein kinase 1 alpha (CK1α) phosphorylates Cdc25A on both S79 and S82 in a hierarchical manner requiring prior phosphorylation of serine 76 by Chk1 or GSK-3β. This facilitates β-TrCP binding and ubiquitin-mediated proteolysis of Cdc25A throughout interphase and following exposure to genotoxic stress. The priming of Cdc25A by at least three kinases (Chk1, GSK-3β, CK1α), some of which also require priming, ensures diverse extra- and intra-cellular signals interface with Cdc25A to precisely control cell division.
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