Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit
Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit
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DOI：
10.1128/mcb.00447-06
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发表时间：
2006-10-01
影响因子：
5.3
通讯作者：
Piwnica-Worms, Helen
中科院分区：
文献类型：
--
作者：
Leung-Pineda, Van;Ryan, Christine E.;Piwnica-Worms, Helen
在高等真核生物中，检查点激酶1（Chk 1）对细胞周期和检查点控制都具有重要功能。Chk 1执行这些功能，部分是通过靶向Cdc 25 A蛋白磷酸酶进行泛素介导的蛋白水解。在遗传毒性应激反应中，Chk 1通过共济失调-毛细血管扩张相关（ATR）蛋白激酶在丝氨酸317（S317）和345（S345）上磷酸化。这些C-末端丝氨酸残基上Chk 1的磷酸化被用作体内Chk 1活化的指标。在这里，我们报告说，Chk 1激酶活性的抑制矛盾地导致积累的S317-和S345-磷酸化的Chk 1在体内和ATR催化Chk 1磷酸化在这些条件下。我们证明，Chk 1的ATR磷酸化是拮抗蛋白磷酸酶2A（PP 2A）。重要的是，PP 2A对Chk 1的去磷酸化作用部分受Chk 1激酶活性的调节。我们建议，ATR-Chk 1-PP 2A调节电路的功能，以保持Chk 1在一个低活性的状态，在一个未受干扰的细胞分裂周期，但在同一时间保持Chk 1启动迅速响应的情况下，细胞遇到遗传毒性应激。
In higher eukaryotic organisms, the checkpoint kinase 1 (Chk1) contributes essential functions to both cell cycle and checkpoint control. Chk1 executes these functions, in part, by targeting the Cdc25A protein phosphatase for ubiquitin-mediated proteolysis. In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo. Here, we report that inhibition of Chk1 kinase activity paradoxically leads to the accumulation of S317- and S345-phosphorylated Chk1 in vivo and that ATR catalyzes Chk1 phosphorylation under these conditions. We demonstrate that Chk1 phosphorylation by ATR is antagonized by protein phosphatase 2A (PP2A). Importantly, dephosphorylation of Chk1 by PP2A is regulated, in part, by the kinase activity of Chk1. We propose that the ATR-Chk1-PP2A regulatory circuit functions to keep Chk1 in a low-activity state during an unperturbed cell division cycle but at the same time keeps Chk1 primed to respond rapidly in the event that cells encounter genotoxic stress.