Protein phosphatase 1 is essential for Greatwall inactivation at mitotic exit
Protein phosphatase 1 is essential for Greatwall inactivation at mitotic exit
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DOI：
10.15252/embr.201540876
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发表时间：
2015-11-01
期刊：
影响因子：
7.7
通讯作者：
Mayer, Thomas U.
中科院分区：
文献类型：
--
作者：
Heim, Andreas;Konietzny, Anja;Mayer, Thomas U.
进入有丝分裂是由细胞周期蛋白依赖性激酶1（Cdk 1）磷酸化关键细胞周期调节因子介导的。在非洲爪蟾胚胎中，Cdk 1的M期促进活性被蛋白磷酸酶PP 2A-B55拮抗。因此，为了确保稳健的细胞周期转换，必须调节Cdk 1和PP 2A-B55，使它们的活性相互排斥。PP 2A-B55在有丝分裂进入时失活的潜在机制是很好理解的：Cdk 1激活的长城（Gwl）激酶磷酸化Ensa/Arpp 19，从而使它们能够结合并抑制PP 2A-B55。然而，PP 2A-B55在有丝分裂退出过程中的再活化，这是细胞周期进展所必需的，还不太清楚。在这里，我们确定蛋白磷酸酶PP 1的PP 2A-B55的重新激活途径在非洲爪蟾胚胎提取物的一个重要组成部分。PP 1通过使Gwl去磷酸化来启动PP 2A-B55的再活化。我们提供的证据表明，PP 1靶向Gwl的自磷酸化位点，导致有效的Gwl失活。该步骤对于促进随后通过PP 2A-B55使Gwl完全去磷酸化是必要的。因此，通过鉴定PP 1作为启动Gwl失活的磷酸酶，我们的研究提供了Cdk 1失活如何与PP 2A-B55在有丝分裂退出时的再激活相耦合的分子解释。
Entry into mitosis is mediated by the phosphorylation of key cell cycle regulators by cyclin-dependent kinase 1 (Cdk1). In Xenopus embryos, the M-phase-promoting activity of Cdk1 is antagonized by protein phosphatase PP2A-B55. Hence, to ensure robust cell cycle transitions, Cdk1 and PP2A-B55 must be regulated so that their activities are mutually exclusive. The mechanism underlying PP2A-B55 inactivation at mitotic entry is well understood: Cdk1-activated Greatwall (Gwl) kinase phosphorylates Ensa/Arpp19, thereby enabling them to bind to and inhibit PP2A-B55. However, the re-activation of PP2A-B55 during mitotic exit, which is essential for cell cycle progression, is less well understood. Here, we identify protein phosphatase PP1 as an essential component of the PP2A-B55 re-activation pathway in Xenopus embryo extracts. PP1 initiates the re-activation of PP2A-B55 by dephosphorylating Gwl. We provide evidence that PP1 targets the auto-phosphorylation site of Gwl, resulting in efficient Gwl inactivation. This step is necessary to facilitate subsequent complete dephosphorylation of Gwl by PP2A-B55. Thus, by identifying PP1 as the phosphatase initiating Gwl inactivation, our study provides the molecular explanation for how Cdk1 inactivation is coupled to PP2A-B55 re-activation at mitotic exit.