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Cyclin A/Cdk1 modulates Plk1 activity in prometaphase to regulate kinetochore-microtubule attachment stability
eLife ( IF 6.4 ) Pub Date : 2017-11-20 , DOI: 10.7554/elife.29303
Ana Maria G Dumitru 1, 2 , Scott F Rusin 1, 2 , Amber E M Clark 1, 2 , Arminja N Kettenbach 1, 2 , Duane A Compton 1, 2
Affiliation  

The fidelity of chromosome segregation in mitosis is safeguarded by the precise regulation of kinetochore microtubule (k-MT) attachment stability. Previously, we demonstrated that Cyclin A/Cdk1 destabilizes k-MT attachments to promote faithful chromosome segregation. Here, we use quantitative phosphoproteomics to identify 156 Cyclin A/Cdk1 substrates in prometaphase. One Cyclin A/Cdk1 substrate is myosin phosphatase targeting subunit 1 (MYPT1), and we show that MYPT1 localization to kinetochores depends on Cyclin A/Cdk1 activity and that MYPT1 destabilizes k-MT attachments by negatively regulating Plk1 at kinetochores. Thus, Cyclin A/Cdk1 phosphorylation primes MYPT1 for Plk1 binding. Interestingly, priming of PBIP1 by Plk1 itself (self-priming) increased in MYPT1-depleted cells showing that MYPT1 provides a molecular link between the processes of Cdk1-dependent priming and self-priming of Plk1 substrates. These data demonstrate cross-regulation between Cyclin A/Cdk1-dependent and Plk1-dependent phosphorylation of substrates during mitosis to ensure efficient correction of k-MT attachment errors necessary for high mitotic fidelity.



中文翻译:

细胞周期蛋白A / Cdk1调节前中期的Plk1活性,以调节线粒体-微管的附着稳定性。

通过控制动粒微管(k-MT)附着稳定性,可以保证有丝分裂中染色体分离的保真度。以前,我们证明了细胞周期蛋白A / Cdk1破坏了k-MT附件的稳定性,从而促进了忠实的染色体分离。在这里,我们使用定量磷酸化蛋白质组学来鉴定前中期的156个Cyclin A / Cdk1底物。一种细胞周期蛋白A / Cdk1底物是针对肌球蛋白磷酸酶的亚基1(MYPT1),我们显示MYPT1定位于动植物的活性取决于细胞周期蛋白A / Cdk1的活性,而MYPT1通过负调节动植物的Plk1来破坏k-MT的连接。因此,细胞周期蛋白A / Cdk1磷酸化引发MYPT1与Plk1结合。有趣的是,MYPT1耗尽的细胞中由Plk1自身引发的PBIP1引发(自引发)增加,表明MYPT1提供了Cdk1依赖性引发和Plk1底物自引发过程之间的分子联系。这些数据表明有丝分裂期间底物的细胞周期蛋白A / Cdk1依赖性和Plk1依赖性磷酸化之间的交叉调节,以确保有效校正高有丝分裂保真度所必需的k-MT附着错误。

更新日期:2017-11-20
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