Spatiotemporal dynamics of Aurora B-PLK1-MCAK signaling axis orchestrates kinetochore bi-orientation and faithful chromosome segregation.
Spatiotemporal dynamics of Aurora B-PLK1-MCAK signaling axis orchestrates kinetochore bi-orientation and faithful chromosome segregation.
复制标题
Aurora B-PLK1-MCAK 信号轴的时空动力学协调动粒双向和忠实的染色体分离。
DOI：
10.1038/srep12204
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发表时间：
2015-07-24
影响因子：
4.6
通讯作者：
Yao X
中科院分区：
文献类型：
--
作者：
Shao H;Huang Y;Zhang L;Yuan K;Chu Y;Dou Z;Jin C;Garcia-Barrio M;Liu X;Yao X
有丝分裂中染色体的分离是由动粒和纺锤体微管之间的动态相互作用协调的。微管解聚酶有丝分裂着丝粒相关驱动蛋白（MCAK）是一个关键的调节器，精确的着丝粒微管附着。然而，在有丝分裂过程中精确控制MCAK解聚酶活性的调控机制仍然是难以捉摸的。在这里，我们描述了一种新的途径，涉及极光B-PLK 1轴调节MCAK活性的有丝分裂。Aurora B磷酸化Thr 210上的PLK 1以在有丝分裂期间激活其在动粒处的激酶活性。Aurora B-协调PLK 1激酶活性在实时有丝分裂中使用基于荧光共振能量转移的报告和天然PLK 1底物磷酸化的定量分析进行检查。活性PLK 1反过来使MCAK在Ser 715处磷酸化，这促进了其微管解聚酶活性，这对于忠实的染色体分离是必需的。重要的是，PLK 1激酶活性的抑制或不可磷酸化的MCAK突变体的表达阻止了正确的着丝粒-微管附着，导致染色体桥的异常后期。我们的理由是，极光B-PLK 1信号在动粒协调MCAK活动，这是必要的，及时纠正异常的动粒附着，以确保准确的染色体分离在有丝分裂。
Chromosome segregation in mitosis is orchestrated by the dynamic interactions between the kinetochore and spindle microtubules. The microtubule depolymerase mitotic centromere-associated kinesin (MCAK) is a key regulator for an accurate kinetochore-microtubule attachment. However, the regulatory mechanism underlying precise MCAK depolymerase activity control during mitosis remains elusive. Here, we describe a novel pathway involving an Aurora B-PLK1 axis for regulation of MCAK activity in mitosis. Aurora B phosphorylates PLK1 on Thr210 to activate its kinase activity at the kinetochores during mitosis. Aurora B-orchestrated PLK1 kinase activity was examined in real-time mitosis using a fluorescence resonance energy transfer-based reporter and quantitative analysis of native PLK1 substrate phosphorylation. Active PLK1, in turn, phosphorylates MCAK at Ser715 which promotes its microtubule depolymerase activity essential for faithful chromosome segregation. Importantly, inhibition of PLK1 kinase activity or expression of a non-phosphorylatable MCAK mutant prevents correct kinetochore-microtubule attachment, resulting in abnormal anaphase with chromosome bridges. We reason that the Aurora B-PLK1 signaling at the kinetochore orchestrates MCAK activity, which is essential for timely correction of aberrant kinetochore attachment to ensure accurate chromosome segregation during mitosis.