Phosphorylation of Microtubule-binding Protein Hec1 by Mitotic Kinase Aurora B Specifies Spindle Checkpoint Kinase Mps1 Signaling at the Kinetochore*
Phosphorylation of Microtubule-binding Protein Hec1 by Mitotic Kinase Aurora B Specifies Spindle Checkpoint Kinase Mps1 Signaling at the Kinetochore*
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DOI：
10.1074/jbc.m113.507970
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发表时间：
2013-11
期刊：
影响因子：
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通讯作者：
Tongge Zhu;Zhen Dou;Bo Qin;Changjiang Jin;Xinghui Wang;Leilei Xu;Zhaoyang Wang;Lijuan Zhu;Fusheng Liu;Xinjiao Gao;Yuwen Ke;Zhiyong Wang;F. Aikhionbare;Chuanhai Fu;Xia Ding;X. Yao
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文献类型：
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作者：
Tongge Zhu;Zhen Dou;Bo Qin;Changjiang Jin;Xinghui Wang;Leilei Xu;Zhaoyang Wang;Lijuan Zhu;Fusheng Liu;Xinjiao Gao;Yuwen Ke;Zhiyong Wang;F. Aikhionbare;Chuanhai Fu;Xia Ding;X. Yao
背景：Hec1 是外着丝粒的核心组成部分，对于有丝分裂中的染色体分离至关重要。结果：Hec1 与有丝分裂检查点激酶 Mps1 相互作用，Aurora B 对 Hec1 的磷酸化将 Mps1 招募到动粒。结论：Aurora B 对 Hec1 的磷酸化指定了动粒处的 Mps1 信号传导。意义：Aurora B-Hec1-Mps1 轴协调有丝分裂中的染色体动力学和稳定性。纺锤体装配检查点 (SAC) 是一种质量控制装置，可确保染色体准确附着到纺锤体微管上，以实现姐妹染色单体的平等分离。 Aurora B 通过动粒基质的空间调节来感知染色体双向，对于 SAC 功能至关重要。然而，Aurora B 如何将着丝粒-微管附着与 SAC 信号传导结合起来仍然难以捉摸。在这里，我们证明 Hec1 与 Mps1 相互作用，并通过其钙调蛋白同源 (CH) 结构域和 N 端 80 个氨基酸指定其着丝点定位。有趣的是，Aurora B 对 Hec1 的磷酸化削弱了其与微管的相互作用，但促进了 Hec1 与 Mps1 的结合。值得注意的是，Hec1 磷酸化的时间调控协调了着丝粒-微管的附着和 Mps1 加载到着丝粒上。拟磷酸化 Hec1 突变体的持续表达会诱导 SAC 过度激活，这表明磷酸化引起的 Hec1 构象变化可用作协调 SAC 激活以同时导致异常着丝粒附着不稳定的开关。总而言之，这些结果定义了 Aurora B-Hec1-Mps1 信号轴在控制有丝分裂中精确染色体分离方面的新作用。
Background: Hec1 is a core component of outer kinetochore essential for chromosome segregation in mitosis. Results: Hec1 interacts with mitotic checkpoint kinase Mps1, and phosphorylation of Hec1 by Aurora B recruits Mps1 to kinetochore. Conclusion: Phosphorylation of Hec1 by Aurora B specifies Mps1 signaling at the kinetochore. Significance: Aurora B-Hec1-Mps1 axis orchestrates chromosome dynamics and stability in mitosis. The spindle assembly checkpoint (SAC) is a quality control device to ensure accurate chromosome attachment to spindle microtubule for equal segregation of sister chromatid. Aurora B is essential for SAC function by sensing chromosome bi-orientation via spatial regulation of kinetochore substrates. However, it has remained elusive as to how Aurora B couples kinetochore-microtubule attachment to SAC signaling. Here, we show that Hec1 interacts with Mps1 and specifies its kinetochore localization via its calponin homology (CH) domain and N-terminal 80 amino acids. Interestingly, phosphorylation of the Hec1 by Aurora B weakens its interaction with microtubules but promotes Hec1 binding to Mps1. Significantly, the temporal regulation of Hec1 phosphorylation orchestrates kinetochore-microtubule attachment and Mps1 loading to the kinetochore. Persistent expression of phosphomimetic Hec1 mutant induces a hyperactivation of SAC, suggesting that phosphorylation-elicited Hec1 conformational change is used as a switch to orchestrate SAC activation to concurrent destabilization of aberrant kinetochore attachment. Taken together, these results define a novel role for Aurora B-Hec1-Mps1 signaling axis in governing accurate chromosome segregation in mitosis.