MST1 Limits the Kinase Activity of Aurora B to Promote Stable Kinetochore-Microtubule Attachment
MST1 Limits the Kinase Activity of Aurora B to Promote Stable Kinetochore-Microtubule Attachment
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DOI：
10.1016/j.cub.2009.12.054
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发表时间：
2010-03-09
期刊：
影响因子：
9.2
通讯作者：
Lim, Dae-Sik
中科院分区：
文献类型：
--
作者：
Oh, Hyun Jung;Kim, Mi Ju;Lim, Dae-Sik
需要建立和维持着丝粒与微管的适当连接，以防止染色体错误分离和随后的染色体不稳定性和肿瘤发生。尽管MST 1（哺乳动物不育20样激酶1）与细胞周期调控和肿瘤抑制的许多方面有关[1]，但其确切的作用机制在很大程度上仍然未知。我们现在发现MST 1通过调节Aurora B的激酶活性来促进精确的运动舞蹈微管附着。HeLa细胞耗尽MST 1未能开发稳定的端对着丝粒微管附件，引起不对齐的有丝分裂染色体。未对齐的染色体激活Mad 2和BubR 1依赖的纺锤体检查点响应，导致后期开始延迟。Aurora B的激酶活性促进了着丝粒-微管附着的不稳定性[2-4]，在MST 1或NDR 1（MST 1的下游激酶）缺失的细胞中增加。MST 1和NDR 1与Aurora B相关。此外，MST 1在体外直接磷酸化Aurora B并抑制其激酶活性。极光B的耗尽恢复了MST 1或NDR 1耗尽的细胞中的着丝粒微管附着的稳定性。因此，MST 1是Aurora B活性的关键调节因子，其确保有丝分裂染色体聚集和准确的染色体分离。
The establishment and maintenance of proper attachment of kinetochores to microtubules are required to prevent chromosome missegregation and consequent chromosomal instability and tumorigenesis. Although MST1 (mammalian sterile 20-like kinase 1) has been implicated in many aspects of cell cycle regulation and tumor suppression [1], its precise mechanism of action has remained largely unknown. We now show that MST1 promotes accurate kinetochore-microtubule attachment by modulating the kinase activity of Aurora B. HeLa cells depleted of MST1 failed to develop stable end-on kinetochore-microtubule attachment, giving rise to unaligned mitotic chromosomes. The misaligned chromosomes activated the Mad2- and BubR1-dependent spindle checkpoint response, resulting in a delay in anaphase onset. The kinase activity of Aurora B, which promotes destabilization of kinetochore-microtubule attachment [2-4], was increased in cells depleted of MST1 or NDR1, a downstream kinase of MST1. MST1 and NDR1 associated with Aurora B. Moreover, MST1 directly phosphorylated Aurora B and inhibited its kinase activity in vitro. Depletion of Aurora B restored the stability of kinetochore-microtubule attachment in cells depleted of MST1 or NDR1. MST1 is thus a key regulator of Aurora B activity that ensures mitotic chromosome congression and accurate chromosome segregation.