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首页> 外文期刊>Cell discovery. >Aurora-A promotes the establishment of spindle assembly checkpoint by priming the Haspin-Aurora-B feedback loop in late G2 phase
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Aurora-A promotes the establishment of spindle assembly checkpoint by priming the Haspin-Aurora-B feedback loop in late G2 phase

机译：Aurora-A通过在G2后期启动Haspin-Aurora-B反馈回路来促进主轴装配检查点的建立

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摘要

Aurora-A kinase functions mainly in centrosome maturation, separation and spindle formation. It has also been found to be amplified or overexpressed in a range of solid tumors, which is linked with tumor progression and poor prognosis. Importantly, Aurora-A inhibitors are being studied in a number of ongoing clinical trials. However, whether and how Aurora-A has a role in the regulation of the mitotic checkpoint is controversial. Additionally, the function of nuclear-accumulated Aurora-A in late G2 phase is not clear. Here we show that knockout, inhibition or blockade of the nuclear entry of Aurora-A severely decreased the centromere localization of Aurora-B and the phosphorylation of histone H3 threonine 3 (H3T3-ph) mediated by the kinase Haspin in late G2 phase. We further reveal that nuclear-accumulated Aurora-A phosphorylates Haspin at multiple sites at its N-terminus and that this promotes H3T3-ph and the rapid recruitment to the centromere of the chromosomal passenger complex. In addition, Aurora-A facilitates the association of Aurora-B with their common substrates: Haspin and Plk1. Notably, these functions of Aurora-A are mostly independent of Plk1. Thus we demonstrate that, in late G2 and prophase, Aurora-A phosphorylates Haspin to trigger the Haspin-H3T3-ph-Aurora-B positive feedback loop that supports the timely establishment of the chromosomal passenger complex and the mitotic checkpoint before spindle assembly.
机译：Aurora-A激酶主要在中心体成熟，分离和纺锤体形成中起作用。还发现它在一系列实体瘤中被扩增或过表达，这与肿瘤进展和不良预后有关。重要的是，许多正在进行的临床试验正在研究Aurora-A抑制剂。但是，Aurora-A是否以及如何在有丝分裂检查点的调节中发挥作用是有争议的。此外，G2期后期核积累的Aurora-A的功能尚不清楚。在这里，我们显示敲除，抑制或阻断Aurora-A的核进入会严重降低Aurora-B的着丝粒定位以及在G2期后期由激酶Haspin介导的组蛋白H3苏氨酸3（H3T3-ph）的磷酸化。我们进一步揭示了核积累的Aurora-A在其N末端的多个位点使Haspin磷酸化，这促进了H3T3-ph并迅速募集到染色体乘客复合体的着丝粒。另外，Aurora-A促进了Aurora-B与它们的常见底物Haspin和Plk1的结合。值得注意的是，Aurora-A的这些功能大多独立于Plk1。因此，我们证明，在G2晚期和前期，Aurora-A使Haspin磷酸化，从而触发Haspin-H3T3-ph-Aurora-B正反馈环，从而支持在纺锤体组装之前及时建立染色体乘客复合体和有丝分裂检查点。

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