Aurora-A promotes the establishment of spindle assembly checkpoint by priming the Haspin-Aurora-B feedback loop in late G2 phase.
Aurora-A promotes the establishment of spindle assembly checkpoint by priming the Haspin-Aurora-B feedback loop in late G2 phase.
复制标题
Aurora-A 通过在 G2 期后期启动 Haspin-Aurora-B 反馈回路来促进纺锤体组装检查点的建立
DOI：
10.1038/celldisc.2016.49
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发表时间：
2017
期刊：
影响因子：
33.5
通讯作者：
Yang Z
中科院分区：
文献类型：
--
作者：
Yu F;Jiang Y;Lu L;Cao M;Qiao Y;Liu X;Liu D;Van Dyke T;Wang F;Yao X;Guo J;Yang Z
Aurora-A激酶主要参与中心体的成熟、分离和纺锤体的形成。还发现它在一系列实体瘤中扩增或过表达，这与肿瘤进展和预后不良有关。重要的是，Aurora-A抑制剂正在许多正在进行的临床试验中进行研究。然而，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，细胞核积累的Aurora-A在G2晚期的功能尚不清楚。在这里，我们表明，敲除，抑制或阻断Aurora-A的核进入严重降低了Aurora-B的着丝粒定位和磷酸化的组蛋白H3苏氨酸3（H3 T3-ph）介导的激酶Haspin在G2晚期。我们进一步揭示，核积累的Aurora-A磷酸化Haspin在其N-末端的多个位点，这促进了H3 T3-ph和快速招募到染色体乘客复合物的着丝粒。此外，Aurora-A促进Aurora-B与其共同底物Haspin和Plk 1的结合。值得注意的是，Aurora-A的这些功能大多独立于Plk 1。因此，我们证明，在G2晚期和前期，Aurora-A磷酸化Haspin以触发Haspin-H3 T3-ph-Aurora-B正反馈环，其支持在纺锤体组装之前及时建立染色体乘客复合物和有丝分裂检查点。
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.