Yu Fazhi, Jiang Ya, Lu Lucy, Cao Mimi, Qiao Yulong, Liu Xing, Liu Dan, Van Dyke Terry, Wang Fangwei, Yao Xuebiao, Guo Jing, Yang Zhenye
Key Laboratory of Innate Immunity and Chronic Disease of CAS, Innovation Center for Cell Biology, School of Life Sciences, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China , Hefei, China.
Center for Advanced Preclinical Research, the Center for Cancer Research, National Cancer Institute , Frederick, MD, USA.
Cell Discov. 2017 Jan 10;3:16049. doi: 10.1038/celldisc.2016.49. eCollection 2017.
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.
极光激酶A主要在中心体成熟、分离和纺锤体形成过程中发挥作用。人们还发现它在一系列实体瘤中发生扩增或过表达，这与肿瘤进展和不良预后相关。重要的是，目前多项正在进行的临床试验正在研究极光激酶A抑制剂。然而，极光激酶A是否以及如何在有丝分裂检查点的调控中发挥作用仍存在争议。此外，G2晚期核内积累的极光激酶A的功能尚不清楚。在此我们表明，敲除、抑制或阻断极光激酶A的核内进入会严重降低G2晚期极光激酶B在着丝粒的定位以及由激酶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，核内积累的极光激酶A在其N端的多个位点磷酸化Haspin，这促进了H3T3-ph以及染色体乘客复合体向着丝粒的快速募集。此外，极光激酶A促进了极光激酶B与其共同底物Haspin和Plk1的结合。值得注意的是，极光激酶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，极光激酶A磷酸化Haspin以触发Haspin-H3T3-ph-极光激酶B正反馈回路，该回路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。
