Phosphatase 1 Nuclear Targeting Subunit (PNUTS) Regulates Aurora Kinases and Mitotic Progression
Phosphatase 1 Nuclear Targeting Subunit (PNUTS) Regulates Aurora Kinases and Mitotic Progression
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DOI：
10.1158/1541-7786.mcr-17-0670
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发表时间：
2019-01-01
影响因子：
5.2
通讯作者：
Peng, Aimin
中科院分区：
文献类型：
--
作者：
Wang, Feifei;Wang, Ling;Peng, Aimin
有丝分裂进展很大程度上受有丝分裂激酶和磷酸酶介导的可逆磷酸化事件的调节。蛋白磷酸酶 1 (PP1) 已被证明在调节有丝分裂进入、进展和退出中发挥着至关重要的作用。我们之前在非洲爪蟾卵提取物中观察到，磷酸酶 1 核靶向亚基 (PPP1R10/PNUTS) 通过负调节 PP1 作为有丝分裂调节剂。本研究调查了 PNUTS 在哺乳动物细胞有丝分裂进展中的作用，并证明 PNUTS 表达在有丝分裂中升高，并且耗尽会部分阻止有丝分裂进入。 PNUTS 敲低后进入有丝分裂的细胞表现出频繁的染色体错误分离。 Aurora A/B 激酶复合物和几种动粒成分被鉴定为 PNUTS 相关蛋白。 PNUTS 缺失会抑制 Aurora A/B 激酶的激活，并破坏染色体乘客复合体 (CPC) 的时空调节。 PNUTS 动态定位于动粒，是激活纺锤体装配检查点所必需的。最后，PNUTS 的缺失使肿瘤细胞对 Aurora 抑制的反应敏感，表明 PNUTS 是联合抗癌治疗中的潜在药物靶点。 意义：描述 PNUTS 如何控制 Aurora 激酶的有丝分裂激活和功能将提高对有丝分裂进展中复杂的磷酸调节的理解，并提出增强 Aurora 抑制剂治疗功效的新选择。
Mitotic progression is regulated largely by reversible phosphorylation events that are mediated by mitotic kinases and phosphatases. Protein phosphatase 1 (PP1) has been shown to play a crucial role in regulation of mitotic entry, progression, and exit. We previously observed, in Xenopus egg extracts, that phosphatase 1 nuclear targeting subunit (PPP1R10/PNUTS) acts as a mitotic regulator by negatively modulating PP1. This study investigates the role of PNUTS in mitotic progression in mammalian cells, and demonstrates that PNUTS expression is elevated in mitosis and depletion partially blocks mitotic entry. Cells that enter mitosis after PNUTS knockdown exhibit frequent chromosome mis-segregation. Aurora A/B kinase complexes and several kinetochore components are identified as PNUTS-associated proteins. PNUTS depletion suppresses the activation of Aurora A/B kinases, and disrupts the spatiotemporal regulation of the chromosomal passenger complex (CPC). PNUTS dynamically localizes to kinetochores, and is required for the activation of the spindle assembly checkpoint. Finally, PNUTS depletion sensitizes the tumor cell response to Aurora inhibition, suggesting that PNUTS is a potential drug target in combination anticancer therapy.Implications: Delineation of how PNUTS governs the mitotic activation and function of Aurora kinases will improve the understanding of the complex phospho-regulation in mitotic progression, and suggest new options to enhance the therapeutic efficacy of Aurora inhibitors.