Ubiquitin-Mediated Degradation of Aurora Kinases.
Ubiquitin-Mediated Degradation of Aurora Kinases.
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DOI：
10.3389/fonc.2015.00307
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发表时间：
2015
影响因子：
4.7
通讯作者：
Min M
中科院分区：
文献类型：
--
作者：
Lindon C;Grant R;Min M
极光激酶是真核生物有丝分裂的重要调节因子。在高等真核生物的体细胞分裂中，旁系同源极光激酶 A (AurA) 和极光激酶 B (AurB) 根据其不同的时空活性发挥不重叠的作用。 Aurora 激酶的这些有丝分裂作用取决于它们与不同伙伴的相互作用，这些伙伴将它们引导至不同的有丝分裂目的地和不同的底物：AurB 是染色体过客复合体的一个组成部分，负责协调染色体分离和胞质分裂的任务，而 AurA 具有许多已知的结合伙伴和有丝分裂作用，包括与 TPX2 的良好表征的相互作用，介导其在有丝分裂纺锤体组装中的作用。除了不同结合伙伴赋予的空间控制之外，极光激酶还受到其激活和失活的时间控制。泛素介导的蛋白水解是这些激酶不可逆失活的关键途径，从有丝分裂回到间期的有序转变必须发生这种失活。 AurA 和 AurB 在后期开始后作为后期促进复合物/环体 (APC/C) 泛素连接酶的底物进行靶向蛋白水解，即使它们在有丝分裂退出期间继续调节步骤。对 Aurora 激酶破坏的时间控制可确保 AurB 在胞质分裂期间在 AurA 活性已从细胞中大部分消除后很长时间内仍保持在中体活性。尽管 Aurora 激酶同时被相同的泛素连接酶靶向，但它们还是实现了差异化破坏，这使得这些底物成为研究高等真核生物中泛素介导的蛋白水解的分子决定因素的有趣案例研究。 Aurora 在癌症中过度表达的普遍性及其作为治疗靶点的潜力，增加了了解 Aurora 激酶稳定性的分子决定因素的重要性。在这里，我们回顾了泛素介导的这些关键有丝分裂调节因子的靶向作用，并讨论了有助于细胞内极光激酶活性蛋白水解控制的不同因素。
The Aurora kinases are essential regulators of mitosis in eukaryotes. In somatic cell divisions of higher eukaryotes, the paralogs Aurora kinase A (AurA) and Aurora kinase B (AurB) play non-overlapping roles that depend on their distinct spatiotemporal activities. These mitotic roles of Aurora kinases depend on their interactions with different partners that direct them to different mitotic destinations and different substrates: AurB is a component of the chromosome passenger complex that orchestrates the tasks of chromosome segregation and cytokinesis, while AurA has many known binding partners and mitotic roles, including a well-characterized interaction with TPX2 that mediates its role in mitotic spindle assembly. Beyond the spatial control conferred by different binding partners, Aurora kinases are subject to temporal control of their activation and inactivation. Ubiquitin-mediated proteolysis is a critical route to irreversible inactivation of these kinases, which must occur for ordered transition from mitosis back to interphase. Both AurA and AurB undergo targeted proteolysis after anaphase onset as substrates of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase, even while they continue to regulate steps during mitotic exit. Temporal control of Aurora kinase destruction ensures that AurB remains active at the midbody during cytokinesis long after AurA activity has been largely eliminated from the cell. Differential destruction of Aurora kinases is achieved despite the fact that they are targeted at the same time and by the same ubiquitin ligase, making these substrates an interesting case study for investigating molecular determinants of ubiquitin-mediated proteolysis in higher eukaryotes. The prevalence of Aurora overexpression in cancers and their potential as therapeutic targets add importance to the task of understanding the molecular determinants of Aurora kinase stability. Here, we review what is known about ubiquitin-mediated targeting of these critical mitotic regulators and discuss the different factors that contribute to proteolytic control of Aurora kinase activity in the cell.