Phosphorylation signaling in cell division

摘要 蛋白质磷酸化是一种重要的翻译后修饰，在调节过程中起着关键作用。 蛋白质的功能、定位和稳定性，并控制大多数细胞过程，包括细胞分裂。 蛋白激酶的磷酸化，包括主要调控因子CDK1、Plk1、Aurora Kinase A和Aurora 激酶B需要协调多种底物的功能，以促进细胞的忠实运输 通过有丝分裂。事实上，有丝分裂酶功能的失调是许多人类疾病的基础，例如出生 缺陷和癌症。 特别是，激酶Plk1通过调节中心体CDK1/Cyclin B的活性来促进有丝分裂的进入 分离和成熟，以及纺锤体组装。PLK1是去除姐妹染色单体所必需的 内聚力和纺锤体组装检查点(SAC)信号以及微管-动粒连接的微调 动力学。PLK1还通过调节后期促进作用促进有丝分裂退出和胞质分裂。 复合体/环体(APC/C)和向中心纺锤体和中体募集蛋白质。示例Plk1 促进这些功能的底物包括对接/支架蛋白，包括动蛋白在内的马达蛋白， 结构蛋白、蛋白水解酶、E3泛素连接酶和其他激酶。 而进入有丝分裂是由激酶的激活和磷酸化的净增加驱动的，动态的 有丝分裂的进展和退出需要调节磷酸化水平。我们发现Plk1抑制PP6 以促进自身的激活。然而，PP1和PP2A-B56抑制Plk1的活性，使SAC沉默。因此， 激酶和磷酸酶之间复杂的调控相互作用控制着有丝分裂。 我们的首要目标是确定和发现管理磷酸化信号转导的原理 有丝分裂是更好地理解细胞分裂的一种手段。具体地说，我们将重点关注Plk1作为心尖细胞的作用 它是有丝分裂的中介物，是与其他激酶和磷酸酶相互作用的调节因子。为了实现这一目标，我们 将开发和应用蛋白质组学、生物信息学、细胞生物学和生化策略的组合来 将激酶连接到它们的底物上，研究底物功能，并发现新的调节相互作用 激酶和磷酸酶 我们过去的研究使我们和其他研究人员能够从功能上询问特定的机制 这是许多令人感兴趣的生物过程的基础。我们致力于与研究人员分享我们的发现 社区，并将继续这样做，作为公共可用的资源。

ABSTRACT Protein phosphorylation is an essential post-translational modification that plays pivotal roles in the regulation of protein function, localization, and stability and governs most cellular processes, including cell division. Phosphorylation by protein kinases, including the master regulators Cdk1, Plk1, Aurora kinase A and Aurora kinase B, are required to coordinate the functions of a wide array of substrates to promote faithful transit of cells through mitosis. Indeed, dysregulation of mitotic kinase functions underlies many human diseases such as birth defects and cancer. In particular, the kinase Plk1 promotes mitotic entry by regulating Cdk1/cyclin B activity, centrosome separation and maturation, as well as spindle assembly. Plk1 is required for the removal of sister chromatid cohesion and spindle assembly checkpoint (SAC) signaling, and fine-tunes microtubule-kinetochore attachment dynamics. Plk1 also contributes to mitotic exit and cytokinesis by regulating the anaphase promoting complex/cyclosome (APC/C) and recruiting proteins to the central spindle and the midbody. Example Plk1 substrates that facilitate these functions include docking/scaffolding proteins, motor proteins including kinesins, structural proteins, proteases, E3 ubiquitin ligases, and other kinases. While entry into mitosis is driven by the activation of kinases and a net increase in phosphorylation, dynamic regulation of phosphorylation levels is needed for mitotic progression and exit. We found that Plk1 inhibits PP6 to promote its own activation. However, PP1 and PP2A-B56 restrain Plk1 activity to silence the SAC. Thus, complex regulatory interactions between kinases and phosphatases control mitosis. Our overarching goals are to identify and uncover the principles that govern phosphorylation signaling in mitosis as a means to better understand cell division. Specifically, we will focus on the role of Plk1 as an apical mediator in mitosis and it is regulatory interactions with other kinases and phosphatases. To accomplish this, we will develop and apply a combination of proteomic, bioinformatic, cell biological and biochemical strategies to connect kinases to their substrates, investigate substrate function, and uncover new regulatory interactions of kinases and phosphatases Our past studies have enabled us and other researchers to functionally interrogate specific mechanisms that underlie many biological processes of interest. We are dedicated to sharing our findings with the research community and will continue to do so as publically available resources.