Phosphorylation signaling in cell division

摘要 蛋白质磷酸化是一种重要的翻译后修饰，在蛋白质磷酸化的调控中起着关键作用 蛋白质的功能，定位和稳定性，并支配大多数细胞过程，包括细胞分裂。 蛋白激酶磷酸化，包括主调节因子Cdk 1、Plk 1、Aurora激酶A和Aurora 激酶B是协调多种底物的功能以促进细胞的忠实转运所必需的 通过有丝分裂事实上，有丝分裂激酶功能失调是许多人类疾病的基础， 缺陷和癌症。 具体地说，激酶Plk 1通过调节Cdk 1/细胞周期蛋白B活性、中心体和细胞周期蛋白B活性来促进有丝分裂进入。 分离和成熟，以及纺锤体组装。plk 1是去除姐妹染色单体所必需的 内聚和纺锤体组装检查点（SAC）信号传导，并微调微管-动粒附着 动力学plk 1还通过调节后期促进细胞分裂，参与有丝分裂的退出和胞质分裂。 在细胞周期中，APC/C（APC/Cyclosome）和募集蛋白质到中央纺锤体和中间体。实施例Plk 1 促进这些功能的底物包括对接/支架蛋白，包括驱动蛋白的马达蛋白， 结构蛋白、蛋白酶、E3泛素连接酶和其它激酶。 虽然进入有丝分裂是由激酶的激活和磷酸化的净增加驱动的，但动态的 磷酸化水平的调节是有丝分裂进程和退出所必需的。我们发现Plk 1抑制PP 6， 以促进自身的激活。然而，PP 1和PP 2A-B56抑制Plk 1活性以沉默SAC。因此，在本发明中， 激酶和磷酸酶之间复杂的调节相互作用控制有丝分裂。 我们的首要目标是确定和揭示在细胞内控制磷酸化信号传导的原则。 有丝分裂作为更好地理解细胞分裂的手段。具体来说，我们将重点放在Plk 1作为一个顶端的作用， 它是有丝分裂中的一种重要介质，并与其他激酶和磷酸酶相互调节。为了做到这一点，我们 将开发和应用蛋白质组学，生物信息学，细胞生物学和生物化学策略的组合， 将激酶连接到其底物，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在功能上询问特定的机制， 是许多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，作为可利用的资源。

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.