Phosphorylation signaling in cell division

细胞分裂中的磷酸化信号传导

• 批准号: 10414603
• 负责人: Scott A. Gerber
• 金额: $ 41万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10414603
• 关键词: Apical; Biochemical; Bioinformatics; Biological; Biological Process; Cell division; Cell physiology; Cells; Centrosome; Chemicals; Communities; Complex; Congenital Abnormality; Cyclin B; Cytokinesis; Docking; Excision; Goals; Kinesin; Kinetochores; Malignant Neoplasms; Mediator of activation protein; Microtubules; Mitosis; Mitotic; Motor; Peptide Hydrolases; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Post-Translational Protein Processing; Protein Kinase; Protein Phosphatase 2A Regulatory Subunit PR53; Proteins; Proteomics; Regulation; Research; Research Personnel; Resources; Role; Scaffolding Protein; Signal Transduction; Sister Chromatid; Structural Protein; anaphase-promoting complex; aurora B kinase; aurora kinase A; cohesion; human disease; interest; protein function; protein phosphatase 6; recruit; ubiquitin-protein ligase

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.

抽象的 蛋白质磷酸化是一种重要的翻译后修饰，在调节中发挥着关键作用 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，包括主调节因子 Cdk1、Plk1、Aurora 激酶 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，有丝分裂激酶功能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 Cdk1/cyclin B 活性、中心体促进有丝分裂进入 分离和成熟，以及主轴组装。去除姐妹染色单体需要 Plk1 内聚力和纺锤体装配检查点 (SAC) 信号传导，并微调微管-着丝粒附着 动力学。 Plk1 还通过调节后期促进促进有丝分裂退出和胞质分裂。 复合体/环体（APC/C）并将蛋白质募集到中央纺锤体和中体。示例 Plk1 促进这些功能的底物包括对接/支架蛋白、运动蛋白（包括驱动蛋白）、 结构蛋白、蛋白酶、E3 泛素连接酶和其他激酶。 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 有丝分裂的进展和退出需要磷酸化水平的调节。我们发现Plk1抑制PP6 以促进其自身的活化。然而，PP1 和 PP2A-B56 抑制 Plk1 活性以使 SAC 沉默。因此， 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控制磷酸化信号传导的原理 有丝分裂是更好地理解细胞分裂的一种手段。具体来说，我们将重点关注 Plk1 作为顶端的作用。 有丝分裂中的介质，它是与其他激酶和磷酸酶的调节相互作用。为了实现这一目标，我们 将开发并应用蛋白质组学、生物信息学、细胞生物学和生化策略的组合 将激酶与其底物连接起来，研究底物功能，并揭示新的调控相互作用 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机制 是许多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 社区并将继续作为公开资源这样做。