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Regulation of cytokinesis by cell polarity signaling

通过细胞极性信号传导调节胞质分裂

基本信息

批准号：
10454836
负责人：
James B Moseley
金额：
$ 32.8万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454836
关键词：
Actins Actomyosin Animal Model Attention Biochemical Biological Assay Biological Models Cell Polarity Cell Separation Cell Wall Cell division Cell membrane Cell physiology Cells Cellular biology Complex Cytokinesis Cytoskeletal Filaments Cytoskeletal Proteins Cytoskeleton DNA Data Defect Ensure Enzymes Filament Fission Yeast Generations Genetic Goals Grant Growth Homeostasis In Vitro Lead Link Malignant Neoplasms Medial Microscopy Modeling Molecular Myosin ATPase Nutrient PAK-1 kinase Pathway interactions Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Play Positioning Attribute Process Protein Kinase Protein Phosphatase 2A Regulatory Subunit PR53 Protein phosphatase Proteins Publishing Regulation Rod Role Series Signal Transduction Signaling Protein Site Slide Spottings Stress Structure System Testing Tissues Translating Work base biological systems cancer cell cell growth constriction endosulfine experimental study in vivo inhibitor live cell imaging mutant novel phosphoproteomics prevent reconstitution recruit tumorigenesis

项目摘要

Cell polarity orients cytoskeletal filaments toward spatial landmarks, directing local cell growth. Protein kinases play key roles in cell polarity by translating spatial signals into regulation of cytoskeletal proteins including actin and myosin. At cell division, the actomyosin machinery dramatically reorganizes into a cytokinetic ring that constricts to separate the dividing cells. We hypothesize that cell polarity kinases act directly on the contractile actomyosin ring (CAR) to promote its assembly, organization, and function in cytokinesis. In this model, cell polarity signaling proteins regulate the CAR in cytokinesis analogous to their roles on other actomyosin structures in polarized growth. We study cell polarity and cytokinesis using the fission yeast S. pombe as a model system because it offers a well-defined parts list and a host of experimental advantages. Our preliminary data show that three conserved cell polarity protein kinases—Pak1, Kin1, and Pom1—directly phosphorylate CAR proteins and regulate specific steps in CAR assembly and constriction during cell division. In addition, regulators of the phosphatase PP2A are required to keep the CAR anchored in the correct place during cytokinesis. We propose to understand the molecular mechanisms by which these conserved protein kinases and phosphatases act on the CAR to promote cell division. The specific aims of this grant are to: (1) determine how Pak1 regulates the cytoskeleton during cell division, (2) test the hypothesis that Pom1, Kin1, and Pak1 represent sequential regulatory inputs for cytokinesis proteins, and (3) investigate how regulation of PP2A phosphatase positions the CAR. Successful completion of these goals will define a signaling system that prevents defects in cell division, and will identify previously unknown connections between two fundamental cellular processes: cell polarity and cytokinesis.

细胞极性将细胞骨架丝朝向空间地标，引导局部细胞生长。蛋白激酶通过将空间信号转化为细胞极性的调节而在细胞极性中发挥关键作用。细胞骨架蛋白包括肌动蛋白和肌球蛋白。在细胞分裂时，肌动球蛋白机制戏剧性地重组成一个细胞因子环，该环收缩以分离分裂的细胞。我们假设细胞极性激酶直接作用于收缩肌动球蛋白环（CAR）促进其在胞质分裂中的组装、组织和功能。在此模型中，细胞极性信号蛋白在胞质分裂中调节 CAR，类似于它们对其他肌动球蛋白的作用极化生长的结构。我们使用裂殖酵母研究细胞极性和胞质分裂。 pombe 作为一个模型系统，因为它提供了明确定义的零件列表和大量实验优点。我们的初步数据表明，三种保守的细胞极性蛋白激酶——Pak1、 Kin1和Pom1——直接磷酸化CAR蛋白并调节CAR中的特定步骤细胞分裂过程中的组装和收缩。此外，磷酸酶 PP2A 的调节剂需要在胞质分裂过程中将 CAR 固定在正确的位置。我们建议了解这些保守蛋白激酶和磷酸酶作用于CAR，促进细胞分裂。这笔赠款的具体目的是：（1）确定 Pak1 在细胞分裂过程中如何调节细胞骨架，(2) 检验以下假设： Pom1、Kin1 和 Pak1 代表胞质分裂蛋白的顺序调节输入，并且 (3) 研究 PP2A 磷酸酶的调节如何定位 CAR。顺利完成这些目标将定义一个防止细胞分裂缺陷的信号系统，并将识别两个基本细胞过程之间以前未知的联系：细胞极性和胞质分裂。