Multifaceted roles of nonmuscle myosin II in cell adhesion and migration

非肌肉肌球蛋白 II 在细胞粘附和迁移中的多方面作用

基本信息

批准号：
9307035
负责人：
Tatyana Svitkina
金额：
$ 32.2万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9307035
关键词：
Actins Address Adhesions Animals Automobile Driving Cell Adhesion Cell Polarity Cell-Matrix Junction Cells Computer Simulation Contractile System Cytoskeleton Diagnostic Drug Design Elements Environment Filament Focal Adhesions Goals Hybrids Immune System Diseases Knowledge Malignant Neoplasms Mechanics Modeling Modification Molecular Molecular Genetics Motor Muscle Mutation Myosin ATPase Myosin Regulatory Light Chains Myosin Type II Neurodegenerative Disorders Pharmacotherapy Phosphorylation Physiological Play Polymers Property Recycling Regulation Role Site Sorting - Cell Movement Structure Subgroup Testing Tissues cell motility cell type combinatorial copolymer depolymerization design directional cell experimental study fighting follow-up human disease migration monomer mutant non-muscle myosin paralogous gene polarized cell polymerization spatiotemporal tool

项目摘要

Class II (conventional) myosins are actin-dependent motors that are uniquely able to polymerize into bipolar filaments, which makes them capable of driving cell contraction. Nonmuscle myosin II (NMII) is ubiquitously expressed in animal cells, where it executes numerous mechanical tasks including cell adhesion and migration, as well as overall organization of the contractile cytoskeleton in the cell. In contrast to large and stable bipolar filaments formed by muscle-specific myosin II paralogs, NMII filaments are small and highly dynamic. By constantly cycling between polymeric and monomeric states, NMII can accommodate changing cellular needs and help the cell to choose an appropriate mode of migration. We recently discovered two new aspects of NMII dynamics: (1) copolymerization of NMII paralogs into hybrid bipolar filaments and (2) functional significance of activated, but unpolymerized NMII monomers that were previously considered to be only transient intermediates of NMII activation. Our goal is to determine physiological significance of these new aspects of NMII dynamics. Specifically, we will test our hypotheses that (1) copolymerization of NMII paralogs is a key mechanism to establish polarized organization of the contractile system in cells and thus promote directional cell migration and that (2) activated NMII monomers regulate dynamics of cell-matrix adhesions. A key element of both models is regulation of NMII at the heavy chain level, which modulates composition of hybrid bipolar filaments and generates activated NMII monomers. We address the following specific aims: (1) Roles of NMII copolymerization for contractile system organization and cell migration; (2) Roles of heavy chain- dependent mechanisms of NMII turnover for cytoskeleton polarization and cell migration; and (3) Roles of activated NMII monomers in dynamics of cell-matrix adhesions.

II 类（传统）肌球蛋白是肌动蛋白依赖性马达，能够独特地聚合成双极丝，这使得它们能够驱动细胞收缩。非肌肉肌球蛋白 II (NMII) 是在动物细胞中普遍表达，执行许多机械任务，包括细胞粘附和迁移，以及细胞中收缩细胞骨架的整体组织。与大型和由肌肉特异性肌球蛋白 II 旁系同源物形成的稳定双极丝，NMII 丝较小且高度动态的。通过在聚合状态和单体状态之间不断循环，NMII 可以适应不断变化的状态细胞的需求并帮助细胞选择合适的迁移模式。我们最近发现了两个新的 NMII 动力学的各个方面：(1) NMII 旁系同源物共聚成混合双极丝，以及 (2) 功能性活化但未聚合的 NMII 单体的重要性，这些单体以前被认为是唯一的 NMII 激活的瞬时中间体。我们的目标是确定这些新的生理意义 NMII 动力学的各个方面。具体来说，我们将测试我们的假设：(1) NMII 旁系同源物的共聚是建立细胞收缩系统极化组织的关键机制，从而促进定向细胞迁移以及 (2) 激活的 NMII 单体调节细胞基质粘附的动力学。一个两个模型的关键要素是重链水平上的 NMII 调节，它调节混合双极丝并生成活化的 NMII 单体。我们致力于实现以下具体目标：(1) NMII 共聚对收缩系统组织和细胞迁移的作用； (2) 重链的作用- NMII 翻转对细胞骨架极化和细胞迁移的依赖机制； (3) 的角色在细胞基质粘附动力学中激活 NMII 单体。