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

• 批准号: 9891615
• 负责人: Tatyana Svitkina
• 金额: $ 9.87万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/9891615
• 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

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（常规）肌球蛋白是肌动蛋白依赖性马达，其独特地能够介导肌球蛋白的合成。 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） 在动物细胞中广泛表达，在那里它执行许多机械任务，包括细胞粘附 和迁移，以及细胞中收缩性细胞骨架的整体组织。相比之下， 由肌肉特异性肌球蛋白II旁系同源物形成的稳定的双极丝，NMII丝是小的并且高度 动态的通过在聚合物和单体状态之间不断循环，NMII可以适应变化的 细胞需要并帮助细胞选择适当的迁移模式。我们最近发现了两个新的 匪II动力学方面：（1）匪II旁系同源物共聚成混合双极丝和（2）官能化的双极丝。 活化的，但未聚合的NMII单体的意义，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 NMII动力学方面。具体来说，我们将测试我们的假设，（1）共聚的NMII旁系同源物 是在细胞中建立收缩系统的极化组织的关键机制， 定向细胞迁移和（2）活化的匪II单体调节细胞-基质粘附的动力学。一 这两种模型的关键要素是在重链水平调节NMII，其调节 混合双极丝并产生活化的匪II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- 细胞骨架极化和细胞迁移的NMII周转的依赖机制;和（3） 活化的匪II单体在细胞-基质粘附动力学中的作用。