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: 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
• 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

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电机，具有唯一能够聚合到 双极丝，使它们能够驱动细胞收缩。非肌肉肌球蛋白II（NMII）是 在动物细胞中无处不在表达，在动物细胞中执行许多机械任务，包括细胞粘附 和迁移以及细胞收缩细胞骨架的整体组织。与大和 由肌肉特异性肌球蛋白II旁系同源物形成的稳定的双极细丝，NMII细丝很小且高度 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 细胞需求并帮助细胞选择适当的迁移方式。我们最近发现了两个新的 NMII动力学的各个方面：（1）NMII旁系同源物与混合双极丝和（2）功能的共聚 激活但不溶性的NMII单体的意义，以前仅被认为是 NMII激活的瞬态中间体。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。具体而言，我们将测试我们的假设，即（1）NMII旁系同源物的共聚 是在细胞中建立收缩系统两极化组织的关键机制，从而促进 定向细胞迁移，（2）激活的NMII单体调节细胞垫粘附的动力学。一个 这两种模型的关键要素是在重链级别对NMII的调节，该链条调节了 杂交双极丝并生成活化的NMII单体。我们解决以下特定目的：（1） NMII共聚在收缩系统组织和细胞迁移中的作用； （2）重链的角色 NMII周转的依赖机制，用于细胞骨架极化和细胞迁移； （3） 活化的NMII单体在细胞基质粘附动力学中。