Project 3: Mechanical and molecular states of adhesions

细胞迁移是由细胞-基质黏附产生的信号调控的。这些信号汇聚在Rho家族gtpase的激活上，Rho家族gtpase调节肌动蛋白聚合和分支、肌动球蛋白收缩和微管动力学，从而控制驱动细胞迁移的基本过程，例如突起、粘附和极性^反过来，粘附的组装、成熟和信号传递依赖于通过粘附传递和被粘附感知的力^（图1）。粘附信号和力传感之间的反馈了解甚少，因此是本研究的重点。粘附力可产生于细胞外或细胞内，例如，通过含有肌动蛋白丝网的肌凝蛋白II的收缩。

Cell migration is regulated by signals that emanate from cell-matrix adhesions. These signals converge on the activation of Rho family GTPases, which regulate actin polymerization and branching, actomyosin contraction, and microtubule dynamics and thereby control the fundamental processes that drive cell migration, e.g., protrusion, adhesion, and polarity^ In turn, the assembly, maturation and signaling of adhesions depend on the forces transmitted through and sensed by adhesions^ (Fig. 1). The feedback between adhesion signaling and force sensing is poorly understood and hence is the focus of this study. The forces on adhesions can arise extracellularly or intracellularly, for example, by contraction of myosin II containing actin filament networks. As a result of the complex interplay between force generation, sensing and signaling (Fig. 1), migrating cells show a spectrum of adhesion morphologies and compositions that appear to represent a continuum of maturation states and signaling differences(3-5. Nascent adhesions form in the lamellipodium, independently of myosin 11 activity, and are precursors to other adhesion types. They signal to Rac to promote actin polymerization and the formation of new nascent adhesions. Paxillin is a major adapter that functions as a Rac signaling hub. When phosphorylated, it brings together signaling components like Cas/Dock180 and GIT1,2/Pix that activate Rac . Large focal adhesions, in contrast, signal to Rho and inhibit phosphorylation of adhesion components like paxillin. FAK is a major scaffold that regulates Rho activity through binding of molecules like p190Rhe-GEF and p190Rho-GAP[10]. Myosin 11 is a major Rho effector whose activity promotes adhesion maturation(11).