Project 3: Mechanical and molecular states of adhesions

细胞迁移受细胞-基质黏附信号的调控。这些信号集中在Rho家族GTP酶的激活上，Rho家族GTP酶调控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、粘连和极性。反过来，粘连的组装、成熟和信号传递取决于通过粘连传递的力和由粘连感知的力。粘着信号和力感觉之间的反馈机制还不是很清楚，因此这也是本研究的重点。粘附力可以在细胞外或细胞内产生，例如，通过收缩含有肌动蛋白细丝网络的肌球蛋白II。 作为力产生、感知和信号之间复杂相互作用的结果(图1)，迁移细胞显示出一系列黏附形态和成分，似乎代表了成熟状态和信号差异的连续体(3-5)。新生的粘连在板层中形成，独立于肌球蛋白11的活性，是其他粘连类型的前驱。它们向RAC发出信号，促进肌动蛋白聚合和新的新生粘连的形成。帕克西林是一种主要的适配器，起着RAC信号中枢的作用。当磷酸化时，它将激活RAC的信号元件如Cas/Dock180和GIT1，2/Pix聚集在一起。相反，大灶性粘连向Rho发出信号并抑制其磷酸化。 粘附性成分，如巴西林。FAK是一个主要的支架，通过结合p190Rhe-Gap和p190Rho-Gap等分子来调节Rho的活性[10]。 肌球蛋白11是一种主要的Rho效应器，其活性促进黏附成熟(11)。

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).