Protein Tyrosine Phosphatase Alpha in Integrin Signaling and Cell Movement

细胞运动是一个基本的生理过程。细胞运动的主要决定因素是整合素，即细胞膜上的受体，它协调粘附细胞与底物的接触，并不断重组肌动蛋白细胞骨架。整合素参与启动细胞内信号传导，驱动多蛋白复合物的组装，称为局灶粘连（FAs）。FA信号既控制细胞骨架重塑，也控制其自身的动态组装和拆卸，以调节细胞的形状和运动。

Cell movement is a fundamental physiological process. Principal determinants of cell motility are the integrins, receptors on the cell membrane that co-ordinate adhesive cell-substrate contacts with continual re-organization of the actin cytoskeleton. Integrin engagement initiates intracellular signaling that drives the assembly of multiprotein complexes known as focal adhesions (FAs). FA signaling controls both cytoskeletal remodeling and also their own dynamic assembly and disassembly to regulate cell shape and movement. Receptor protein tyrosine phosphatase alpha (PTPa) is a positive regulator of integrin signaling that promotes cell movement. PTPa-deficient mouse embryo fibroblasts exhibit defective integrin-stimulated migration that is characterized by delayed cytoskeletal rearrangement and impaired FA formation. Through investigation of these defects, we have discovered that PTPa plays two roles in integrin-mediated signaling to promote FA assembly and, ultimately, cell migration: (i) a catalytic role as an upstream activator of the Src-FAK kinase complex, and (ii) a non-catalytic role as a downstream target of the Src-FAK complex. In its second role, PTPa is phosphorylated by active Src-FAK on a tyrosine residue in its C-terminal tail, Tyr789. This is pivotal for FA formation and signaling that promotes cell migration, however the signaling actions of PTPa-phosphoTyr789 (PTPa-pTyr789) are largely unknown. We have begun to identify integrin-stimulated molecular mechanisms that regulate PTPa phosphorylation and novel targets of PTPa- and PTPa-pTyr789 signaling. Our evidence indicates that PTPa is a coordinator of molecular interactions integral to the formation and function of FAs. We hypothesize that PTPa, specifically PTPa-phosphoTyr789, is a critical regulator of FA assembly and remodeling and acts as a hub to co-ordinate molecular interactions that direct integrin signaling and determine cell movement. We will investigate this hypothesis by determining the nature and regulated formation of PTPa- and PTPa-pTyr789-containing molecular complexes and elucidating their functional roles in FA signaling and turnover (assembly and disassembly). For this, we will use integrated cell and molecular biology approaches to investigate unique model cell systems that express or lack wild-type and mutant forms of PTPa. Aim 1: Investigate the role of PTPa and PTPa-pTyr789 in regulating FA dynamics: assembly, turnover, and molecular stability. Aim 2: Define the molecular interactions of PTPa, using proteomics, that regulate its FA localization and signaling. Overall, our proposed research will elucidate the regulation and roles of PTPa and PTPa-pTyr789, in integrin-regulated focal adhesion dynamics and signaling. This will further our understanding of the precisely orchestrated molecular network that controls the essential process of cell movement.