Assembly and Functions of the PINCH/ILK/CH-ILKBP Complex

描述(申请人提供)：细胞-细胞外基质黏附是一种 调节细胞形状、增殖和生长的基本过程 差异化。细胞-基质黏附和细胞外基质异常 装配与多种人类疾病的发病密切相关 疾病。我们研究的长期目标是阐明这种机制。 细胞通过其调节细胞与基质的黏附和细胞外基质的组装。 整合素连接激酶(Ilk)是细胞-基质黏附的重要调节因子。 和纤维连接蛋白基质组装体。本研究项目主要集中在分子方面。 ILK在这些过程中发挥作用的机制。我们的假设是 (1)由ILK、PINCH和CH-ILKBP组成的多蛋白复合体提供 细胞黏附受体与肌动蛋白之间的重要物理联系 细胞-基质接触部位的细胞骨架和(2)夹点相关蛋白 申请人最近克隆的(Pinch-RP)调节组装 从而参与PINCH/ILK/CH-ILKBP复合体的调节 细胞黏附、肌动蛋白细胞骨架组织和基质组装。这个 拟议的研究旨在批判性地检验这些假设。首先， 参与组装的PINCH、ILK和CH-ILKBP的位置 PINCH/ILKICH-ILKBP复合体在细胞-基质接触部位的定位 将通过定点突变来定义。第二，政府官员的角色 PINCHILKICH-ILKBP复合体在细胞-基质黏附、铺展和纤维连接蛋白中的作用 将使用调节复合体的试剂来确定基质组装 队形。第三，夹点-RP的特征及其在 PINCHIILKICH-ILKBP复合体Will的组装和功能的调节 要下定决心。 这些研究将提供重要的信息关于组装，功能和 对Pinch/ILK/CH-ILKBP复合体的调节将导致更好的 了解细胞调节细胞黏附的一般机制 和矩阵组装，从而更好地理解 血吸虫病相关疾病发病的分子基础 细胞黏附和基质组装异常。

DESCRIPTION (provided by applicant): Cell-extracellular matrix adhesion is a fundamental process that regulates cell shape, proliferation and differentiation. Abnormalities in cell-matrix adhesion and extracellular matrix assembly are closely associated with the pathogenesis of a variety of human diseases. The long-term objective of our research is to elucidate the mechanism by which cells regulate cell-matrix adhesion and extracellular matrix assembly. Integrin-linked kinase (ILK) is an important regulator of cell-matrix adhesion and fibronectin matrix assembly. This research project focuses on the molecular mechanism by which ILK functions in these processes. Our hypotheses are that (1) a multi-protein complex comprising ILK, PINCH and CH-ILKBP provides an important physical connection between cell adhesion receptors and the actin cytoskeleton at the cell-matrix contact sites and (2) a PINCH-related protein (PINCH-RP), which was recently cloned by the applicant, regulates the assembly of the PINCH/ILK/CH-ILKBP complex and thereby participates in the regulation of cell adhesion, actin cytoskeleton organization and matrix assembly. The proposed studies are designed to critically test these hypotheses. First, the sites of PINCH, ILK and CH-ILKBP that are involved in the assembly and the localization of the PINCH/ILKICH-ILKBP complex to cell-matrix contact sites will be defined by site-directed mutagenesis. Second, the role of the PINCHIILKICH-ILKBP complex in cell-matrix adhesion, spreading and fibronectin matrix assembly will be determined using reagents that modulate the complex formation. Third, PINCH-RP will be characterized and its potential role in the regulation of the assembly and functions of the PINCHIILKICH-ILKBP complex will be determined. These studies will provide important information on the assembly, function and regulation of the PINCH/ILK/CH-ILKBP complex and will lead to a better understanding of the general mechanism by which cells regulate cell adhesion and matrix assembly, and consequentially, a better understanding of the molecular basis underlying the pathogenesis of diseases associated with abnormal cell adhesion and matrix assembly.