Rho Family GTPases in Integrin Signaling

描述(申请人提供)：Rho家族GTP酶Rac、Rho和CDC42是调节肌动蛋白细胞骨架、细胞迁移、基因表达和细胞增殖的信号转导途径的中央协调者。我们过去的工作表明，整合素是细胞外基质蛋白的主要受体，通过两种方式调节Rho家族GTP酶。首先，整合素控制GTP的加载(即激活)。整合素控制激活的GTP酶的膜靶向性，这是一个单独的调控水平。激活和膜定位这两个步骤对于GTP酶激活下游效应器是必不可少的。在目前的拨款申请中，我们建议进行两个项目，以阐明这两个机制。首先，我们将研究我们最近克隆的一种新的cdc42核苷酸交换因子。它的蛋白结合伙伴、调节方式和在信号转导中的作用将被研究。其次，我们将研究整合素控制活性RAC膜靶向的机制。该项目将基于初步数据，表明整合素对脂筏和/或小窝的影响介导了这一效应。因此，整合素对脂筏/小窝的调节及其在RAC信号转导中的作用将被研究。这些研究将有助于我们从根本上理解整合素如何调控Rho家族GTP酶。这些调节事件是正常生理和人类疾病中细胞迁移、生长和功能的中心。

DESCRIPTION (provided by applicant): The Rho family GTPases Rac, Rho and Cdc42 are central coordinators of the signal transduction pathways that regulate the actin cytoskeleton, cell migration, gene expression and cell proliferation. Our past work demonstrated that integrins, which are the major receptors for extracellular matrix proteins, regulate Rho family GTPases in two ways. First, integrins controls GTP loading (i.e., activation). There is a separate level of regulation in which integrins control membrane targeting of the activated GTPases. Both steps, activation and membrane targeting, are essential for GTPases to activate downstream effectors. In the current grant application, we propose to pursue two projects to elucidate these two mechanisms. First, we will study a new nucleotide exchange factor for Cdc42 that we have recently cloned. It's protein binding partners, mode of regulation and roles in signal transduction will be investigated. Second, we will investigate the mechanism by which integrins control the membrane targeting of active Rac. The project will be based on preliminary data suggesting that effects of integrins on lipid rafts and/or caveolae mediate this effect. Thus, the regulation of lipid rafts/caveolae by integrins and their role in Rac signal transduction will be investigated. These studies will contribute to our fundamental understanding of how integrins regulate Rho family GTPases. These regulatory events are central to cell migration, growth and function in normal physiology and human diseases.