Rho Family GTPases in Integrin Signaling

描述（由申请人提供）：Rho家族GTP酶Rac、Rho和Cdc 42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心协调者。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，整联蛋白控制GTP加载（即，激活）。存在单独的调节水平，其中整合素控制活化的GTP酶的膜靶向。激活和膜靶向这两个步骤对于GTP酶激活下游效应物是必不可少的。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Cdc 42的新核苷酸交换因子。它的蛋白质结合伙伴，调节模式和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的膜靶向的机制。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种影响。因此，调节脂筏/小窝的整合素和它们的作用，Rac信号转导将进行研究。这些研究将有助于我们对整合素如何调节Rho家族GTP酶的基本理解。这些调节事件是细胞迁移、生长和正常生理和人类疾病中的功能的核心。

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.