RHO FAMILY GTPASES IN INTEGRIN SIGNALING

描述：拟议研究的目标是了解 受体酪氨酸对小GTP酶Rho、Rac和Cdc 42的调节 激酶和整合素。 这些研究的一个目的是使用测定 已经由申请人和其他人开发的用于蜂窝通信的通信系统。 Rho、Rac和Cdc 42的激活，以描述 整合素和生长因子对这些小GTP酶的功能的影响。 一 第二个目标是鉴定鸟嘌呤核苷酸交换因子， 负责这些GTP酶的整合素依赖性活化， 特别强调的是Vav 2蛋白。 第三个目标将涉及 磷脂酰肌醇4磷酸5激酶（PIP） 5激酶）的肌动蛋白细胞骨架。 这一目标将扩大重要的 申请人的实验室关于Rho的能力的发现 刺激PIP 5激酶。 利用这一事实， 该激酶家族已经被克隆，申请人提出鉴定 与Rho和/或Rac结合从而鉴定小区域的PIP 5激酶 负责这些相互作用的激酶。 这个想法是使用 这些片段作为竞争性抑制剂，以确定阻断是否 通过Rho和/或Rac激活PIP 5激酶抑制特异性的 这些GTP酶对肌动蛋白细胞骨架的影响。

DESCRIPTION: The goal of the proposed studies will be to understand the regulation of the small GTPases, Rho, Rac, and Cdc42 by receptor tyrosine kinases and by integrins. One aim of these studies will be to use assays that have been developed by the applicant and others for the cellular activation of Rho, Rac, and Cdc42 to delineate the contributions of integrins and growth factors to the function of these small GTPases. A second aim will be to identify the guanine nucleotide exchange factors that are responsible for the integrin dependent activation of these GTPases, with a particular emphasis being the Vav2 protein. The third aim will involve studies of the effects of the phosphatidylinositol 4 phosphate 5 kinase (PIP 5 kinase) on the actin cytoskeleton. This aim will extend the important discovery made by the applicant's laboratory regarding the ability of Rho to stimulate the PIP 5 kinase. Taking advantage of the fact that members of this kinase family have been cloned, the applicant proposes to identify the PIP 5 kinase that binds to Rho and/or Rac and thereby identify small regions of the kinase(s) responsible for these interactions. The idea is to use these fragments as competitive inhibitors to determine whether the blockade of the activation of the PIP 5 kinase by Rho and/or Rac inhibits specific effects by these GTPases on the actin cytoskeleton.