RHO FAMILY GTPASES IN INTEGRIN SIGNALING

描述：拟议研究的目标将是了解 受体酪氨酸对小分子GTP酶Rho、Rac和CDc42的调节 激酶和整合素。这些研究的目的之一将是使用化验 由申请人和其他人为蜂窝网络开发的 激活Rho、Rac和CDC42以描绘 整合素和生长因子对这些小GTP酶的功能的影响。一个 第二个目标将是确定鸟嘌呤核苷酸交换因子 负责这些GTP酶的整合素依赖的激活， 特别强调的是Vav2蛋白。第三个目标将涉及 磷脂酰肌醇4-磷酸-5-激酶(PIP)作用的研究 5激酶)在肌动蛋白细胞骨架上。这一目标将扩大重要的 申请人的实验室对Rho的能力作出的发现 刺激PIP-5激活酶。利用以下事实： 该激酶家族已被克隆，申请人建议鉴定 与Rho和/或Rac结合从而识别小区域的PIP 5激酶 负责这些相互作用的激酶(S)。我们的想法是用 这些片段作为竞争性抑制物来确定是否封锁 Rho和/或Rac激活PIP5激酶抑制特异性 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.