Regulation of p190 RhoGAP activity by phospholipids

磷脂对 p190 RhoGAP 活性的调节

• 批准号: 6783737
• 负责人: JEFFREY E SETTLEMAN
• 金额: $ 4.03万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6783737
• 关键词: Baculoviridae; Drosophilidae; Europe; biological signal transduction; cell differentiation; enzyme activity; enzyme substrate; guanosinetriphosphatase activating protein; guanosinetriphosphatases; histogenesis; phospholipids; phosphorylation; protein kinase C; protein protein interaction; protein structure function; site directed mutagenesis; tissue /cell culture

DESCRIPTION (provided by applicant) The small GTPases of the Ras-related Rho family have been implicated in the progression of human tumors to an invasive metastatic state. Among the key regulators of these proteins are the GTPase activating proteins (GAPs), which promote the inactivation of Rho GTPases. However, relatively little is known regarding the regulation of the GAPs. Dr. Settleman has been investigating the biological function of one of the major RhoGAPs, known as p190 RhoGAP, for more than 10 years. Recently, collaborative efforts between Drs. Settleman and Ligeti have revealed that phospholipids regulate the GTPase substrate specificity of p190 RhoGAP--inhibiting its activity toward the Rho GTPase, while promoting its activity toward the Rac GTPase. This finding indicates a novel regulatory mechanism for the Rho GTPases--altering the specificity of GAPs for their GTPase substrates. The newly proposed studies will examine the biochemical nature of the phospholipid effects on p190 RhoGAP, and include an analysis of the major classes of cellular phospholipids that could potentially regulate p190 RhoGAP, a mutational analysis to identify the lipid-interacting domain, and studies to address the mechanism by which lipids affect GAPGTPase interactions. In addition, the role of PKC-mediated phosphorylation of the catalytic GAP domain of p190 in regulating GTPase substrate specificity will be examined. It is anticipated that these collective studies will reveal important insights into this novel regulatory mechanism for Rho GTPases that could potentially extend to some of the many other classes of related GTPases that play a role in tumor initiation and progression.

描述（由申请人提供） Ras 相关 Rho 家族的小 GTP 酶与人类肿瘤向侵袭性转移状态的进展有关。这些蛋白质的关键调节因子包括 GTP 酶激活蛋白 (GAP)，它可促进 Rho GTP 酶失活。然而，人们对 GAP 的监管知之甚少。 Settleman 博士十多年来一直致力于研究主要 RhoGAP 之一（即 p190 RhoGAP）的生物学功能。最近，博士之间的合作努力。 Settleman 和 Ligeti 揭示，磷脂调节 p190 RhoGAP 的 GTP 酶底物特异性，抑制其对 Rho GTP 酶的活性，同时促进其对 Rac GTP 酶的活性。这一发现表明了 Rho GTPases 的一种新的调控机制——改变 GAP 对其 GTPase 底物的特异性。新提出的研究将检查磷脂对 p190 RhoGAP 影响的生化性质，包括对可能调节 p190 RhoGAP 的主要细胞磷脂类别的分析、识别脂质相互作用结构域的突变分析，以及解决脂质影响 GAPGTPase 相互作用的机制的研究。此外，还将检查 PKC 介导的 p190 催化 GAP 结构域磷酸化在调节 GTPase 底物特异性中的作用。预计这些集体研究将揭示对 Rho GTPases 这种新型调节机制的重要见解，该机制可能会扩展到在肿瘤发生和进展中发挥作用的许多其他类别的相关 GTPases 中的一些。