Regulation of p190 RhoGAP activity by phospholipids

磷脂对 p190 RhoGAP 活性的调节

• 批准号: 6881133
• 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/6881133
• 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） 与RAS相关的RHO家族的小GTPase与人类肿瘤发展为侵入性转移状态有关。这些蛋白质的关键调节剂中有GTPase激活蛋白（GAP），它们促进了Rho GTPases的失活。但是，关于差距的调节知之甚少。 Settleman博士一直在研究10年以上的主要Rhogap（称为P190 Rhogap）的生物学功能。最近，DRS之间的合作努力。 Settleman和Ligeti透露，磷脂调节p190 rhogap的GTPase底物特异性 - 抑制其对Rho GTPase的活性，同时促进其对RAC GTPase的活性。这一发现表明了Rho GTPases的一种新型调节机制 - 改变了其GTPase底物的间隙的特异性。新提出的研究将检查磷脂对P190 Rhogap的生化性质，并包括对主要类细胞磷脂的分析，这些分析可能会调节P190 RhoGap，这是一种可能调节脂质相互作用域的突变分析，以及解决脂质相互作用域，以解决研究以解决脂质相互作用域，以解决研究以解决脂质磷脂。脂质影响GAPGTPase相互作用的机制。此外，将检查PKC介导的P190催化间隙结构域在调节GTPase底物特异性中的作用。可以预料，这些集体研究将揭示对这种新型调节机制的重要见解，这些调节机制可能会扩展到许多其他相关的GTPases中的一些，这些类别在肿瘤起始和进展中起着作用。