Regulation of p190 RhoGAP activity by phospholipids

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是促进Rho GTP酶失活的GTP酶激活蛋白（GAP）。然而，对《性别平等行动计划》的监管知之甚少。Settleman博士已经研究了一个主要的RhoGAP的生物学功能，称为p190 RhoGAP，超过10年。最近，Settleman博士和Ligeti博士之间的合作研究表明，磷脂调节p190 RhoGAP的GT3底物特异性-抑制其对Rho GT3的活性，同时促进其对Rac GT3的活性。这一发现表明Rho GTP酶的一种新的调节机制-改变GAP对其GTP酶底物的特异性。新提出的研究将检查磷脂对p190 RhoGAP影响的生物化学性质，并包括可能调节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GAPGTbR相互作用机制的研究。此外，PKC介导的磷酸化的催化GAP结构域的p190在调节GTP酶底物特异性的作用将被检查。预计这些集体研究将揭示对Rho GTP酶的这种新的调节机制的重要见解，该机制可能扩展到在肿瘤起始和进展中发挥作用的许多其他类型的相关GTP酶中的一些。

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.