title: Phospholipids can switch the GTPase substrate preference of a GTPase-activating protein.
abstract: The major cellular inhibitors of the small GTPases of the Ras superfamily are the GTPase-activating proteins (GAPs), which stimulate the intrinsic GTP hydrolyzing activity of GTPases, thereby inactivating them. The catalytic activity of several GAPs is reportedly inhibited or stimulated by various phospholipids and fatty acids in vitro, indicating a likely physiological role for lipids in regulating small GTPases. We find that the p190 RhoGAP, a potent GAP for the Rho and Rac GTPases, is similarly sensitive to phospholipids. Interestingly, however, several of the tested phospholipids were found to effectively inhibit the RhoGAP activity of p190 but stimulate its RacGAP activity. Thus, phospholipids have the ability to "switch" the GTPase substrate preference of a GAP, thereby providing a novel regulatory mechanism for the small GTPases.
authors.affiliation: Department of Physiology, Semmelweis University, 1444 Budapest, Hungary.
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Ligeti
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Dagher
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Hernandez
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Koleske
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000737:chemistry*; D020690:GTPase-Activating Proteins / Q000737:chemistry* / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006868:Hydrolysis; D007313:Insecta; D008055:Lipids / Q000737:chemistry; D010718:Phosphatidylserines / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction; D012967:Sodium Dodecyl Sulfate / Q000494:pharmacology; D013379:Substrate Specificity
chemical_list: D020690:GTPase-Activating Proteins; D008055:Lipids; D010718:Phosphatidylserines; D010743:Phospholipids; D011994:Recombinant Proteins; C085379:rho GTPase-activating protein; D012967:Sodium Dodecyl Sulfate; D006160:Guanosine Triphosphate; D020558:GTP Phosphohydrolases