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.
Highlights
From the ‡Department of Physiology, Semmelweis University, 1444 Budapest, Hungary, §Laboratoire de Biochimie, CEA Grenoble, 38054 Grenoble, France, ¶Department of Molecular Biochemistry and Biophysics, Yale University, New Haven, Connecticut 06520, and ʈMassachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129
We find that the p190 RhoGAP, a potent GTPase-activating proteins (GAPs) for the Rho and Rac GTPases, is sensitive to phospholipids
Phosphatidylserine Inhibits p190 RhoGAP Activity and Promotes RacGAP Activity—We tested the possibility that phospholipids can regulate the catalytic activity of the p190 RhoGAPs
Summary
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. GTPase-activating proteins (GAPs) for the small GTPases of the Ras superfamily are potent stimulators of intrinsic GTP hydrolyzing activity and are the major down-modulators of GTPase function. Some of the phospholipids are potent inhibitors of p190 RhoGAP activity but are stimulators of its RacGAP activity This finding indicates that phospholipids have the potential to “switch” the GTPase substrate preference for a GAP, thereby providing a novel regulatory mechanism for determining signaling specificity in vivo
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