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Originally published In Press as doi:10.1074/jbc.M004386200 on August 22, 2000

J. Biol. Chem., Vol. 275, Issue 45, 35021-35027, November 10, 2000
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The Ras/p120 GTPase-activating Protein (GAP) Interaction Is Regulated by the p120 GAP Pleckstrin Homology Domain*

Jonelle K. DruganDagger , Kelley Rogers-Graham§, Tona Gilmer, Sharon CampbellDagger , and Geoffrey J. Clark||**

From the || Department of Cell and Cancer Biology, NCI, National Institutes of Health, Rockville, Maryland 20850-3300, the § Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599-7365, and the  Department of Cell Biology, Glaxo-Wellcome, Research Triangle Park, North Carolina 27709-3398, and the Dagger  Department of Biochemistry, University of North Carolina, Chapel Hill, North Carolina 27599-7260.

Pleckstrin homology domains are structurally conserved functional domains that can undergo both protein/protein and protein/lipid interactions. Pleckstrin homology domains can mediate inter- and intra-molecular binding events to regulate enzyme activity. They occur in numerous proteins including many that interact with Ras superfamily members, such as p120 GAP. The pleckstrin homology domain of p120 GAP is located in the NH2-terminal, noncatalytic region of p120 GAP. Overexpression of the noncatalytic domains of p120 GAP may modulate Ras signal transduction pathways. Here, we demonstrate that expression of the isolated pleckstrin homology domain of p120 GAP specifically inhibits Ras-mediated signaling and transformation but not normal cellular growth. Furthermore, we show that the pleckstrin homology domain binds the catalytic domain of p120 GAP and interferes with the Ras/GAP interaction. Thus, we suggest that the pleckstrin homology domain of p120 GAP may specifically regulate the interaction of Ras with p120 GAP via competitive intra-molecular binding.

* This work was supported by National Institutes of Health Grants CA72644-10 (to G. J. C.) and CA64569 and CA70308 (to S. L. C.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** Recipient of United States of America Medical Research and Material Command Career Development Award DAMD17-97-1-7050. To whom correspondence should be addressed: Dept. of Cell and Cancer Biology, NCI, National Institutes of Health, 9610 Medical Center Dr., Rockville, MD 20850-3300. Tel.: 301-402-3128, Ext. 307; Fax: 310-402-4422; E-mail: clarkg@pop.nci.nih.gov.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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