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J. Biol. Chem., Vol. 283, Issue 6, 3023-3030, February 8, 2008

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Activity of the Bcr GTPase-activating Domain Is Regulated through Direct Protein/Protein Interaction with the Rho Guanine Nucleotide Dissociation Inhibitor^*

Soo-Mi Kweon, Young Jin Cho¹, Parviz Minoo², John Groffen^¶, and Nora Heisterkamp^¶3

From the Section of Molecular Carcinogenesis, Division of Hematology/Oncology, The Saban Research Institute, Childrens Hospital Los Angeles, Los Angeles, California 90027 and the Departments of Pediatrics and ^¶Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033

The cycling of Rac GTPases, alternating between an active GTP- and an inactive GDP-bound state, is controlled by guanine nucleotide exchange factors, GTPase-activating proteins (GAPs), and guanine nucleotide dissociation inhibitors (GDIs). Little is known about how these controlling activities are coordinated. Studies using null mutant mice have demonstrated that Bcr and Abr are two physiologically important GAPs for Rac. Here, we report that in the presence of RhoGDI, Bcr is unable to convert Rac-GTP to Rac-GDP because RhoGDI forms a direct protein complex with Bcr. Interestingly, RhoGDI binds to the GAP domain in Bcr and Abr, a domain that also binds to Rac-GTP and catalyzes conversion of the bound GTP to GDP on Rac. The presence of activated Rac diminished the Bcr/RhoGDI interaction. Moreover, a Bcr mutant that lacks the ability to promote hydrolysis of Rac-GTP bound to its GAP domain did not bind to RhoGDI in cell lysates, indicating that binding of RhoGDI and Rac-GTP to the Bcr GAP domain is mutually exclusive. Our results provide the first identification of a protein that regulates BcrGAP activity.

Received for publication, July 5, 2007 , and in revised form, November 26, 2007.

^* This work was supported by United States Public Health Service Grants HL071945 (to J. G.) and HL060231 (to P. M., J. G., and N. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–3.

This article was selected as a Paper of the Week.

¹ Present address: Mary Babb Randolph Cancer Center, University of West Virginia, Morgantown, WV 26505.

² Hastings Foundation Professor of Pediatrics.

³ To whom correspondence should be addressed: Div. of Hematology/Oncology, Ms#54, Childrens Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027. Tel.: 323-361-4595; Fax: 323-671-3613; E-mail: heisterk{at}hsc.usc.edu.

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