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J. Biol. Chem., Vol. 278, Issue 36, 34641-34653, September 5, 2003
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GC-GAP, a Rho Family GTPase-activating Protein That Interacts with Signaling Adapters Gab1 and Gab2*
¶ ||
From the
Burnham Institute, La Jolla, California
92037 and the Department of Biochemistry and
Molecular Biology, Indiana University School of Medicine, Indianapolis,
Indiana 46202
Gab1 and Gab2 are scaffolding proteins acting downstream of cell surface
receptors and interact with a variety of cytoplasmic signaling proteins such
as Grb2, Shp-2, phosphatidylinositol 3-kinase, Shc, and Crk. To identify new
binding partners for GAB proteins and better understand their functions, we
performed a yeast two-hybrid screening with hGab2-(120–587) as bait.
This work led to identification of a novel GTPase-activating protein (GAP) for
Rho family GTPases. The GAP domain shows high similarity to the recently
cloned CdGAP and displays activity toward RhoA, Rac1, and Cdc42 in
vitro. The protein was named GC-GAP for its ability to interact with GAB
proteins and its activity toward Rac and Cdc42. GC-GAP is predominantly
expressed in the brain with low levels detected in other tissues. Antibodies
directed against GC-GAP recognized a protein of 
200 kDa. Expression of
GC-GAP in 293T cells led to a reduction in active Rac1 and Cdc42 levels but
not RhoA. Suppression of GC-GAP expression by siRNA inhibited proliferation of
C6 astroglioma cells. In addition, GC-GAP contains several classic
proline-rich motifs, and it interacts with the first SH3 domain of Crk and
full-length Nck in vitro. We propose that Gab1 and Gab2 in
cooperation with other adapter molecules might regulate the cellular
localization of GC-GAP under specific stimuli, acting to regulate precisely
Rac and Cdc42 activities. Given that GC-GAP is specifically expressed in the
nervous system and that it is localized to the dendritic processes of cultured
neurons, GC-GAP may play a role in dendritic morphogenesis and also possibly
in neural/glial cell proliferation.
Received for publication, May 2, 2003 , and in revised form, June 15, 2003.
* This work was supported by National Institutes of Health Grants R01HL66208 and R01GM53660 (to G. S. F.). 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.
¶ Present address: The Salk Institute, 10010 N. Torrey Pines Rd., La Jolla, CA 92037.
|| To whom the correspondence should be addressed: The Burnham Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-713-6265; Fax: 858-713-6274; E-mail: gfeng{at}burnham.org.
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