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J. Biol. Chem., Vol. 283, Issue 49, 34002-34012, December 5, 2008

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FGD2, a CDC42-specific Exchange Factor Expressed by Antigen-presenting Cells, Localizes to Early Endosomes and Active Membrane Ruffles^*

From the Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California 92037

Members of the Fgd (faciogenital dysplasia) gene family encode a group of critical guanine nucleotide exchange factors (GEFs), which, by specifically activating Cdc42, control cytoskeleton-dependent membrane rearrangements. In its first characterization, we find that FGD2 is expressed in antigen-presenting cells, including B lymphocytes, macrophages, and dendritic cells. In the B lymphocyte lineage, FGD2 levels change with developmental stage. In both mature splenic B cells and immature bone marrow B cells, FGD2 expression is suppressed upon activation through the B cell antigen receptor. FGD2 has a complex intracellular localization, with concentrations found in membrane ruffles and early endosomes. Although endosomal localization of FGD2 is dependent on a conserved FYVE domain, its C-terminal pleckstrin homology domain mediates recruitment to membrane ruffles. FGD2 overexpression promotes the activation of Cdc42 and leads to elevated JNK1 activity in a Cdc42- but not Rac1-dependent fashion. These findings are consistent with a role of FGD2 in leukocyte signaling and vesicle trafficking in cells specialized to present antigen in the immune system.

Received for publication, May 23, 2008 , and in revised form, September 22, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01AI033608 and R01AI067403. 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 and 2.

¹ Both of these authors contributed equally to this work.

² Present address: Cebix Inc., 1298 Prospect St., Suite 2a, La Jolla, CA 92037.

³ To whom correspondence should be addressed: 10550 N. Torrey Pines Rd., IMM-29, La Jolla, CA 92037. Tel.: 858-784-9551; Fax: 858-784-9554; E-mail: agavin{at}scripps.edu.

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