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J. Biol. Chem., Vol. 278, Issue 43, 41661-41669, October 24, 2003
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From the Section of Hematology/Oncology, Department of Pediatrics, Biochemistry and Molecular Biology, Herman B Wells Center for Pediatric Research, Indiana University of School of Medicine, Indianapolis, Indiana 46202
Herein we report that, despite the similarity of Rac2 to Rac1 (92% amino acid identity), macrophages derived from Rac2/ mice, which continue to express Rac1, display a marked defect in
v
3/
v
5 and
4
1 integrin-directed migration measured on vitronectin and fibronectin fragments (FN-H296), respectively. In contrast, mouse embryo fibroblasts derived from the Rac2 knockout mice utilize Rac1 for migration via
v
3/
v
5 and
4
1. The genetic reconstitution of bone marrow-derived macrophages (BMM
) with Rac2 restores the integrin-dependent migration of Rac2-deficient macrophages on vitronectin (VN) and FN-H296. The levels of GTP-Rac2 generated upon specific integrin engagement in wild type macrophages parallels the phenotypic defect observed in Rac2-deficient macrophages; i.e. FN-H296,
4
1 > VN,
v
3/
v
5 > FN-CH271,
5
1 > intact FN. In a COS7 cell system, the expression of Syk kinase alone is sufficient to convert the
4
1 migration response to Rac2 dependence. Therefore, we present the first evidence that the
4
1 receptor in blood cells has evolved a Syk-Rac2 signaling axis to transmit signals required for integrin-directed migration suggesting that Syk kinase in part encodes myeloid Rac2 specificity in vivo.
Received for publication, June 18, 2003 , and in revised form, August 4, 2003.
* This work was supported by National Institutes of Health Grants CA81403 and CA94233 (to D. L. D.) and by the Riley Research Foundation. 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.
To whom correspondence should be addressed: Herman B Wells Center for Pediatric Research, Department of Pediatrics, Biochemistry and Molecular Biology, Indiana University of School of Medicine, 1044 W. Walnut St., Indianapolis, IN 46202. Tel.: 317-278-3718; Fax: 317-274-8679; E-mail: ddurden{at}iupui.edu.
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