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Published online 12 July 2004. doi:10.1083/jcb.200404166
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 2, 273-282
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Article

Vav GEFs are required for ß2 integrin-dependent functions of neutrophils



M. Angelica Martinez Gakidis1, Xavier Cullere2, Timothy Olson3, Julie L. Wilsbacher1, Bin Zhang2, Sheri L. Moores1, Klaus Ley3, Wojciech Swat4, Tanya Mayadas2, and Joan S. Brugge1

1 Department of Cell Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
2 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
3 University of Virginia Health Sciences Center, Charlottesville, VA 22908
4 Washington University School of Medicine, St. Louis, MO 63110

Address correspondence to Joan S. Brugge, Dept. of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115. Tel.: (617) 432-3974. Fax: (617) 432-3969. email: Joan_Brugge{at}hms.harvard.edu

Integrin regulation of neutrophils is essential for appropriate adhesion and transmigration into tissues. Vav proteins are Rho family guanine nucleotide exchange factors that become tyrosine phosphorylated in response to adhesion. Using Vav1/Vav3-deficient neutrophils (Vav1/3ko), we show that Vav proteins are required for multiple ß2 integrin-dependent functions, including sustained adhesion, spreading, and complement-mediated phagocytosis. These defects are not attributable to a lack of initial ß2 activation as Vav1/3ko neutrophils undergo chemoattractant-induced arrest on intercellular adhesion molecule-1 under flow. Accordingly, in vivo, Vav1/3ko leukocytes arrest on venular endothelium yet are unable to sustain adherence. Thus, Vav proteins are specifically required for stable adhesion. ß2-induced activation of Cdc42, Rac1, and RhoA is defective in Vav1/3ko neutrophils, and phosphorylation of Pyk2, paxillin, and Akt is also significantly reduced. In contrast, Vav proteins are largely dispensable for G protein-coupled receptor–induced signaling events and chemotaxis. Thus, Vav proteins play an essential role coupling ß2 to Rho GTPases and regulating multiple integrin-induced events important in leukocyte adhesion and phagocytosis.

Key Words: integrins; cell adhesion; Rho GTPases; chemotaxis; phagocytosis

Abbreviations used in this paper: AAM, adhesion assay media; fMLP, formyl-Met-Leu-Phe; GEF, guanine nucleotide exchange factor; GPCR, G protein-coupled receptor; ICAM, intercellular adhesion molecule; IRR, immune response receptor; LTB4, leukotriene B4; MLC, myosin light chain; SFK, Src family kinase; TCR, T cell receptor.


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