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PMID: 15249579 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Vav GEFs are required for beta2 integrin-dependent functions of neutrophils.

The Journal of cell biology ·Vol. 166 ·No. 2 ·2004-07-19 ·Pages 273-82

Gakidis MA, Cullere X, Olson T, Wilsbacher JL, Zhang B, Moores SL, Ley K, Swat W, Mayadas T, Brugge JS

Abstract

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 beta2 integrin-dependent functions, including sustained adhesion, spreading, and complement-mediated phagocytosis. These defects are not attributable to a lack of initial beta2 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. beta2-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 beta2 to Rho GTPases and regulating multiple integrin-induced events important in leukocyte adhesion and phagocytosis.

MeSH Terms
Animals CD18 Antigens/physiology Cell Adhesion Cell Cycle Proteins Chemotaxis, Leukocyte Endothelium, Vascular/cytology Guanine Nucleotide Exchange Factors/genetics,physiology Mice Mice, Knockout Neutrophils/chemistry,physiology Oncogene Proteins/genetics,physiology Phagocytosis Proto-Oncogene Proteins/genetics,physiology Proto-Oncogene Proteins c-vav Signal Transduction rho GTP-Binding Proteins/metabolism
Chemicals
CD18 Antigens Cell Cycle Proteins Guanine Nucleotide Exchange Factors Oncogene Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-vav Vav1 protein, mouse Vav2 protein, mouse Vav3 protein, mouse rho GTP-Binding Proteins
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Gakidis M Angelica Martinez
Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA.
Cullere Xavier
Olson Timothy
Wilsbacher Julie L
Zhang Bin
Moores Sheri L
Ley Klaus
Swat Wojciech
Mayadas Tanya
Brugge Joan S
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200404166
Published
2004-07-19
Epub
2004-00-12
Pages
273-82
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2172310
Subset
IM
Grants
NHLBI NIH HHS · HL36028 · United States
NHLBI NIH HHS · R01 HL065095 · United States
NHLBI NIH HHS · P01 HL036028 · United States
NHLBI NIH HHS · HL059561 · United States
NCI NIH HHS · R01 CA078773 · United States
NHLBI NIH HHS · HL65095 · United States
NHLBI NIH HHS · P01 HL059561 · United States
NCI NIH HHS · CA78773 · United States
External Links
PubMed source DOI: 10.1083/jcb.200404166 PMC Full Text View journal details
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