Journal
JOURNAL OF CELL BIOLOGY
Volume 166, Issue 2, Pages 273-282Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200404166
Keywords
integrins; cell adhesion; Rho GTPases; chemotaxis; phagocytosis
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Funding
- NCI NIH HHS [R01 CA078773, CA78773] Funding Source: Medline
- NHLBI NIH HHS [HL36028, R01 HL065095, P01 HL036028, HL059561, P01 HL059561, HL65095] Funding Source: Medline
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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 (Vav1/3(ko)), we show that Vav proteins are required for multiple beta(2) integrin-dependent functions, including sustained adhesion, spreading, and complement-mediated phagocytosis. These defects are not attributable to a lack of initial beta(2) activation as Vav1/3(ko) neutrophils undergo chemoattractant-induced arrest on intercellular adhesion molecule-1 under flow. Accordingly, in vivo, Vav1/3(ko) leukocytes arrest on venular endothelium yet are unable to sustain adherence. Thus, Vav proteins are specifically required for stable adhesion. beta(2)-induced activation of Cdc42, Rac1, and RhoA is defective in Vav1/3(ko) 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 beta(2) to Rho GTPases and regulating multiple integrin-induced events important in leukocyte adhesion and phagocytosis.
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