Vav GEFs are required for β2 integrin-dependent functions of neutrophils

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 β2 integrin-dependent functions, including sustained adhesion, spreading, and complement-mediated phagocytosis. These defects are not attributable to a lack of initial β2 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. β2-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 β2 to Rho GTPases and regulating multiple integrin-induced events important in leukocyte adhesion and phagocytosis.

Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase

“…6), suggesting that there is selective pressure to maintain this residue. Functional activation of neutrophils and macrophages via integrins or Fcγ receptors (FcγR) is markedly impaired in mice lacking both Vav1 and Vav3 (23)(24)(25), consistent with the finding that these are the main Vav isoforms expressed by these cells (23,24). Vav1 residues E509, N510, E556, and G559 in the ZF domain, predicted to interact with NCF2 His-389 (Fig.…”

The Src Family Kinases Hck and Fgr Regulate Neutrophil Responses to N-Formyl-Methionyl-Leucyl-Phenylalanine

“…36 and references contained therein), are relevant players in the integrin-dependent organization of actin-bound protein complexes. Despite the fact that regulation of integrin affinity by chemoattractants is not dependent on Hck and Fgr (71), firm adhesion to integrin ligands was recently reported to be strictly dependent on Hck and Fgr, as well as Vav proteins both in vitro and in vivo (71)(72)(73). Hence, one step of neutrophil recruitment that may be regulated by Src family kinases is certainly stabilization of adhesion.…”

Oncogenic Vav1 induces Rac-dependent apoptosis via inhibition of Bcl-2 family proteins and collaborates with p53 deficiency to promote hematopoietic progenitor cell proliferation

“…Vav1 À/À mast cells display impaired FceR-mediated degranulation and cytokine production (Manetz et al, 2001). Also, it has recently been shown that Vav1 and Vav3 are essential for b2 integrin-dependent neutrophil adhesion and phagocytosis via b2 integrin signaling through Rho GTPases (Gakidis et al, 2004).…”