Vav1, the hematopoietic Rho/Rac guanine nucleotide exchange factor regulates FMLP-activated neutrophil functions

초록

Vav1 is a hematopoietic-specific Rho/Rac guanine nucleotide exchange factor (GEF) that plays a prominent role in responses to multi-subunit immune recognition receptors in lymphoid cells. Activated Rho family GTPases are critical participants in neutrophil signaling cascades initiated by binding of FMLP and other chemoattractants to their cognate G protein-coupled receptors. We therefore investigated whether Vav1 regulates chemoattractant-induced responses in neutrophils. We found that superoxide production elicited by FMLP in Vav1-/- murine neutrophils isolated from either bone marrow or from peritoneal exudates was substantially reduced compared to wild-type. F-actin generation in FMLP-stimulated Vav1-/- neutrophils was also markedly reduced while it was normal in response to interleukin 8 or leukotriene B4. FMLP induced tyrosine phosphorylation of Vav1 whereas interleukin 8 or leukotriene B4 did not, was also reduced. Neutrophil chemotaxis in vitro and neutrophil mobilization into peripheral blood in vivo elicited by FMLP were both decreased in Vav1-/- mice. Hence, this study defines a new role for Vav1 in regulating granulocytic leukocytes as well as linking Vav1 to specific cellular responses downstream of a seven transmembrane domain receptors.