Vav GEFs are required for beta2 integrin-dependent functions of neutrophils.
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.
Gakidis
M Angelica Martinez
MA
Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA.
Cullere
Xavier
X
Olson
Timothy
T
Wilsbacher
Julie L
JL
Zhang
Bin
B
Moores
Sheri L
SL
Ley
Klaus
K
Swat
Wojciech
W
Mayadas
Tanya
T
Brugge
Joan S
JS
D000818:Animals; D018821:CD18 Antigens / Q000502:physiology*; D002448:Cell Adhesion; D018797:Cell Cycle Proteins; D002634:Chemotaxis, Leukocyte; D004730:Endothelium, Vascular / Q000166:cytology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000737:chemistry / Q000502:physiology*; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology; D010587:Phagocytosis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D051567:Proto-Oncogene Proteins c-vav; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D018821:CD18 Antigens; D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; C496619:Vav1 protein, mouse; C490565:Vav2 protein, mouse; C496622:Vav3 protein, mouse; D020741:rho GTP-Binding Proteins