Role for the Rac1 exchange factor Vav in the signaling pathways leading to NK cell cytotoxicity.
Here we investigate the activation of and a possible role for the hematopoietic Rac1 exchange factor, Vav, in the signaling mechanisms leading to NK cell-mediated cytotoxicity. Our data show that direct contact of NK cells with a panel of sensitive tumor targets leads to a rapid and transient tyrosine phosphorylation of Vav and to its association with tyrosine-phosphorylated Syk. Vav tyrosine phosphorylation is also observed following the activation of NK cells through the low-affinity Fc receptor for IgG (Fc gamma RIII). In addition, we demonstrate that both direct and Ab-mediated NK cell binding to target cells result in the activation of nucleotide exchange on endogenous Rac1. Furthermore, Vav antisense oligodeoxynucleotide treatment leads to an impairment of NK cytotoxicity, with Fc gamma RIII-mediated killing being more sensitive to the abrogation of Vav expression. These results provide new insight into the signaling pathways leading to cytotoxic effector function and define a role for Vav in the activation of NK cell-mediated killing.
Galandrini
R
R
Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University La Sapienza, Rome, Italy.
Palmieri
G
G
Piccoli
M
M
Frati
L
L
Santoni
A
A
D000818:Animals; D018797:Cell Cycle Proteins; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D019204:GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav; D017452:Receptors, IgG / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D020744:rac GTP-Binding Proteins
D018797:Cell Cycle Proteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D017452:Receptors, IgG; C496618:VAV1 protein, human; C496619:Vav1 protein, mouse; D014443:Tyrosine; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins