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*
Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University "La Sapienza", Rome, Italy;
Biotechnology Section, Institute for the Study and Cure of Tumors, Genda, Italy;
Laboratory of Pathophysiology, Regina Elena Cancer Institute, Rome, Italy; and
§
Istituto Mediterraneo di Neuroscienze "Neuromed", Pozzilli, Italy
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
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
FcRIII-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.
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