Regulation of NK cell-mediated cytotoxicity by the VAV-RAC1 pathway

The Rac-1 guanine nucleotide exchange factor (GEF), Vav, is activated in hematopoietic cells in response to a large variety of stimuli. The downstream signaling events derived from Vav have been primarily characterized as leading to transcription or transformation. However, we report here that Vav and Rac-1 are also key regulators of NK cell-mediated cytotoxicity. Specifically, Vav is tyrosine phosphorylated during the development of antibody-dependent cellular cytotoxicity (ADCC) or natural killing, and overexpression of Vav enhances this killing. In contrast, expression of dominant-negative forms of either Vav or Rac-1 inhibit granule polarization and the subsequent development of NK cell-mediated cytotoxicity. Interestingly, Vav-Rac-1 dependent killing can be abrogated by MHC-recognizing killer cell inhibitory receptors (KIR). Our results therefore suggest that in addition to participating in transcription initiation, Vav and Rac-1 are pivotal regulators of granule exocytosis and cellular cytotoxicity.