The Rho-family GTP exchange factor Vav is a critical transducer of T cell receptor signals to the calcium, ERK, and NF-kappa B pathways

Vav is a GTP/GDP er;change factor (GFF) for members of the Rho-family of GT Pases that is rapidly tyrosine-phosphorylated after engagement of the T cel l receptor (TCR), suggesting that it may transduce signals from the recepto r. T cells from mice made Vav-deficient by gene targeting (Vav(-/-)) fail t o proliferate in response to TCR stimulation because they fail to secrete I L-2, We now show that this is due at least in part to the failure to initia te IL-2 gene transcription. Furthermore, we analyze TCR-proximal signaling pathways in Vav(-/-) T cells and show that despite normal activation of the Lck and ZAP-70 tyrosine kinases, the mutant cells have specific defects in TCR-induced intracellular calcium fluxes, in the activation of extracellul ar signal-regulated mitogen-activated protein kinases and in the activation of the NF-kappa B transcription factor. Finally, we show that the greatly reduced TCR-induced calcium flux of Vav-deficient T cells is an important c ause of their proliferative defect, because restoration of the calcium flux with a calcium ionophore reverses the phenotype.