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The Rho-Family GTP Exchange Factor Vav Is a Critical Transducer of T Cell Receptor Signals to the Calcium, ERK, and NF-κ B Pathways
Patrick S. Costello, Alice E. Walters, P. Joseph Mee, Martin Turner, Lucinda F. Reynolds, Antonella Prisco, Nitza Sarner, Rose Zamoyska and Victor L. J. Tybulewicz
Proceedings of the National Academy of Sciences of the United States of America
Vol. 96, No. 6 (Mar. 16, 1999), pp. 3035-3040
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/47484
Page Count: 6
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Vav is a GTP/GDP exchange factor (GEF) for members of the Rho-family of GTPases that is rapidly tyrosine-phosphorylated engagement of the T cell receptor (TCR), suggesting that it may transduce signals from the receptor. T cells from mice made Vav-deficient by gene targeting (Vav-/-) fail to proliferate in response to TCR stimulation because they fail to secrete IL-2. We now show that this is due at least in part to the failure to initiate 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 extracellular signal-regulated mitogen-activated protein kinases and in the activation of the NF-κ B transcription factor. Finally, we show that the greatly reduced TCR-induced calcium flux of Vav-deficient T cells is an important cause of their proliferative defect, because restoration of the calcium flux with a calcium ionophore reverses the phenotype.
Proceedings of the National Academy of Sciences of the United States of America © 1999 National Academy of Sciences