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J. Exp. Med.,
Volume 188, Number 11, December 7, 1998 2099-2111
By
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From the * Amgen Institute, The protooncogene Vav functions as a GDP/GTP exchange factor (GEF) for Rho-like small
GTPases involved in cytoskeletal reorganization and cytokine production in T cells. Gene-targeted mice lacking Vav have a severe defect in positive and negative selection of T cell antigen
receptor transgenic thymocytes in vivo, and vav Ontario Cancer Institute, § Department of Medical Biophysics and
Department of Immunology, and 
Department of Medical Genetics, University of Toronto, Toronto,
Ontario, Canada M5G 2C1; the ¶ Institute for Radiation and Cell Research, University of
Würzburg, D-97078 Würzburg, Germany; the ** Basel Institute for Immunology, CH 4005 Basel,
Switzerland; and the Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto,
Ontario, Canada M5G 1X5
/ thymocytes are completely resistant to
peptide-specific and anti-CD3/anti-CD28-mediated apoptosis. Vav acts upstream of mitochondrial pore opening and caspase activation. Biochemically, Vav regulates peptide-specific Ca2+ mobilization and actin polymerization. Peptide-specific cell death was blocked both by
cytochalasin D inhibition of actin polymerization and by inhibition of protein kinase C (PKC).
Activation of PKC with phorbol ester restored peptide-specific apoptosis in vav/ thymocytes. Vav was found to bind constitutively to PKC-
in thymocytes. Our results indicate
that peptide-triggered thymocyte apoptosis is mediated via Vav activation, changes in the actin cytoskeleton, and subsequent activation of a PKC isoform.
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