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Young-Yun Kong^*,,, Klaus-Dieter Fischer^¶, Martin F. Bachmann^**, Sanjeev Mariathasan^,, Ivona Kozieradzki^*,,, Mai P. Nghiem^*,,, Dennis Bouchard^*,,, Alan Bernstein, Pamela S. Ohashi^,, and Josef M. Penninger^*,,

From the ^* Amgen Institute, 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

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^–/– 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.

Key Words: Vav • negative selection • actin cytoskeleton • signaling transduction • protein kinase C

Y.-Y. Kong and K.-D. Fischer contributed equally to this work.

Abbreviations used: 7-AAD, 7-amino-actinomycin D; β2m, β2-microglobulin; CytD, cytochalasin D; F-actin, filamentous actin; JNK, c-Jun NH₂-terminal kinase; LCMV, lymphocytic choriomeningitis virus; MAPK, mitogen-activated protein kinase; NF-B, nuclear factor B; PI3'K, phosphatidylinositol 3'-kinase; PKC, protein kinase C; SAPK, stress-activated protein kinase; Tg, transgenic.

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