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© The Rockefeller University Press, 0022-1007/1998/12/2099/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 11, December 7, 1998 2099-2111

Articles

Vav Regulates Peptide-specific Apoptosis in Thymocytes

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

From the * Amgen Institute, {ddagger} 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 {dagger}{dagger} 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-{theta} 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

Address correspondence to Josef M. Penninger, The Amgen Institute, Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, University of Toronto, 620 University Ave., Toronto, Ontario M5G 2C1, Canada. Phone: 416-204-2241; Fax: 416-204-2278; E-mail: jpenning{at}amgen.com

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-{kappa}B, nuclear factor {kappa}B; PI3'K, phosphatidylinositol 3'-kinase; PKC, protein kinase C; SAPK, stress-activated protein kinase; Tg, transgenic.


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