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-θ 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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7 December 1998
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December 07 1998
Vav Regulates Peptide-specific Apoptosis in Thymocytes
Young-Yun Kong,
Young-Yun Kong
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
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Klaus-Dieter Fischer,
Klaus-Dieter Fischer
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
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Martin F. Bachmann,
Martin F. Bachmann
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
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Sanjeev Mariathasan,
Sanjeev Mariathasan
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
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Ivona Kozieradzki,
Ivona Kozieradzki
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
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Mai P. Nghiem,
Mai P. Nghiem
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
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Dennis Bouchard,
Dennis Bouchard
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
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Alan Bernstein,
Alan Bernstein
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
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Pamela S. Ohashi,
Pamela S. Ohashi
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
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Josef M. Penninger
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
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Young-Yun Kong
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
Klaus-Dieter Fischer
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
Martin F. Bachmann
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
Sanjeev Mariathasan
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
Ivona Kozieradzki
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
Mai P. Nghiem
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
Dennis Bouchard
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
Alan Bernstein
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
Pamela S. Ohashi
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
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
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: [email protected]
Y.-Y. Kong and K.-D. Fischer contributed equally to this work.
Received:
July 07 1998
Revision Received:
September 10 1998
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 188 (11): 2099–2111.
Article history
Received:
July 07 1998
Revision Received:
September 10 1998
Citation
Young-Yun Kong, Klaus-Dieter Fischer, Martin F. Bachmann, Sanjeev Mariathasan, Ivona Kozieradzki, Mai P. Nghiem, Dennis Bouchard, Alan Bernstein, Pamela S. Ohashi, Josef M. Penninger; Vav Regulates Peptide-specific Apoptosis in Thymocytes . J Exp Med 7 December 1998; 188 (11): 2099–2111. doi: https://doi.org/10.1084/jem.188.11.2099
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