Vav regulates peptide-specific apoptosis in thymocytes.
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.
Kong
Y Y
YY
Amgen Institute, University of Toronto, Toronto, Ontario, Canada M5G 2C1.
Fischer
K D
KD
Bachmann
M F
MF
Mariathasan
S
S
Kozieradzki
I
I
Nghiem
M P
MP
Bouchard
D
D
Bernstein
A
A
Ohashi
P S
PS
Penninger
J M
JM
D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D018797:Cell Cycle Proteins; D016207:Cytokines / Q000276:immunology; D003599:Cytoskeleton / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051567:Proto-Oncogene Proteins c-vav; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology*
D018106:CD28 Antigens; D017252:CD3 Complex; D018797:Cell Cycle Proteins; D016207:Cytokines; D010455:Peptides; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; C496619:Vav1 protein, mouse