Vav cooperates with CD28 to induce NF-kappaB activation via a pathway involving Rac-1 and mitogen-activated kinase kinase 1.
CD28-delivered costimulatory signals are required to induce NF-kappaB activation in response to TCR stimulation. We have recently demonstrated that the mitogen-activated kinase kinase 1 (MEKK1), a kinase known to regulate the c-jun N-terminal kinase (JNK) pathway, is also involved in the CD28- and TCR-induced inhibitor of kappaB factor (IkappaB) kinases (IKK) and NF-kappaB activation. Searching for molecules that couple TCR and CD28 to MEKK1, we found that the guanine nucleotide exchange factor Vav synergized with CD28 stimulation in Jurkat cells to induce NF-kappaB transcriptional activity through the activation of IKKalpha and IKKbeta. Dominant negative mutants of Vav inhibited TCR- and CD28-NF-kappaB-dependent transcription by interfering with the activation of the IKK complex. Blocking Rac signaling downstream of Vav by dominant negative RacN17 exerts similar effects on IKK and NF-kappaB activation after TCR/CD28 stimulation. Finally, Vav-induced NF-kappaB activation in CD28 costimulated cells was inhibited by dominant negative MEKK(KM). These results identify Vav, Rac-1 and MEKK1 as components of a common pathway regulating both NF-kappaB and AP-1 that contributes to full activation of the CD28 response element (CD28RE).
Marinari
Barbara
B
Department of Cellular and Developmental Biology, University of Rome La Sapienza, Via del Sardi 70, I-00185 Rome, Italy.
Costanzo
Antonio
A
Viola
Antonella
A
Michel
Frederique
F
Mangino
Giorgio
G
Acuto
Oreste
O
Levrero
Massimo
M
Piccolella
Enza
E
Tuosto
Loretta
L
D018106:CD28 Antigens / Q000378:metabolism*; D018797:Cell Cycle Proteins; D017930:Genes, Reporter; D006801:Humans; D051550:I-kappa B Kinase; D019169:Jurkat Cells; D008156:Luciferases / Q000235:genetics; D008213:Lymphocyte Activation; D048728:MAP Kinase Kinase Kinase 1; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D018106:CD28 Antigens; D018797:Cell Cycle Proteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; C496618:VAV1 protein, human; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D020830:rac1 GTP-Binding Protein