Vav-1 and the IKK alpha subunit of I kappa B kinase functionally associate to induce NF-kappa B activation in response to CD28 engagement.
We have recently observed that CD28 engagement initiates a signaling pathway leading to the activation of I kappa B kinase (IKK) complex and, consequently, to NF-kappa B activation, and we identified Vav-1 as an important mediator of this function. Here we report for the first time that Vav-1 constitutively associates with IKK alpha in both Jurkat and primary CD4(+) T cells. Vav-1/IKK alpha association is mediated by their helix-loop-helix domains, does not involve IKK beta, and is functionally relevant in that Vav-1-associated IKK alpha kinase activity is increased following CD28 engagement by B7. Moreover, we demonstrate that CD28-induced NF-kappa B activation is augmented by both IKK alpha and Vav-1, but not IKK beta. Confocal microscopy showed that endogenous Vav-1 and IKK alpha, but not IKK beta, were recruited to the membrane and colocalized in response to CD28 stimulation. Taken together, these data evidence that Vav-1 plays a key role in the control of NF-kappa B pathway by targeting IKK alpha in the T cell membrane and favoring its activation in response to CD28 stimulation.
Piccolella
Enza
E
Department of Cellular and Developmental Biology, University of Rome La Sapienza, Rome, Italy.
Spadaro
Francesca
F
Ramoni
Carlo
C
Marinari
Barbara
B
Costanzo
Antonio
A
Levrero
Massimo
M
Thomson
Lesley
L
Abraham
Robert T
RT
Tuosto
Loretta
L
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018122:B7-1 Antigen / Q000494:pharmacology; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D018797:Cell Cycle Proteins; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D018257:Helix-Loop-Helix Motifs / Q000276:immunology; D006801:Humans; D051550:I-kappa B Kinase; D019169:Jurkat Cells; D007739:L Cells; D008213:Lymphocyte Activation; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000172:deficiency / Q000235:genetics / Q000502:physiology
D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; D018106:CD28 Antigens; D018797:Cell Cycle Proteins; D016328:NF-kappa B; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D017260:Receptor-CD3 Complex, Antigen, T-Cell; C496618:VAV1 protein, human; C496619:Vav1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse