Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology
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B7-1 Antigen / pharmacology
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CD28 Antigens / immunology
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CD28 Antigens / metabolism
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CD28 Antigens / physiology*
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CD4-Positive T-Lymphocytes / enzymology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Cell Cycle Proteins*
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Cell Membrane / immunology
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Cell Membrane / metabolism
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Cells, Cultured
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Helix-Loop-Helix Motifs / immunology
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Humans
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I-kappa B Kinase
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Jurkat Cells
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L Cells
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Lymphocyte Activation
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Mice
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NF-kappa B / metabolism*
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Protein Serine-Threonine Kinases / metabolism
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Protein Serine-Threonine Kinases / physiology*
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Protein Structure, Tertiary
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Protein Subunits / metabolism
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Protein Subunits / physiology*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-vav
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Receptor-CD3 Complex, Antigen, T-Cell / deficiency
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Receptor-CD3 Complex, Antigen, T-Cell / genetics
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Receptor-CD3 Complex, Antigen, T-Cell / physiology
Substances
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Antibodies, Monoclonal
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B7-1 Antigen
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CD28 Antigens
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Cell Cycle Proteins
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NF-kappa B
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Protein Subunits
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-vav
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Receptor-CD3 Complex, Antigen, T-Cell
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VAV1 protein, human
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Vav1 protein, mouse
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Protein Serine-Threonine Kinases
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CHUK protein, human
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Chuk protein, mouse
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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Ikbkb protein, mouse
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Ikbke protein, mouse