Abstract
The p38 MAP kinase (MAPK) is phosphorylated and activated by upstream MAPK kinases. T cells have an alternative pathway in which T cell receptor-activated tyrosine kinase Zap70 phosphorylates p38 on Tyr323. Mice lacking Gadd45alpha, a small p38-binding molecule, develop a lupus-like autoimmune disease. Here we show that resting T cells but not B cells from Gadd45a(-/-) mice had spontaneously increased p38 activity in the absence of 'upstream' MAPK kinase activation. The p38 from resting Gadd45a(-/-) T cells was spontaneously phosphorylated on Tyr323, and its activity was specifically inhibited by recombinant Gadd45alpha in vitro. Thus, constitutive activation of T cell p38 through the alternative pathway is prevented by Gadd45alpha, the absence of which results in p38 activation, T cell hyperproliferation and autoimmunity.
MeSH terms
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Animals
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Cell Cycle Proteins / immunology*
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Cell Cycle Proteins / metabolism
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Enzyme Activation
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MAP Kinase Signaling System / immunology*
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Mice
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Mice, Knockout
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Nuclear Proteins / immunology*
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Nuclear Proteins / metabolism
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Phosphorylation
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Protein-Tyrosine Kinases / immunology
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Protein-Tyrosine Kinases / metabolism
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Receptors, Antigen, T-Cell / immunology
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T-Lymphocytes / enzymology*
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T-Lymphocytes / immunology*
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Tyrosine / immunology
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Tyrosine / metabolism
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ZAP-70 Protein-Tyrosine Kinase
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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p38 Mitogen-Activated Protein Kinases / immunology
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Cell Cycle Proteins
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Gadd45a protein, mouse
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Nuclear Proteins
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Receptors, Antigen, T-Cell
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Tyrosine
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Protein-Tyrosine Kinases
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ZAP-70 Protein-Tyrosine Kinase
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Zap70 protein, mouse
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p38 Mitogen-Activated Protein Kinases