The autoimmune suppressor Gadd45α inhibits the T cell alternative p38 activation pathway
Copyright policy )The autoimmune suppressor Gadd45α inhibits the T cell alternative p38 activation pathway
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.
- National Cancer Institute United States
- Spanish National Research Council Spain
- National Institute of Health Pakistan
- Harvard University United States
- National Institutes of Health United States
Mice, Knockout, ZAP-70 Protein-Tyrosine Kinase, MAP Kinase Signaling System, T-Lymphocytes, Receptors, Antigen, T-Cell, Nuclear Proteins, Cell Cycle Proteins, Protein-Tyrosine Kinases, p38 Mitogen-Activated Protein Kinases, Enzyme Activation, Mice, Animals, Tyrosine, Phosphorylation
Mice, Knockout, ZAP-70 Protein-Tyrosine Kinase, MAP Kinase Signaling System, T-Lymphocytes, Receptors, Antigen, T-Cell, Nuclear Proteins, Cell Cycle Proteins, Protein-Tyrosine Kinases, p38 Mitogen-Activated Protein Kinases, Enzyme Activation, Mice, Animals, Tyrosine, Phosphorylation
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