The autoimmune suppressor Gadd45alpha 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.
Salvador
Jesus M
JM
Gene Response Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Mittelstadt
Paul R
PR
Belova
Galina I
GI
Fornace
Albert J
AJ
Ashwell
Jonathan D
JD
D000818:Animals; D018797:Cell Cycle Proteins / Q000276:immunology* / Q000378:metabolism; D004789:Enzyme Activation; D020935:MAP Kinase Signaling System / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D014443:Tyrosine / Q000276:immunology / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; D051746:ZAP-70 Protein-Tyrosine Kinase; D048051:p38 Mitogen-Activated Protein Kinases; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins; C497262:Zap70 protein, mouse