Salvador Jesus M, Mittelstadt Paul R, Belova Galina I, Fornace Albert J, Ashwell Jonathan D
Gene Response Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nat Immunol. 2005 Apr;6(4):396-402. doi: 10.1038/ni1176. Epub 2005 Feb 27.
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.
p38丝裂原活化蛋白激酶（MAPK）可被上游的MAPK激酶磷酸化并激活。T细胞具有一条替代途径，其中T细胞受体激活的酪氨酸激酶Zap70可使p38的Tyr323位点磷酸化。缺乏Gadd45α（一种与p38结合的小分子）的小鼠会患上狼疮样自身免疫性疾病。在此我们表明，来自Gadd45a(-/-)小鼠的静息T细胞而非B细胞，在没有“上游”MAPK激酶激活的情况下，p38活性会自发增加。来自静息Gadd45a(-/-) T细胞的p38在Tyr323位点自发磷酸化，并且其活性在体外被重组Gadd45α特异性抑制。因此，Gadd45α可防止通过替代途径对T细胞p38的组成性激活，缺乏Gadd45α会导致p38激活、T细胞过度增殖和自身免疫。
