Regulation of the TAK1 signaling pathway by protein phosphatase 2C
Regulation of the TAK1 signaling pathway by protein phosphatase 2C
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DOI：
10.1074/jbc.m007773200
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发表时间：
2001-02-23
影响因子：
4.8
通讯作者：
Tamura, S
中科院分区：
文献类型：
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作者：
Hanada, M;Ninomiya-Tsuji, J;Tamura, S
蛋白磷酸酶2C(PP2C)与酵母和哺乳动物细胞中应激激活的蛋白激酶级联反应的负调控有关。在这项研究中，我们确定了哺乳动物PP2C的主要亚型PP2Cβ-1在Tak1信号通路中的作用，Tak1信号通路是一种由白细胞介素2 L、转化生长因子β或应激激活的应激激活蛋白激酶级联反应。PP2Cβ-1的异位表达抑制了TAK1介导的丝裂原活化蛋白激酶4-c-jun氨基末端激酶和丝裂原活化蛋白激酶6-p38信号通路。在体外，PP2Cβ-1使TAK1去磷酸化和失活。免疫共沉淀实验表明，PP2Cβ-1与TAK1的中心区结合。PP2Cβ-1的磷酸酶阴性突变体PP2Cβ-1(R/G)是一个显性负性突变体，在体外抑制野生型PP2Cβ-1对TAK1的去磷酸化作用。此外，PP2Cβ1(R/G)的异位表达增强了白介素L诱导的AP-1报告基因的激活。综上所述，这些结果表明，PP2Cβ通过直接去磷酸化TAK1来负向调节TAK1信号通路。
Protein phosphatase 2C (PP2C) is implicated in the negative regulation of stress-activated protein kinase cascades in yeast and mammalian cells. In this study, we determined the role of PP2C beta -1, a major isoform of mammalian PP2C, in the TAK1 signaling pathway, a stress-activated protein kinase cascade that is activated by interleukin-l, transforming growth factor-beta, or stress. Ectopic expression of PP2C beta -1 inhibited the TAK1-mediated mitogen-activated protein kinase kinase 4-c-Jun amino-terminal kinase and mitogen activated protein kinase kinase 6-p38 signaling pathways. In vitro, PP2C beta -1 dephosphorylated and inactivated TAK1. Coimmunoprecipitation experiments indicated that PP2C beta -1 associates with the central region of TAK1. A phosphatase-negative mutant of PP2C beta -1, PP2C beta -1 (R/G), acted as a dominant negative mutant, inhibiting dephosphorylation of TAK1 by wild type PP2C beta -1 in vitro. In addition, ectopic expression of PP2C beta -1(R/G) enhanced interleukin-l-induced activation of an AP-1 reporter gene. Collectively, these results indicate that PP2C beta negatively regulates the TAK1 signaling pathway by direct dephosphorylation of TAK1.