Regulation of the TAK1 signaling pathway by protein phosphatase 2C

Protein phosphatase 2C (PP2C) is implicated in the negative regulation of s tress-activated protein kinase cascades in yeast and mammalian cells. In th is study, we determined the role of PP2C beta -1, a major isoform of mammal ian 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 regul ates the TAK1 signaling pathway by direct dephosphorylation of TAK1.