Selective suppression of stress-activated protein kinase pathway by protein phosphatase 2C in mammalian cells

Protein phosphatase 2C alpha (PP2C alpha) or PP2C beta-1 expressed in COS7 cells suppressed anisomycin- and NaCl-enhanced phosphorylations of p38 co-expressed in the cells. PP2C alpha or PP2C beta-1 expression also suppressed both basal and stress-enhanced phosphorylations of MKK3b and MKK6b, which are upstream protein kinases of p38, and of MKK4, which is one of the major upstream protein kinases of JNK. Basal activity of MKK7, another upstream protein kinase of JNK, was also suppressed by PP2C alpha or PP2C beta-1 expression. However, basal as well as serum-activated phosphorylation of MKK1a, an upstream protein kinase of ERKs, was not affected by PP2C beta or PP2C beta-1. A catalytically inactive mutant of PP2C beta-1 further enhanced the NaCl-stimulated phosphorylations of MMK3b, MKK4 and MKK6b, suggesting that this mutant PP2C beta-1 works as a dominant negative form. These results suggest that PP2C selectively inhibits the SAPK pathways through suppression of MKK3b, MKK4, MKK6b and MKK7 activities in mammalian cells. (C) 1998 Federation of European Biochemical Societies.