Essential role for mitogen-activated protein (MAP) kinase phosphatase-1 in stress-responsive MAP kinase and cell survival signaling.

Mitogen-activated protein kinase (MAPK) phosphatases (MKPs) constitute a family of 11 dual-specificity phosphatases that inactivate the MAPKs by dephosphorylation. Although the contribution of MAPKs to cell growth and cell death has been examined extensively, it remains unclear whether MKPs play an essential role in the regulation of these processes. To clarify the role of MKP-1, we determined the effects on the MAPKs and cell growth and death in primary fibroblasts derived from mice lacking MKP-1. Here we have shown that MKP-1 is critical for the inactivation of p38 MAPK and JNK following stimulation with serum, anisomycin, and osmotic stress. In addition, MKP-1 was identified as a critical negative regulator of the cAMP-mediated p38 MAPK pathway. MKP-1-deficient mouse embryonic fibroblasts (MEFs) displayed enhanced p38 MAPK activity and cAMP-response element-dependent transcriptional activation in response to forskolin. Surprisingly, MKP-1-deficient fibroblasts exhibited reduced cell growth compared with wild type MEFs as a result of enhanced cell death. The enhanced level of cell death in MKP-1-deficient MEFs was rescued by SB203580, an inhibitor of p38 MAPK. MKP-1-deficient MEFs were also sensitive to anisomycin-induced apoptosis. Collectively, these data demonstrate that MKP-1 promotes cell survival by attenuating stress-responsive MAPK-mediated apoptosis.