MKP-1 (3CH134), AN IMMEDIATE-EARLY GENE-PRODUCT, IS A DUAL-SPECIFICITY PHOSPHATASE THAT DEPHOSPHORYLATES MAP KINASE IN-VIVO

Mitogenic stimulation of cells induces rapid and transient activation of MAP kinases. Here we report that a growth factor-inducible gene, 3C H134, encodes a dual specificity phosphatase that dephosphorylates and inactivates p42MAPK both in vitro and in vivo. In vitro, 3CH134 prote in dephosphorylates both T183 and Y185 in p42MAPK. In serum-stimulated normal fibroblasts, the kinetics of inactivation of p42MAPK coincides with the appearance of newly synthesized 3CH134 protein, and the prot ein synthesis inhibitor cycloheximide leads to persistent activation o f MAP kinase. Expression of 3CH134 in COS cells leads to selective dep hosphorylation of p42MAPK from the spectrum of phosphotyrosyl proteins . 3CH134 blocks phosphorylation and activation of p42MAPK Mediated by serum, oncogenic Ras, or activated Raf, whereas the catalytically inac tive mutant of the phosphatase, Cys-258-->Ser, augments MAP kinase pho sphorylation under similar conditions. The mutant 3CH134 protein also forms a physical complex with the phosphorylated form of p42MAPK. Thes e findings suggest that 3CH134 is a physiological MAP kinase phosphata se; we propose the name MKP-1 for this phosphatase.