MKP5, a new member of the MAP kinase phosphatase family, which selectivelydephosphorylates stress-activated kinases

Dual-specificity protein tyrosine phosphatases are a burgeoning family of e nzymes, some of which, the MKPs, are implicated in the regulation of mitoge n-activated protein (MAP) kinases. MKPs have been shown to reverse the acti vation of the MAP kinases by hydrolyzing phosphothreonine and phosphotyrosi ne residues present in the substrates. Here we describe the characterizatio n of a novel member of the MKP family, MKP5. The MKP5 gene, which maps to h uman chromosome lq32, is expressed tissue-specifically as two transcripts o f approximately 3.4 and 2.4kb in human liver and skeletal muscle. When expr essed in mammalian cells, MKP5 blocks the enzymatic activation of MAP kinas es with the selectivity p38 approximate to JNK/SAPK>>ERK. Immunoprecipitati on of endogenous MAP kinases by the catalytically inactive transfected MKP5 demonstrates that it preferentially binds to the p38 and JNK/SAPK kinases. These findings suggest that the selectivity of this phosphatase may be det ermined at least in part at the level of substrate binding.