A novel MAPK phosphatase MKP-7 acts preferentially on JNK/SAPK and p38 alpha and beta MAPKs

Mitogen-activated protein kinases (MAPKs) are inactivated via dephosphoryla tion of either the threonine or tyrosine residue or both in the P-loop cata lyzed by protein phosphatases which include serine/threonine phosphatases, tyrosine phosphatases, and dual specificity phosphatases. Nine members of t he dual specificity phosphatases specific for MAPKs, termed MKPs, have been reported. Each member has its own substrate specificity, tissue distributi on, and subcellular localization. In this study, we have cloned and charact erized a novel MKP, designated MKP-7. MKP-7 is most similar to hVH5, a memb er of previously known MKPs, in the primary structure. MKP-7 is predominant ly localized in the cytoplasm when expressed in cultured cells, whereas hVH 5 is both in the nucleus and the cytoplasm, MKP-7 binds to and inactivates p38 MAPK and JNK/SAPK, but not ERK, Furthermore, we have found that MKPs ha ve the substrate specificity toward the isoforms of the p38 family (alpha, beta, gamma, and delta). MKP-7 binds to and inactivates p38 alpha and -beta , but not gamma or delta. MKP-5 and CL100/MKP-1 also bind to p38 alpha and -beta, but not gamma or delta. Finally, we propose a tentative classificati on of MKPs based on the sequence characteristics of their MAPK-docking site .