Molecular cloning and characterization of a novel dual specificity phosphatase, MKP-5

A group of dual specificity protein phosphatases negatively regulates membe rs of the mitogen-activated protein kinase (MAPK) superfamily, which consis ts of three major subfamilies, MAPK/extracellular signal-regulated kinase ( ERK), stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), and p38. Nine members of this group of dual specificity phosphatases have previously been cloned. They show distinct substrate specificities for MAPK s, different tissue distribution and subcellular localization, and differen t modes of inducibility of their expression by extracellular stimuli. Here we have cloned and characterized a novel dual specificity phosphatase, whic h we have designated MKP-5, MKP-5 is a protein of 482 amino acids with a ca lculated molecular mass of 52.6 kDa and consists of 150 N-terminal amino ac ids of unknown function, two Cdc25 homology 2 regions in the middle, and a C-terminal catalytic domain. MKP-5 binds to p38 and SAPK/JNK, but not to MA PK/ERK, and inactivates p38 and SAPK/JNK, but not MAPK/ERK. p38 is a prefer red substrate, The subcellular localization of MKP-5 is unique; it is prese nt evenly in both the cytoplasm and the nucleus. MKP-5 mRNA is widely expre ssed in various tissues and organs, and its expression in cultured cells is elevated by stress stimuli. These results suggest that MKP-5 is a novel ty pe of dual specificity phosphatase specific for p38 and SAPK/JNK.