MKP-7, a novel mitogen-activated protein kinase phosphatase, functions as a shuttle protein.
Mitogen-activated protein kinase (MAPK) phosphatases (MKPs) negatively regulate MAPK activity. In the present study, we have identified a novel MKP, designated MKP-7, and mapped it to human chromosome 12p12. MKP-7 possesses a long C-terminal stretch containing both a nuclear export signal and a nuclear localization signal, in addition to the rhodanese-like domain and the dual specificity phosphatase catalytic domain, both of which are conserved among MKP family members. When expressed in mammalian cells MKP-7 protein was localized exclusively in the cytoplasm, but this localization became exclusively nuclear following leptomycin B treatment or introduction of a mutation in the nuclear export signal. These findings indicate that MKP-7 is the first identified leptomycin B-sensitive shuttle MKP. Forced expression of MKP-7 suppressed activation of MAPKs in COS-7 cells in the order of selectivity, JNK p38 > ERK. Furthermore, a mutant form MKP-7 functioned as a dominant negative particularly against the dephosphorylation of JNK, suggesting that MKP-7 works as a JNK-specific phosphatase in vivo. Co-immunoprecipitation experiments and histological analysis suggested that MKP-7 determines the localization of MAPKs in the cytoplasm.
Pubmed ID: 11489891 RIS Download
Active Transport, Cell Nucleus | Amino Acid Motifs | Amino Acid Sequence | Animals | Base Sequence | Blotting, Northern | COS Cells | Carrier Proteins | Catalytic Domain | Cell Nucleus | Chromosome Mapping | Chromosomes, Human, Pair 12 | Cytoplasm | DNA, Complementary | Databases as Topic | Dual-Specificity Phosphatases | Exons | Expressed Sequence Tags | Fatty Acids, Unsaturated | Genes, Dominant | HeLa Cells | Humans | JNK Mitogen-Activated Protein Kinases | MAP Kinase Kinase 4 | MAP Kinase Signaling System | Mice | Mitogen-Activated Protein Kinase Kinases | Mitogen-Activated Protein Kinase Phosphatases | Mitogen-Activated Protein Kinases | Models, Genetic | Molecular Sequence Data | Mutation | Phosphorylation | Plasmids | Precipitin Tests | Protein Binding | Protein Structure, Tertiary | Protein Tyrosine Phosphatases | Sequence Homology, Amino Acid | Substrate Specificity | Tissue Distribution | Transfection | p38 Mitogen-Activated Protein Kinases