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.
Mesh Terms:
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
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
J. Biol. Chem.
Date: Oct. 19, 2001
PubMed ID: 11489891
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