Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Amino Acid Motifs
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Amino Acid Sequence
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Animals
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Base Sequence
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Blotting, Northern
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COS Cells
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Carrier Proteins / metabolism
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Catalytic Domain
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Cell Nucleus / metabolism
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Chromosome Mapping
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Chromosomes, Human, Pair 12
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Cytoplasm / metabolism
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DNA, Complementary / metabolism
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Databases as Topic
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Dual-Specificity Phosphatases
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Exons
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Expressed Sequence Tags
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Fatty Acids, Unsaturated / pharmacology
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Genes, Dominant
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HeLa Cells
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Humans
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JNK Mitogen-Activated Protein Kinases*
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MAP Kinase Kinase 4
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MAP Kinase Signaling System
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Mice
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinase Phosphatases
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Mitogen-Activated Protein Kinases / metabolism
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Models, Genetic
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Molecular Sequence Data
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Mutation
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Phosphorylation
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Plasmids / metabolism
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Precipitin Tests
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Protein Binding
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Protein Structure, Tertiary
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Protein Tyrosine Phosphatases / biosynthesis
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Protein Tyrosine Phosphatases / chemistry*
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism*
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Protein Tyrosine Phosphatases / physiology*
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Sequence Homology, Amino Acid
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Substrate Specificity
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Tissue Distribution
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Transfection
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p38 Mitogen-Activated Protein Kinases
Substances
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Carrier Proteins
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DNA, Complementary
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Fatty Acids, Unsaturated
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases
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Mitogen-Activated Protein Kinase Phosphatases
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DUSP16 protein, human
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Dual-Specificity Phosphatases
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Protein Tyrosine Phosphatases
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leptomycin B
Associated data
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GENBANK/AB052156
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GENBANK/AB052157