Abstract
T cell activation requires the import of NF-AT transcription factors to the nucleus, a process promoted by calcineurin-dependent dephosphorylation and inhibited by poorly understood protein kinases. Here, we report the identification of two protein kinases that oppose NF-AT4 nuclear import. Casein kinase Ialpha directly binds and phosphorylates NF-AT4, resulting in the inhibiton of NF-AT4 nuclear translocation. MEKK1 indirectly suppresses NF-AT4 nuclear import by stabilizing the interaction between NF-AT4 and CKIalpha. CKIalpha thus acts to establish an intramolecular masking of the nuclear location signal on NF-AT4, while MEKK1 augments this mechanism, and may further provide a link to signal transduction pathways regulating NF-AT4.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Biological Transport
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Blotting, Western
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Casein Kinases
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Cell Nucleus / metabolism
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Cells, Cultured
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Chromatography, Affinity
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Culture Media, Serum-Free
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DNA-Binding Proteins / metabolism*
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Fluorescent Antibody Technique
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases*
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Models, Biological
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Molecular Sequence Data
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NFATC Transcription Factors
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Nuclear Localization Signals*
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Nuclear Proteins*
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Phosphorylation
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Precipitin Tests
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Protein Binding
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Protein Kinases / genetics
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Protein Kinases / isolation & purification
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Protein Kinases / metabolism*
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / isolation & purification
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Protein Serine-Threonine Kinases / metabolism*
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / isolation & purification
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Protein-Tyrosine Kinases / metabolism*
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Signal Transduction
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Transcription Factors / metabolism*
Substances
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Culture Media, Serum-Free
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DNA-Binding Proteins
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NFATC Transcription Factors
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Nuclear Localization Signals
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Nuclear Proteins
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Transcription Factors
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Protein Kinases
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Protein-Tyrosine Kinases
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Casein Kinases
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Protein Serine-Threonine Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases