Abstract
Hepatocyte nuclear factors 3 alpha, beta, and gamma (Foxa-1, -2, and -3) are transcriptional activators of important metabolic genes in the liver that are suppressed by the actions of insulin. Here, we show that the activation of phosphatidylinositol 3-kinase-Akt by insulin induces Foxa-2 phosphorylation, nuclear exclusion, and inhibition of Foxa-2-dependent transcriptional activity. Foxa-2 physically interacts with Akt, a key mediator of the phosphatidylinositol 3-kinase pathway and is phosphorylated at a single conserved site (T156) that is absent in Foxa-1 and Foxa-3 proteins. This Akt phosphorylation site in Foxa-2 is highly conserved from mammals to insects. Mutant Foxa-2T156A is resistant to Akt-mediated phosphorylation, nuclear exclusion, and transcriptional inactivation of Foxa-2-regulated gene expression. These results implicate an evolutionarily conserved mechanism in the regulation of Foxa-2-dependent transcriptional control by extracellular signals such as insulin.
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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Cell Line
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Cell Nucleus / enzymology
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Cell Nucleus / metabolism*
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Cytosol / enzymology
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Cytosol / metabolism*
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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Enzyme Activation
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Hepatocyte Nuclear Factor 3-beta
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Humans
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Insulin / physiology*
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Molecular Sequence Data
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Nuclear Proteins / metabolism
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Nuclear Proteins / physiology*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases*
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Protein Transport
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Recombinant Proteins / metabolism
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Sequence Homology, Amino Acid
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Transcription Factors*
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Transcription, Genetic / physiology
Substances
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DNA-Binding Proteins
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FOXA2 protein, human
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Insulin
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Nuclear Proteins
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Proto-Oncogene Proteins
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Recombinant Proteins
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Transcription Factors
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Hepatocyte Nuclear Factor 3-beta
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt