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    Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11624-9. Epub 2003 Sep 19.

    Insulin regulates the activity of forkhead transcription factor Hnf-3beta/Foxa-2 by Akt-mediated phosphorylation and nuclear/cytosolic localization.

    Wolfrum C, Besser D, Luca E, Stoffel M.

    Source

    Laboratories of Metabolic Diseases and Molecular Vertebrate Embryology, The Rockefeller University, New York, NY 10021, USA.

    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.

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    PMID:
    14500912
    [PubMed - indexed for MEDLINE]
    PMCID:
    PMC208808
    Free PMC Article

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