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

Item Type:Article
Title:Insulin regulates the activity of forkhead transcription factor Hnf-3beta/Foxa-2 by Akt-mediated phosphorylation and nuclear/cytosolic localization
Creators Name:Wolfrum, C. and Besser, D. and Luca, E. and Stoffel, M.
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.
Keywords:Phosphoenolpyruvate Carboxykinase, Foxo-1, Phosphatidylinositol 3-Kinase
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:100
Number:20
Page Range:11624-11629
Date:30 September 2003
Official Publication:https://doi.org/10.1073/pnas.1931483100
PubMed:View item in PubMed

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