Insulin regulates the activity of forkhead transcription factor Hnf-3β/Foxa-2 by Akt-mediated phosphorylation and nuclear/cytosolic localization
- Laboratories of *Metabolic Diseases and †Molecular Vertebrate Embryology, The Rockefeller University, New York, NY 10021
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Edited by Donald F. Steiner, University of Chicago, Chicago, IL, and approved July 23, 2003 (received for review March 13, 2003)
Abstract
Hepatocyte nuclear factors 3 α, β, and γ (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.
Footnotes
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↵ ‡ To whom correspondence should be addressed. E-mail: stoffel{at}rockefeller.edu.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: PEPCK, phosphoenolpyruvate carboxykinase; PI3-kinase, phosphatidylinositol 3-kinase; G6pc, glucose-6-phosphatase; Igfbp-1, insulin growth factor binding protein 1; HA, hemagglutinin; HEK, human embryonic kidney; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase.
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See commentary on page 11198.
- Copyright © 2003, The National Academy of Sciences
