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PMID: 14500912 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 100 ·No. 20 ·2003-09-30 ·Pages 11624-9

Wolfrum C, Besser D, Luca E, 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.

MeSH Terms
Amino Acid Sequence Cell Line Cell Nucleus/enzymology,metabolism Cytosol/enzymology,metabolism DNA-Binding Proteins/metabolism,physiology Enzyme Activation Hepatocyte Nuclear Factor 3-beta Humans Insulin/physiology Molecular Sequence Data Nuclear Proteins/metabolism,physiology Phosphatidylinositol 3-Kinases/metabolism Phosphorylation Protein Serine-Threonine Kinases Protein Transport Proto-Oncogene Proteins/metabolism Proto-Oncogene Proteins c-akt Recombinant Proteins/metabolism Sequence Homology, Amino Acid Transcription Factors Transcription, Genetic/physiology
Chemicals
DNA-Binding Proteins FOXA2 protein, human Insulin Nuclear Proteins Proto-Oncogene Proteins Recombinant Proteins Transcription Factors Hepatocyte Nuclear Factor 3-beta AKT1 protein, human Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Wolfrum Christian
Laboratories of Metabolic Diseases and Molecular Vertebrate Embryology, The Rockefeller University, New York, NY 10021, USA.
Besser Daniel
Luca Edlira
Stoffel Markus
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.1931483100
Published
2003-09-30
Epub
2003-00-19
Pages
11624-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC208808
Subset
IM
Grants
NIDDK NIH HHS · R01 DK055033 · United States
NIDDK NIH HHS · R01 DK55033 · United States
Corrections
CommentIn
PMID: 14506300
External Links
PubMed source DOI: 10.1073/pnas.1931483100 PMC Full Text View journal details
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