Protein Kinase B/Akt-Mediated Phosphorylation Promotes Nuclear Exclusion of the Winged Helix Transcription Factor FKHR1

Although genetic analysis has demonstrated that members of the winged helix, or forkhead, family of transcription factors play pivotal roles in the regulation of cellular differentiation and proliferation, both during development and in the adult, little is known of the mechanisms underlying their r...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1999-06, Vol.96 (13), p.7421-7426
Main Authors: Biggs, William H., Meisenhelder, Jill, Hunter, Tony, Cavenee, Webster K., Arden, Karen C.
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Biological Transport - genetics
Cell Line
Cell lines
Cell nucleus
Cell Nucleus - metabolism
Cellular immunity
Cellular metabolism
DNA
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Enzymes
Gene Expression Regulation
Genetics
Mutation
Phosphatidylinositol 3-Kinases - metabolism
Phosphorylation
Protein-Serine-Threonine Kinases
Proteins
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-akt
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Transcription factors
Transcription Factors - genetics
Transcription Factors - metabolism
Transcriptional regulatory elements
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Summary:Although genetic analysis has demonstrated that members of the winged helix, or forkhead, family of transcription factors play pivotal roles in the regulation of cellular differentiation and proliferation, both during development and in the adult, little is known of the mechanisms underlying their regulation. Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. These results indicate that phosphorylation by PKB/Akt negatively regulates FKHR1 by promoting export from the nucleus.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.96.13.7421