Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1

Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7421-6. doi: 10.1073/pnas.96.13.7421.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Biological Transport / genetics
  • Cell Line
  • Cell Nucleus / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation
  • Mutation
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Transcription Factors
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt