Direct control of the Forkhead transcription factor AFX by protein kinase B

Nature. 1999 Apr 15;398(6728):630-4. doi: 10.1038/19328.

Abstract

The phosphatidylinositol-3-OH-kinase (PI(3)K) effector protein kinase B regulates certain insulin-responsive genes, but the transcription factors regulated by protein kinase B have yet to be identified. Genetic analysis in Caenorhabditis elegans has shown that the Forkhead transcription factor daf-16 is regulated by a pathway consisting of insulin-receptor-like daf-2 and PI(3)K-like age-1. Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf-16, both in vitro and in vivo. Inhibition of endogenous PI(3)K and protein kinase B activity prevents protein kinase B-dependent phosphorylation of AFX and reveals residual protein kinase B-independent phosphorylation that requires Ras signalling towards the Ral GTPase. In addition, phosphorylation of AFX by protein kinase B inhibits its transcriptional activity. Together, these results delineate a pathway for PI(3)K-dependent signalling to the nucleus.

Publication types

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

MeSH terms

  • 3T3 Cells
  • Animals
  • Blood Proteins / antagonists & inhibitors
  • Blood Proteins / genetics
  • Blood Proteins / metabolism*
  • Cloning, Molecular
  • Humans
  • Insulin / metabolism
  • Mice
  • Phosphorylation
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Cells, Cultured
  • ras Proteins / metabolism

Substances

  • Blood Proteins
  • FOXO4 protein, human
  • Insulin
  • Proto-Oncogene Proteins
  • Recombinant Fusion Proteins
  • Transcription Factors
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • ras Proteins