Differential regulation of gene expression by insulin and IGF-1 receptors correlates with phosphorylation of a single amino acid residue in the forkhead transcription factor FKHR

EMBO J. 2000 Mar 1;19(5):989-96. doi: 10.1093/emboj/19.5.989.


The transcription factor FKHR is inhibited by phosphorylation in response to insulin and IGF-1 through Akt kinase. Here we show that FKHR phosphorylation in hepatocytes conforms to a hierarchical pattern in which phosphorylation of the Akt site at S(253), in the forkhead DNA binding domain, is a prerequisite for the phosphorylation of two additional potential Akt sites, T(24) and S(316). Using insulin receptor-deficient hepatocytes, we show that T(24) fails to be phosphorylated by IGF-1 receptors, suggesting that this residue is targeted by a kinase specifically activated by insulin receptors. Lack of T(24) phosphorylation is associated with the failure of IGF-1 to induce nuclear export of FKHR, and to inhibit expression of a reporter gene under the transcriptional control of the IGF binding protein-1 insulin response element. We propose that site-specific phosphorylation of FKHR is one of the mechanisms by which insulin and IGF-1 receptors exert different effects on gene expression.

MeSH terms

  • Animals
  • Cell Line, Transformed
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Gene Expression Regulation* / drug effects
  • Hypoglycemic Agents / metabolism
  • Hypoglycemic Agents / pharmacology
  • Insulin / metabolism
  • Insulin / pharmacology
  • Insulin-Like Growth Factor I / metabolism
  • Insulin-Like Growth Factor I / pharmacology
  • Liver
  • Mice
  • Phosphorylation
  • Receptor, IGF Type 1 / genetics*
  • Receptor, IGF Type 1 / metabolism
  • Receptor, Insulin / genetics*
  • Receptor, Insulin / metabolism
  • Signal Transduction / drug effects
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • DNA-Binding Proteins
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Hypoglycemic Agents
  • Insulin
  • Transcription Factors
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1
  • Receptor, Insulin