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

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Abstract
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 S253, in the forkhead DNA binding domain, is a prerequisite for the phosphorylation of two additional potential Akt sites, T24 and S316. Using insulin receptor‐deficient hepatocytes, we show that T24 fails to be phosphorylated by IGF‐1 receptors, suggesting that this residue is targeted by a kinase specifically activated by insulin receptors. Lack of T24 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.