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.
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.
Nakae
J
J
Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Barr
V
V
Accili
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D000818:Animals; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D008099:Liver; D051379:Mice; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007004:Hypoglycemic Agents; D007328:Insulin; D014157:Transcription Factors; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin