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

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2000 Mar 4

PMID 10698940

Citations 113

Authors

J Nakae

V Barr

D Accili

Affiliations

Soon will be listed here.

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 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.

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