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
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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DOI：
10.1093/emboj/19.5.989
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发表时间：
2000-03-01
期刊：
影响因子：
11.4
通讯作者：
Accili, D
中科院分区：
文献类型：
--
作者：
Nakae, J;Barr, V;Accili, D
转录因子FKHR通过Akt激酶响应胰岛素和IGF-1而被磷酸化抑制。在这里，我们表明，FKHR磷酸化在肝细胞符合一个层次模式，其中Akt位点的磷酸化在S-253，在叉头DNA结合域，是一个先决条件的磷酸化的两个额外的潜在Akt位点，T-24和S-316。使用胰岛素受体缺陷的肝细胞，我们表明T-24不能被IGF-1受体磷酸化，这表明该残基被胰岛素受体特异性激活的激酶靶向。T-24磷酸化的缺乏与IGF-1诱导FKHR核输出的失败有关，并抑制在IGF结合蛋白-1胰岛素应答元件的转录控制下的报道基因的表达。我们认为FKHR的位点特异性磷酸化是胰岛素和IGF-I受体对基因表达产生不同影响的机制之一。
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-I receptors exert different effects on gene expression.