Mitogen-activated protein kinases, Erk and p38, phosphorylate and regulate Foxo1
Mitogen-activated protein kinases, Erk and p38, phosphorylate and regulate Foxo1
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DOI：
10.1016/j.cellsig.2006.08.015
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发表时间：
2007-03-01
影响因子：
4.8
通讯作者：
Fukamizu, Akiyoshi
中科院分区：
文献类型：
--
作者：
Asada, Sachie;Daitoku, Hiroaki;Fukamizu, Akiyoshi
转录因子Foxo家族的成员调节与应激反应、细胞周期和细胞异生有关的基因的表达。Foxo I（FKHR）含有丝裂原活化蛋白激酶（MAPK）家族的15个共有磷酸化位点。因此，我们推测MAPKs可以通过磷酸化直接调节Foxo I的转录活性。体外激酶活性测定显示Foxo 1可被细胞外信号调节激酶（Erk）和p38 MAPK（p38）磷酸化，而不被c-jun氨基末端激酶（JNK）磷酸化。在NIH 3 T3细胞中，表皮生长因子或茴香霉素增加外源Foxo 1的磷酸化，这是显着抑制预处理与MEK 1抑制剂，PD 98059，或p38抑制剂，SB 203580。使用MAPK磷酸化位点突变的二维磷酸肽图谱显示，Foxo 1中的9个丝氨酸残基被Erk特异性磷酸化，并且9个残基中的5个在体内被p38磷酸化。此外，我们还发现Foxo I与Ets-1相互作用，并在牛颈动脉内皮细胞中作为Ets-1或胎肝激酶（Flk）-1启动子的共激活剂发挥作用。与野生型Foxo 1相比，FoxoI中Erk的9个磷酸化位点的突变显示出Flk-1启动子上Ets-1的结合和协同活性较低。这些结果表明，Foxo 1是特异性磷酸化的Erk和p38，这种磷酸化调节Foxo 1作为Ets-1的共激活剂的功能。(c)2006年爱思唯尔公司All rights reserved.
The members of the transcription factor Foxo family regulate the expression of genes concerned with the stress response, cell cycle and gluconeogenesis. Foxo I (FKHR) contains 15 consensus phosphorylation sites for the mitogen-activated protein kinase (MAPK) family. Therefore, we hypothesized that MAPKs could directly regulate the transcriptional activity of Foxo I via phosphorylation. In vitro kinase assay showed that Foxo1 was phosphorylated by extracellular signal-regulated kinase (Erk) and p38 MAPK (p38) but not by c-jun NH2-terminal kinase (JNK). In NIH3T3 cells, epidermal growth factor or anisomycin increased phosphorylation of exogenous Foxo1, which was significantly inhibited by pretreatment with an MEK 1 inhibitor, PD98059, or a p38 inhibitor, SB203580. Two-dimensional phosphopeptide mapping using mutation of phosphorylation sites for MAPK revealed that the nine serine residues in Foxo1 are specifically phosphorylated by Erk and that five of the nine residues are phosphorylated by p38 in vivo. Moreover, we also found that Foxo I interacts with Ets-1 and functions as a coactivator for Ets-1 oil the fetal liver kinase (Flk)-1 promoter in bovine carotid artery endothelial cells. Mutation of the nine phosphorylation sites for Erk in Foxo I was shown to lead to less binding and synergistic activity for Ets-1 on the Flk-1 promoter when compared with wild-type Foxo1. These results suggest that Foxo1 is specifically phosphorylated by Erk and p38, and that this phosphorylation regulates the function of Foxo1 as a coactivator for Ets-1. (c) 2006 Elsevier Inc. All rights reserved.