IGF-1-stimulated protein synthesis in oligodendrocyte progenitors requires PI3K/mTOR/Akt and MEK/ERK pathways
IGF-1-stimulated protein synthesis in oligodendrocyte progenitors requires PI3K/mTOR/Akt and MEK/ERK pathways
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DOI：
10.1111/j.1471-4159.2009.06071.x
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发表时间：
2009-06-01
影响因子：
4.7
通讯作者：
Almazan, Guillermina
中科院分区：
文献类型：
--
作者：
Bibollet-Bahena, Olivia;Almazan, Guillermina
胰岛素样生长因子-1（IGF-1）与I型受体相互作用，激活两条主要信号通路，即促分裂原活化蛋白激酶激酶（MEK）-细胞外信号调节激酶（ERK）和磷脂酰肌醇3-激酶（PI 3 K）-Akt级联，介导少突胶质细胞（OL）祖细胞（OLP）的增殖或存活。在其他细胞系统中，哺乳动物雷帕霉素靶蛋白（mTOR）和p70 S6激酶是磷酸化翻译起始因子（例如eIF-4 E）、其调节因子（例如4 E-结合蛋白1，4 E-BP 1）和核糖体蛋白S6（S6）的下游效应物。本研究的目的是确定这些途径是否参与IGF-1刺激的蛋白质合成，这对OLs的生长和分化很重要。用IGF-1处理大鼠培养的OLP，所述IGF-1具有或不具有PI 3 K（LY 294002或渥曼青霉素）、mTOR（雷帕霉素）、MEK（PD 98059）和Akt（III或IV）的抑制剂，以及编码显性阴性形式Akt的腺病毒。通过[S-35]-甲硫氨酸掺入评估的蛋白质合成由IGF-1刺激，并且需要PI 3 K、Akt、mTOR和MEK/ERK的上游激活。与使用蛋白激酶抑制剂的实验一致，蛋白质印迹显示IGF-1刺激Akt、mTOR、ERK、S6和4 E-BP 1的磷酸化。S6的激活和4 E-BP 1的失活是蛋白质合成发生所必需的，依赖于PI 3 K和mTOR的上游激活。最后，IGF-1始终刺激蛋白质合成，通过mTOR在分化OLP，但mRNA转录是不需要在第4天，表明IGF-1的分化作用，在整个OL发展。
Insulin-like growth factor-1 (IGF-1) interacts with the Type I receptor to activate two main signaling pathways, the mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) and the phosphatidylinositol 3-kinase (PI3K)-Akt cascades, which mediate proliferation or survival of oligodendrocyte (OL) progenitors (OLPs). In other cellular systems, mammalian target of rapamycin (mTOR) and the p70 S6 kinase are downstream effectors that phosphorylate translation initiation factors (e.g. eIF-4E), their regulators (e.g. 4E-binding protein 1, 4E-BP1) and ribosomal protein S6 (S6). The aim of this study was to determine whether these pathways are involved in IGF-1-stimulated protein synthesis, important for growth and differentiation of OLs. Rat cultured OLPs were treated with IGF-1 with or without inhibitors of PI3K (LY294002 or Wortmannin), mTOR (rapamycin), MEK (PD98059), and Akt (III or IV), as well as an adenovirus encoding a dominant negative form of Akt. Protein synthesis, as assessed by [S-35]-methionine incorporation, was stimulated by IGF-1 and required the upstream activation of PI3K, Akt, mTOR and MEK/ERK. Concordant with the experiments using protein kinase inhibitors, western blotting revealed that IGF-1 stimulates phosphorylation of Akt, mTOR, ERK, S6 and 4E-BP1. Activation of S6 and inactivation of 4E-BP1, necessary for protein synthesis to take place, were dependent on the upstream activation of PI3K and mTOR. Finally, IGF-1 consistently stimulated protein synthesis through mTOR in differentiating OLPs but mRNA transcription was not required at day 4, indicating a differential role of IGF-1 throughout OL development.