mTOR complex 2 phosphorylates IMP1 cotranslationally to promote IGF2 production and the proliferation of mouse embryonic fibroblasts
mTOR complex 2 phosphorylates IMP1 cotranslationally to promote IGF2 production and the proliferation of mouse embryonic fibroblasts
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DOI：
10.1101/gad.209130.112
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发表时间：
2013-02-01
影响因子：
10.5
通讯作者：
Avruch, Joseph
中科院分区：
文献类型：
--
作者：
Dai, Ning;Christiansen, Jan;Avruch, Joseph
由于细胞增殖减少，小鼠缺乏IGF 2导致胚胎生长减少。在这里，我们表明，小鼠胚胎成纤维细胞缺乏的RNA结合蛋白IMP 1（IGF 2 mRNA结合蛋白1）有缺陷的剪接和翻译的IGF 2 mRNA，显着减少IGF 2多肽的生产，并减少增殖。IMP 1缺失的成纤维细胞的增殖可以通过体外IGF 2或通过IMP 1的再表达恢复到野生型水平，这纠正了IGF 2 RNA剪接和翻译中的缺陷。IMP 1纠正这些缺陷的能力取决于IMP 1在Ser 181处的磷酸化，其由mTOR复合物2（mTORC 2）协同催化。磷酸化强烈增强IMP 1与IGF 2-前导3 5'非翻译区的结合，这是通过内部核糖体进入使IGF 2-前导3 mRNA翻译启动所绝对需要的。这些发现揭示了mTOR通过mTORC 2催化的共翻译IMP 1/IMP 3磷酸化促进小鼠胚胎中IGF 2的产生来调节生物体生长的新机制。由于TORC 2通过与核糖体结合而被激活，因此本结果表明mTORC 2催化的共翻译蛋白磷酸化是该复合物的核心功能。
Lack of IGF2 in mice results in diminished embryonic growth due to diminished cell proliferation. Here we show that mouse embryonic fibroblasts lacking the RNA-binding protein IMP1 (IGF2 mRNA-binding protein 1) have defective splicing and translation of IGF2 mRNAs, markedly reduced IGF2 polypeptide production, and diminished proliferation. The proliferation of the IMP1-null fibroblasts can be restored to wild-type levels by IGF2 in vitro or by re-expression of IMP1, which corrects the defects in IGF2 RNA splicing and translation. The ability of IMP1 to correct these defects is dependent on IMP1 phosphorylation at Ser181, which is catalyzed cotranslationally by mTOR complex 2 (mTORC2). Phosphorylation strongly enhances IMP1 binding to the IGF2-leader 3 5' untranslated region, which is absolutely required to enable IGF2-leader 3 mRNA translational initiation by internal ribosomal entry. These findings uncover a new mechanism by which mTOR regulates organismal growth by promoting IGF2 production in the mouse embryo through mTORC2-catalyzed cotranslational IMP1/IMP3 phosphorylation. Inasmuch as TORC2 is activated by association with ribosomes, the present results indicate that mTORC2-catalyzed cotranslational protein phosphorylation is a core function of this complex.