Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
Cell. 2011 Mar 4;144(5):757-68. doi: 10.1016/j.cell.2011.02.014.
The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of growth. Mammalian TOR complex 2 (mTORC2) regulates AGC kinase family members and is implicated in various disorders, including cancer and diabetes. Here, we investigated the upstream regulation of mTORC2. A genetic screen in yeast and subsequent studies in mammalian cells revealed that ribosomes, but not protein synthesis, are required for mTORC2 signaling. Active mTORC2 was physically associated with the ribosome, and insulin-stimulated PI3K signaling promoted mTORC2-ribosome binding, suggesting that ribosomes activate mTORC2 directly. Findings with melanoma and colon cancer cells suggest that mTORC2-ribosome association is important in oncogenic PI3K signaling. Thus, TORC2-ribosome interaction is a likely conserved mechanism of TORC2 activation that is physiologically relevant in both normal and cancer cells. As ribosome content determines growth capacity of a cell, this mechanism of TORC2 regulation ensures that TORC2 is active only in growing cells.
雷帕霉素靶蛋白（TOR）是一种高度保守的蛋白激酶，也是生长的核心控制器。哺乳动物 TOR 复合物 2（mTORC2）调节 AGC 激酶家族成员，与包括癌症和糖尿病在内的各种疾病有关。在这里，我们研究了 mTORC2 的上游调控。酵母中的遗传筛选和随后在哺乳动物细胞中的研究表明，核糖体而不是蛋白质合成是 mTORC2 信号所必需的。活性 mTORC2 与核糖体物理结合，胰岛素刺激的 PI3K 信号促进 mTORC2-核糖体结合，表明核糖体直接激活 mTORC2。黑色素瘤和结肠癌细胞的研究结果表明，mTORC2-核糖体的结合对于致癌性 PI3K 信号很重要。因此，mTORC2-核糖体相互作用可能是 mTORC2 激活的一种保守机制，在正常细胞和癌细胞中都具有生理相关性。由于核糖体含量决定细胞的生长能力，这种 mTORC2 调节机制确保只有在生长中的细胞中 mTORC2 才是活跃的。
