Mammalian target of rapamycin complex I (mTORC1) activity in ras homologue enriched in brain (Rheb)-deficient mouse embryonic fibroblasts.
Mammalian target of rapamycin complex I (mTORC1) activity in ras homologue enriched in brain (Rheb)-deficient mouse embryonic fibroblasts.
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DOI：
10.1371/journal.pone.0081649
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Zwartkruis FJ
中科院分区：
文献类型：
--
作者：
Groenewoud MJ;Goorden SM;Kassies J;Pellis-van Berkel W;Lamb RF;Elgersma Y;Zwartkruis FJ
Ras样GTdR Rheb已被鉴定为mTORC 1的关键激活剂。激活最可能需要Rheb和mTOR之间的直接相互作用，但确切的机制仍不清楚。使用一组Rheb缺陷的小鼠胚胎成纤维细胞（MEFs），我们表明，Rheb确实是必不可少的mTORC 1活性的快速增加后，胰岛素或氨基酸的刺激。然而，mTORC 1活性在连续存在血清或用血清刺激时在Rheb缺陷MEF中降低不太严重。这种剩余的mTORC 1活性通过耗尽细胞的氨基酸或施加能量应激来阻断。此外，MEK抑制剂和RSK抑制剂BI-D1870干扰mTORC 1活性，表明RSK在激活mTORC 1中充当Rheb的旁路。最后，我们表明，这种雷帕霉素敏感，Rheb独立的mTORC 1活性是重要的细胞周期进程。总之，mTORC 1活性的快速适应需要Rheb，而第二个Rheb独立的激活机制存在，有助于细胞周期的进展。
The Ras-like GTPase Rheb has been identified as a crucial activator of mTORC1. Activation most likely requires a direct interaction between Rheb and mTOR, but the exact mechanism remains unclear. Using a panel of Rheb-deficient mouse embryonic fibroblasts (MEFs), we show that Rheb is indeed essential for the rapid increase of mTORC1 activity following stimulation with insulin or amino acids. However, mTORC1 activity is less severely reduced in Rheb-deficient MEFs in the continuous presence of serum or upon stimulation with serum. This remaining mTORC1 activity is blocked by depleting the cells for amino acids or imposing energy stress. In addition, MEK inhibitors and the RSK-inhibitor BI-D1870 interfere in mTORC1 activity, suggesting that RSK acts as a bypass for Rheb in activating mTORC1. Finally, we show that this rapamycin-sensitive, Rheb-independent mTORC1 activity is important for cell cycle progression. In conclusion, whereas rapid adaptation in mTORC1 activity requires Rheb, a second Rheb-independent activation mechanism exists that contributes to cell cycle progression.
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