RagC phosphorylation autoregulates mTOR complex 1
RagC phosphorylation autoregulates mTOR complex 1
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DOI：
10.15252/embj.201899548
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发表时间：
2019-02-01
期刊：
影响因子：
11.4
通讯作者：
James, David E.
中科院分区：
文献类型：
--
作者：
Yang, Guang;Humphrey, Sean J.;James, David E.
雷帕霉素复合物1（mTORC 1）的机制（或哺乳动物）目标控制细胞生长，增殖和代谢，以响应不同的刺激。两个主要的平行途径涉及mTORC 1调节，包括通过TSC 2/Rheb介导的生长因子应答途径和通过Rag GTP酶介导的氨基酸应答途径。在这里，我们确定和表征三个高度保守的生长因子反应性磷酸化位点的RagC，一个组成部分的Rag异源二聚体，涉及氨基酸和生长因子介导的调节mTORC 1之间的串扰。我们发现RagC磷酸化与mTORC 1的不稳定相关，并且对于生长因子和氨基酸诱导的mTORC 1活化都是必不可少的。在功能上，RagC磷酸化抑制饥饿诱导的自噬，并且在果蝇中的遗传研究揭示RagC磷酸化在调节细胞生长中起重要作用。最后，我们确定mTORC 1作为S21上RagC的上游激酶。我们的数据突出了RagC磷酸化在其功能中的重要性，并确定了一个以前不受重视的mTORC 1活性的自动调节机制。
The mechanistic (or mammalian) target of rapamycin complex 1 (mTORC1) controls cell growth, proliferation, and metabolism in response to diverse stimuli. Two major parallel pathways are implicated in mTORC1 regulation including a growth factor-responsive pathway mediated via TSC2/Rheb and an amino acid-responsive pathway mediated via the Rag GTPases. Here, we identify and characterize three highly conserved growth factor-responsive phosphorylation sites on RagC, a component of the Rag heterodimer, implicating cross talk between amino acid and growth factor-mediated regulation of mTORC1. We find that RagC phosphorylation is associated with destabilization of mTORC1 and is essential for both growth factor and amino acid-induced mTORC1 activation. Functionally, RagC phosphorylation suppresses starvation-induced autophagy, and genetic studies in Drosophila reveal that RagC phosphorylation plays an essential role in regulation of cell growth. Finally, we identify mTORC1 as the upstream kinase of RagC on S21. Our data highlight the importance of RagC phosphorylation in its function and identify a previously unappreciated auto-regulatory mechanism of mTORC1 activity.