mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin.
mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin.
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DOI：
10.1126/science.1236566
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发表时间：
2013-07-26
期刊：
影响因子：
--
通讯作者：
Sabatini DM
中科院分区：
文献类型：
--
作者：
Kang SA;Pacold ME;Cervantes CL;Lim D;Lou HJ;Ottina K;Gray NS;Turk BE;Yaffe MB;Sabatini DM
mTOR复合物1（mTORC 1）蛋白激酶促进生长，是雷帕霉素的靶点，雷帕霉素是一种临床上有用的药物，也可以延长模型生物的寿命。一个持续的谜团是为什么许多真正的mTORC 1底物的磷酸化对雷帕霉素有抗性。我们发现，在体外激酶活性的mTORC 1对肽涵盖已建立的磷酸化位点变化很大，并与雷帕霉素以及营养和生长因子饥饿细胞内的网站的抗性强烈相关。轻微的修改的网站是足以改变mTORC 1活性对他们在体外，并导致伴随变化的细胞内的敏感性雷帕霉素和饥饿。因此，磷酸化位点作为mTORC 1底物的内在能力，我们称之为底物质量，是其对通路调节剂敏感性的主要决定因素。我们的研究结果揭示了mTORC 1效应器可以对相同信号做出不同反应的机制。
The mTOR Complex 1 (mTORC1) protein kinase promotes growth and is the target of rapamycin, a clinically useful drug that also prolongs lifespan in model organisms. A persistent mystery is why the phosphorylation of many bona fide mTORC1 substrates is resistant to rapamycin. We find that the in vitro kinase activity of mTORC1 toward peptides encompassing established phosphorylation sites varies widely and correlates strongly with the resistance of the sites to rapamycin as well as to nutrient and growth factor starvation within cells. Slight modifications of the sites were sufficient to alter mTORC1 activity toward them in vitro and to cause concomitant changes within cells in their sensitivity to rapamycin and starvation. Thus, the intrinsic capacity of a phosphorylation site to serve as an mTORC1 substrate, a property we call substrate quality, is a major determinant of its sensitivity to modulators of the pathway. Our results reveal a mechanism through which mTORC1 effectors can respond differentially to the same signals.
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DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
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Shaw RJ
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影响因子：
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作者：
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通讯作者：
Sabatini, David M.
影响因子：
3.3
作者：
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通讯作者：
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通讯作者：
Partridge L