The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) protein kinase promotes growth and is the target of rapamycin, a clinically useful drug that also prolongs life span 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.National Institutes of Health (U.S.) (Grant CA103866)National Institutes of Health (U.S.) (Grant AI047389)National Institutes of Health (U.S.) (Grant ES015339)National Institutes of Health (U.S.) (Grant GM59281)National Institutes of Health (U.S.) (Grant CA112967)United States. Dept. of Defense (Grant W81XWH-07-0448)W. M. Keck FoundationLAM FoundationAmerican Cancer Society (Fellowship)LAM Foundation (Fellowship)Damon Runyon Cancer Research Foundation (Fellowship)United States. Dept. of Defense. Breast Cancer Research Program (Fellowship
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