mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin
Open Access
- 26 July 2013
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 341 (6144), 1236566
- https://doi.org/10.1126/science.1236566
Abstract
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.Keywords
This publication has 51 references indexed in Scilit:
- TOR Signaling and Rapamycin Influence Longevity by Regulating SKN-1/Nrf and DAF-16/FoxOCell Metabolism, 2012
- mTOR Signaling in Growth Control and DiseaseCell, 2012
- mTOR Complex 1 Regulates Lipin 1 Localization to Control the SREBP PathwayCell, 2011
- AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1Nature, 2011
- Discovery of 1-(4-(4-Propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one as a Highly Potent, Selective Mammalian Target of Rapamycin (mTOR) Inhibitor for the Treatment of CancerJournal of Medicinal Chemistry, 2010
- Structure of the Human mTOR Complex I and Its Implications for Rapamycin InhibitionMolecular Cell, 2010
- Mechanisms of Life Span Extension by Rapamycin in the Fruit Fly Drosophila melanogasterCell Metabolism, 2010
- Rapamycin fed late in life extends lifespan in genetically heterogeneous miceNature, 2009
- Autophagy fights disease through cellular self-digestionNature, 2008
- mTOR Interacts with Raptor to Form a Nutrient-Sensitive Complex that Signals to the Cell Growth MachineryCell, 2002