mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin

• Published in: Science (American Association for the Advancement of Science) Vol. 341; no. 6144; p. 364
• Main Authors: Kang, Seong A., Pacold, Michael E., Cervantes, Christopher L., Lim, Daniel, Lou, Hua Jane, Ottina, Kathleen, Gray, Nathanael S., Turk, Benjamin E., Yaffe, Michael B., Sabatini, David M.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 26.07.2013; The American Association for the Advancement of Science
• Subjects: Amino Acid Motifs; Amino acids; Amino Acids - metabolism; Animals; Cancer; Cell growth; Cell Line; Culture Media; Dietary supplements; Drug regulation; Feedback (Response); Growth factors; Humans; Inhibition; Kinases; Life span; Literary Devices; longevity; Mechanistic Target of Rapamycin Complex 1; Mice; Multiprotein Complexes; Naphthyridines - pharmacology; neoplasms; Nutrient utilization; Nutrients; Peptides; Peptides - chemistry; Peptides - metabolism; Pharmacology; Phosphorylation; Physiology; protein kinases; Proteins; Proteins - antagonists & inhibitors; Proteins - chemistry; Proteins - metabolism; Rapamycin; RESEARCH ARTICLE SUMMARY; Signal transduction; Sirolimus - pharmacology; Starvation; Substrates; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - chemistry; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.1236566

Inhibition of the protein kinase complex mTORC1 has potentially beneficial therapeutic affects that include inhibition of cancer and extension of life span. However, effects of its inhibition in vivo have sometimes been disappointing. One reason may be that the well-studied inhibitor of mTORC1, rapamycin, inhibits some effects of mTORC1 but not others. In line with this idea, Kang et al. ( 1236566 ) show that the effect of rapamycin depends on the substrate. Characteristics of the phosphorylation sites on various substrates caused them to be phosphorylated with different efficiency by mTORC1. The substrates that were most efficiently phosphorylated were resistant to inhibition of mTORC1. The results explain how various sites, sometimes within the same protein, can differ in their sensitivity to rapamycin. Inhibition of a protein kinase differentially affects its targets, depending on phosphorylation site characteristics. 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.