mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin.

TitlemTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin.
Publication TypeJournal Article
Year of Publication2013
AuthorsKang, SA, Pacold, ME, Cervantes, CL, Lim, D, Lou, HJ, Ottina, K, Gray, NS, Turk, BE, Yaffe, MB, Sabatini, DM
JournalScience
Volume341
Issue6144
Pagination1236566
Date Published2013 Jul 26
ISSN1095-9203
KeywordsAmino Acid Motifs, Amino Acids, Animals, Cell Line, Culture Media, Humans, Mice, Naphthyridines, Peptides, Phosphorylation, Proteins, Sirolimus, TOR Serine-Threonine Kinases
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.

DOI10.1126/science.1236566
Alternate JournalScience
PubMed ID23888043
PubMed Central IDPMC3771538
Grant ListAI047389 / AI / NIAID NIH HHS / United States
CA103866 / CA / NCI NIH HHS / United States
CA112967 / CA / NCI NIH HHS / United States
ES015339 / ES / NIEHS NIH HHS / United States
GM59281 / GM / NIGMS NIH HHS / United States
R01 CA103866 / CA / NCI NIH HHS / United States
R37 AI047389 / AI / NIAID NIH HHS / United States
/ / Howard Hughes Medical Institute / United States