mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin

Science. 2013 Jul 26;341(6144):1236566. doi: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Amino Acids / metabolism
  • Animals
  • Cell Line
  • Culture Media
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes
  • Naphthyridines / pharmacology
  • Peptides / chemistry
  • Peptides / metabolism*
  • Phosphorylation
  • Proteins / antagonists & inhibitors
  • Proteins / chemistry*
  • Proteins / metabolism*
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / chemistry*
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one
  • Amino Acids
  • Culture Media
  • Multiprotein Complexes
  • Naphthyridines
  • Peptides
  • Proteins
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Sirolimus