Nitrogen source activates TOR (target of rapamycin) complex 1 via glutamine and independently of Gtr/Rag proteins

J Biol Chem. 2014 Sep 5;289(36):25010-20. doi: 10.1074/jbc.M114.574335. Epub 2014 Jul 25.


The evolutionary conserved TOR complex 1 (TORC1) activates cell growth in response to nutrients. In yeast, TORC1 responds to the nitrogen source via a poorly understood mechanism. Leucine, and perhaps other amino acids, activates TORC1 via the small GTPases Gtr1 and Gtr2, orthologs of the mammalian Rag GTPases. Here we investigate the activation of TORC1 by the nitrogen source and how this might be related to TORC1 activation by Gtr/Rag. The quality of the nitrogen source, as defined by its ability to promote growth and glutamine accumulation, directly correlates with its ability to activate TORC1 as measured by Sch9 phosphorylation. Preferred nitrogen sources stimulate rapid, sustained Sch9 phosphorylation and glutamine accumulation. Inhibition of glutamine synthesis reduces TORC1 activity and growth. Poor nitrogen sources stimulate rapid but transient Sch9 phosphorylation. A Gtr1 deficiency prevents the transient stimulation of TORC1 but does not affect the sustained TORC1 activity in response to good nitrogen sources. These findings suggest that the nitrogen source must be converted to glutamine, the preferred nitrogen source in yeast, to sustain TORC1 activity. Furthermore, sustained TORC1 activity is independent of Gtr/Rag. Thus, the nitrogen source and Gtr/Rag activate TORC1 via different mechanisms.

Keywords: Amino Acid; Kinetics; Nitrogen Metabolism; Target of Rapamycin (TOR); Yeast.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ammonium Compounds / metabolism
  • Ammonium Compounds / pharmacology
  • Glutamine / metabolism
  • Glutamine / pharmacology*
  • Immunoblotting
  • Leucine / metabolism
  • Leucine / pharmacology
  • Methionine Sulfoximine / pharmacology
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism*
  • Mutation
  • Nitrogen / metabolism
  • Nitrogen / pharmacology*
  • Phosphorylation / drug effects
  • Proline / metabolism
  • Proline / pharmacology
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / growth & development
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Sirolimus / pharmacology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • Ammonium Compounds
  • GTR2 protein, S cerevisiae
  • Gtr1 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • TORC1 protein complex, S cerevisiae
  • Transcription Factors
  • Glutamine
  • Methionine Sulfoximine
  • Proline
  • Protein Serine-Threonine Kinases
  • SCH9 protein, S cerevisiae
  • Monomeric GTP-Binding Proteins
  • Leucine
  • Nitrogen
  • Sirolimus