The Vam6 GEF controls TORC1 by activating the EGO complex

Mol Cell. 2009 Sep 11;35(5):563-73. doi: 10.1016/j.molcel.2009.06.033.

Abstract

The target of rapamycin complex 1 (TORC1) is a central regulator of eukaryotic cell growth that is activated by a variety of hormones (e.g., insulin) and nutrients (e.g., amino acids) and is deregulated in various cancers. Here, we report that the yeast Rag GTPase homolog Gtr1, a component of the vacuolar-membrane-associated EGO complex (EGOC), interacts with and activates TORC1 in an amino-acid-sensitive manner. Expression of a constitutively active (GTP-bound) Gtr1(GTP), which interacted strongly with TORC1, rendered TORC1 partially resistant to leucine deprivation, whereas expression of a growth inhibitory, GDP-bound Gtr1(GDP), caused constitutively low TORC1 activity. We also show that the nucleotide-binding status of Gtr1 is regulated by the conserved guanine nucleotide exchange factor (GEF) Vam6. Thus, in addition to its regulatory role in homotypic vacuolar fusion and vacuole protein sorting within the HOPS complex, Vam6 also controls TORC1 function by activating the Gtr1 subunit of the EGO complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Amino Acid Transport Systems / metabolism
  • Amino Acids / metabolism
  • Cycloheximide / pharmacology
  • DNA-Binding Proteins / metabolism
  • Endosomes / enzymology
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Guanosine Diphosphate / metabolism
  • Guanosine Triphosphate / metabolism
  • Intracellular Membranes / drug effects
  • Intracellular Membranes / enzymology*
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism*
  • Multiprotein Complexes
  • Mutation
  • Protein Binding
  • Protein Synthesis Inhibitors / pharmacology
  • Protein Transport
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism*
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / growth & development
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Signal Transduction
  • Sirolimus / pharmacology
  • Time Factors
  • Transcription Factors / metabolism
  • Vacuoles / drug effects
  • Vacuoles / enzymology*

Substances

  • Adaptor Proteins, Vesicular Transport
  • Amino Acid Transport Systems
  • Amino Acids
  • DNA-Binding Proteins
  • GAP1 protein, S cerevisiae
  • GTR2 protein, S cerevisiae
  • Gtr1 protein, S cerevisiae
  • Guanine Nucleotide Exchange Factors
  • MEH1 protein, S cerevisiae
  • Multiprotein Complexes
  • Protein Synthesis Inhibitors
  • SWI4 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Tco89 protein, S cerevisiae
  • Transcription Factors
  • VAM6 protein, S cerevisiae
  • Guanosine Diphosphate
  • Guanosine Triphosphate
  • Cycloheximide
  • Protein-Serine-Threonine Kinases
  • SCH9 protein, S cerevisiae
  • target of rapamycin protein, S cerevisiae
  • Monomeric GTP-Binding Proteins
  • Sirolimus