The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1

Science. 2008 Jun 13;320(5882):1496-501. doi: 10.1126/science.1157535. Epub 2008 May 22.

Abstract

The multiprotein mTORC1 protein kinase complex is the central component of a pathway that promotes growth in response to insulin, energy levels, and amino acids and is deregulated in common cancers. We find that the Rag proteins--a family of four related small guanosine triphosphatases (GTPases)--interact with mTORC1 in an amino acid-sensitive manner and are necessary for the activation of the mTORC1 pathway by amino acids. A Rag mutant that is constitutively bound to guanosine triphosphate interacted strongly with mTORC1, and its expression within cells made the mTORC1 pathway resistant to amino acid deprivation. Conversely, expression of a guanosine diphosphate-bound Rag mutant prevented stimulation of mTORC1 by amino acids. The Rag proteins do not directly stimulate the kinase activity of mTORC1, but, like amino acids, promote the intracellular localization of mTOR to a compartment that also contains its activator Rheb.

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

  • Adaptor Proteins, Signal Transducing
  • Amino Acids / metabolism*
  • Cell Line
  • Cell Nucleus / metabolism
  • Cytoplasm / metabolism
  • Dimerization
  • Guanosine Triphosphate / metabolism
  • Humans
  • Insulin / metabolism
  • Leucine / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism*
  • Multiprotein Complexes
  • Mutant Proteins / metabolism
  • Mutation
  • Neuropeptides / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Kinases / metabolism
  • Proteins / metabolism*
  • Ras Homolog Enriched in Brain Protein
  • Regulatory-Associated Protein of mTOR
  • Signal Transduction*
  • TOR Serine-Threonine Kinases
  • Transcription Factors / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Amino Acids
  • Insulin
  • Multiprotein Complexes
  • Mutant Proteins
  • Neuropeptides
  • Proteins
  • RHEB protein, human
  • RPTOR protein, human
  • RRAGC protein, human
  • Ras Homolog Enriched in Brain Protein
  • Regulatory-Associated Protein of mTOR
  • Transcription Factors
  • Guanosine Triphosphate
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Monomeric GTP-Binding Proteins
  • Leucine