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Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids.

The mTORC1 kinase promotes growth in response to growth factors, energy levels, and amino acids, and its activity is often deregulated in disease. The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb. We show that amino acids induce the movement of mTORC1 to lysosomal membranes, where the Rag proteins reside. A complex encoded by the MAPKSP1, ROBLD3, and c11orf59 genes, which we term Ragulator, interacts with the Rag GTPases, recruits them to lysosomes, and is essential for mTORC1 activation. Constitutive targeting of mTORC1 to the lysosomal surface is sufficient to render the mTORC1 pathway amino acid insensitive and independent of Rag and Ragulator, but not Rheb, function. Thus, Rag-Ragulator-mediated translocation of mTORC1 to lysosomal membranes is the key event in amino acid signaling to mTORC1.

Pubmed ID: 20381137

Authors

  • Sancak Y
  • Bar-Peled L
  • Zoncu R
  • Markhard AL
  • Nada S
  • Sabatini DM

Journal

Cell

Publication Data

April 16, 2010

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI47389
  • Agency: NCI NIH HHS, Id: CA103866
  • Agency: NIAID NIH HHS, Id: R01 AI047389
  • Agency: NIAID NIH HHS, Id: R01 AI047389-01
  • Agency: NCI NIH HHS, Id: R01 CA103866
  • Agency: NCI NIH HHS, Id: R01 CA103866-01
  • Agency: NCI NIH HHS, Id: R01 CA129105
  • Agency: NIAID NIH HHS, Id: R37 AI047389
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acids
  • Animals
  • Cell Line
  • Drosophila
  • Humans
  • Intracellular Membranes
  • Intracellular Signaling Peptides and Proteins
  • Lysosomal-Associated Membrane Protein 2
  • Lysosome-Associated Membrane Glycoproteins
  • Lysosomes
  • MAP Kinase Signaling System
  • Models, Biological
  • Monomeric GTP-Binding Proteins
  • Multiprotein Complexes
  • Mutation
  • Neuropeptides
  • Protein Binding
  • Protein Transport
  • Protein-Serine-Threonine Kinases
  • Proteins
  • Recombinant Proteins
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Transcription Factors