Document Detail


Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids.
MedLine Citation:
PMID:  20381137     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Yasemin Sancak; Liron Bar-Peled; Roberto Zoncu; Andrew L Markhard; Shigeyuki Nada; David M Sabatini
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2010-04-08
Journal Detail:
Title:  Cell     Volume:  141     ISSN:  1097-4172     ISO Abbreviation:  Cell     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-20     Completed Date:  2010-05-04     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  0413066     Medline TA:  Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  290-303     Citation Subset:  IM    
Copyright Information:
Copyright 2010 Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / metabolism
Amino Acids / metabolism
Animals
Cell Line
Drosophila
Humans
Intracellular Membranes / metabolism
Intracellular Signaling Peptides and Proteins / metabolism
Lysosome-Associated Membrane Glycoproteins / metabolism
Lysosomes / metabolism*
MAP Kinase Signaling System
Models, Biological
Monomeric GTP-Binding Proteins / metabolism
Multiprotein Complexes
Mutation
Neuropeptides / metabolism
Protein Binding
Protein Transport
Protein-Serine-Threonine Kinases / metabolism
Proteins / genetics,  metabolism
Recombinant Proteins / genetics,  metabolism
Signal Transduction
TOR Serine-Threonine Kinases
Transcription Factors / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
AI47389/AI/NIAID NIH HHS; CA103866/CA/NCI NIH HHS; R01 AI047389/AI/NIAID NIH HHS; R01 AI047389-01/AI/NIAID NIH HHS; R01 CA103866/CA/NCI NIH HHS; R01 CA103866-01/CA/NCI NIH HHS; R01 CA129105/CA/NCI NIH HHS; R37 AI047389/AI/NIAID NIH HHS; //Howard Hughes Medical Institute
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Amino Acids; 0/Intracellular Signaling Peptides and Proteins; 0/LAMP2 protein, human; 0/LAMTOR3 protein, human; 0/Lysosome-Associated Membrane Glycoproteins; 0/Multiprotein Complexes; 0/Neuropeptides; 0/Proteins; 0/RHEB protein, human; 0/RPTOR protein, human; 0/Recombinant Proteins; 0/Transcription Factors; 0/mechanistic target of rapamycin complex 1; EC 2.7.1.1/MTOR protein, human; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 3.6.5.2/Monomeric GTP-Binding Proteins
Comments/Corrections
Comment In:
Nat Rev Cancer. 2010 Jun;10(6):381   [PMID:  20506585 ]
Cell Metab. 2010 May 5;11(5):341-2   [PMID:  20444413 ]
Nat Rev Mol Cell Biol. 2010 Jun;11(6):388   [PMID:  20445544 ]

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