Document Detail


mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase.
MedLine Citation:
PMID:  22053050     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The mTOR complex 1 (mTORC1) protein kinase is a master growth regulator that is stimulated by amino acids. Amino acids activate the Rag guanosine triphosphatases (GTPases), which promote the translocation of mTORC1 to the lysosomal surface, the site of mTORC1 activation. We found that the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1. The v-ATPase engages in extensive amino acid-sensitive interactions with the Ragulator, a scaffolding complex that anchors the Rag GTPases to the lysosome. In a cell-free system, ATP hydrolysis by the v-ATPase was necessary for amino acids to regulate the v-ATPase-Ragulator interaction and promote mTORC1 translocation. Results obtained in vitro and in human cells suggest that amino acid signaling begins within the lysosomal lumen. These results identify the v-ATPase as a component of the mTOR pathway and delineate a lysosome-associated machinery for amino acid sensing.
Authors:
Roberto Zoncu; Liron Bar-Peled; Alejo Efeyan; Shuyu Wang; Yasemin Sancak; David M Sabatini
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.    
Journal Detail:
Title:  Science (New York, N.Y.)     Volume:  334     ISSN:  1095-9203     ISO Abbreviation:  Science     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-04     Completed Date:  2012-01-25     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  0404511     Medline TA:  Science     Country:  United States    
Other Details:
Languages:  eng     Pagination:  678-83     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amino Acids / metabolism*
Animals
Cell Line
Drosophila
GTP Phosphohydrolases / metabolism
Humans
Lysosomes / metabolism*
Multiprotein Complexes
Proteins / metabolism*
RNA Interference
Signal Transduction
TOR Serine-Threonine Kinases
Vacuolar Proton-Translocating ATPases / metabolism*
Grant Support
ID/Acronym/Agency:
AI47389/AI/NIAID NIH HHS; CA103866/CA/NCI NIH HHS; R01 CA103866/CA/NCI NIH HHS; R01 CA103866-07/CA/NCI NIH HHS; R01 CA103866-08/CA/NCI NIH HHS; R37 AI047389/AI/NIAID NIH HHS; R37 AI047389-11/AI/NIAID NIH HHS; R37 AI047389-12/AI/NIAID NIH HHS; R37 AI047389-13/AI/NIAID NIH HHS; T32 GM007753/GM/NIGMS NIH HHS; //Howard Hughes Medical Institute
Chemical
Reg. No./Substance:
0/Amino Acids; 0/Multiprotein Complexes; 0/Proteins; 0/mechanistic target of rapamycin complex 1; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 3.6.1.-/GTP Phosphohydrolases; EC 3.6.1.-/Vacuolar Proton-Translocating ATPases
Comments/Corrections
Comment In:
Science. 2011 Nov 4;334(6056):611-2   [PMID:  22053037 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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