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PMID: 24529380 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2.

Cell ·Vol. 156 ·No. 4 ·2014-02-13 ·Pages 786-99

Demetriades C, Doumpas N, Teleman AA

Abstract

TOR complex 1 (TORC1) is a potent anabolic regulator of cellular growth and metabolism. When cells have sufficient amino acids, TORC1 is active due to its lysosomal localization mediated via the Rag GTPases. Upon amino acid removal, the Rag GTPases release TORC1, causing it to become cytoplasmic and inactive. We show here that, upon amino acid removal, the Rag GTPases also recruit TSC2 to the lysosome, where it can act on Rheb. Only when both the Rag GTPases and Rheb are inactive is TORC1 fully released from the lysosome. Upon amino acid withdrawal, cells lacking TSC2 fail to completely release TORC1 from the lysosome, fail to completely inactivate TORC1, and fail to adjust physiologically to amino acid starvation. These data suggest that regulation of TSC2 subcellular localization may be a general mechanism to control its activity and place TSC2 in the amino-acid-sensing pathway to TORC1.

MeSH Terms
Amino Acids/metabolism HeLa Cells Humans Insulin/metabolism Lysosomes/metabolism Mechanistic Target of Rapamycin Complex 1 Monomeric GTP-Binding Proteins/metabolism Multiprotein Complexes/metabolism Neuropeptides/metabolism Phosphatidylinositol 3-Kinases/metabolism Prenylation Ras Homolog Enriched in Brain Protein Signal Transduction TOR Serine-Threonine Kinases/metabolism Tuberous Sclerosis Complex 2 Protein Tumor Suppressor Proteins/metabolism
Chemicals
Amino Acids Insulin Multiprotein Complexes Neuropeptides RHEB protein, human Ras Homolog Enriched in Brain Protein TSC2 protein, human Tuberous Sclerosis Complex 2 Protein Tumor Suppressor Proteins Mechanistic Target of Rapamycin Complex 1 TOR Serine-Threonine Kinases Monomeric GTP-Binding Proteins
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Demetriades Constantinos
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: k.dimitriadis@dkfz.de.
Doumpas Nikolaos
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Teleman Aurelio A
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: a.teleman@dkfz.de.
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2014.01.024
Email
k.dimitriadis@dkfz.de
a.teleman@dkfz.de
Published
2014-02-13
Pages
786-99
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC4346203
Subset
IM
Grants
European Research Council · 260602 · International
Corrections
CommentIn
PMID: 24529368
External Links
PubMed source DOI: 10.1016/j.cell.2014.01.024 PMC Full Text View journal details
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