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PMID: 20053679 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The late endosome is essential for mTORC1 signaling.

Molecular biology of the cell ·Vol. 21 ·No. 5 ·2010-03-01 ·Pages 833-41

Flinn RJ, Yan Y, Goswami S, Parker PJ, Backer JM

Abstract

The multisubunit mTORC1 complex integrates signals from growth factors and nutrients to regulate protein synthesis, cell growth, and autophagy. To examine how endocytic trafficking might be involved in nutrient regulation of mTORC1, we perturbed specific endocytic trafficking pathways and measured mTORC1 activity using S6K1 as a readout. When early/late endosomal conversion was blocked by either overexpression of constitutively active Rab5 (Rab5CA) or knockdown of the Rab7 GEF hVps39, insulin- and amino acid-stimulated mTORC1/S6K1 activation were inhibited, and mTOR localized to hybrid early/late endosomes. Inhibition of other stages of endocytic trafficking had no effect on mTORC1. Overexpression of Rheb, which activates mTOR independently of mTOR localization, rescued mTORC1 signaling in cells expressing Rab5CA, whereas hyperactivation of endogenous Rheb in TSC2-/- MEFs did not. These data suggest that integrity of late endosomes is essential for amino acid- and insulin-stimulated mTORC1 signaling and that blocking the early/late endosomal conversion prevents mTOR from interacting with Rheb in the late endosomal compartment.

MeSH Terms
Animals Endosomes/metabolism Fibroblasts/metabolism Gene Expression Regulation HeLa Cells Humans Mechanistic Target of Rapamycin Complex 1 Mice Monomeric GTP-Binding Proteins/metabolism Multiprotein Complexes Neuropeptides/metabolism Proteins Ras Homolog Enriched in Brain Protein Ribosomal Protein S6 Kinases, 70-kDa/metabolism Ribosomal Protein S6 Kinases, 90-kDa/metabolism Signal Transduction TOR Serine-Threonine Kinases Transcription Factors/metabolism Tuberous Sclerosis Complex 2 Protein Tumor Suppressor Proteins/metabolism rab5 GTP-Binding Proteins/metabolism
Chemicals
Multiprotein Complexes Neuropeptides Proteins RHEB protein, human Ras Homolog Enriched in Brain Protein Rheb protein, mouse TSC2 protein, human Transcription Factors Tsc2 protein, mouse Tuberous Sclerosis Complex 2 Protein Tumor Suppressor Proteins Mechanistic Target of Rapamycin Complex 1 Ribosomal Protein S6 Kinases, 70-kDa Ribosomal Protein S6 Kinases, 90-kDa Rps6ka1 protein, mouse TOR Serine-Threonine Kinases ribosomal protein S6 kinase, 70kD, polypeptide 1 RAB5C protein, human Monomeric GTP-Binding Proteins rab5 GTP-Binding Proteins
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Flinn Rory J
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Yan Ying
Goswami Sumanta
Parker Peter J
Backer Jonathan M
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Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1939-4586
DOI
10.1091/mbc.e09-09-0756
Published
2010-03-01
Epub
2010-00-06
Pages
833-41
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC2828969
Subset
IM
Grants
NIDDK NIH HHS · DK020541 · United States
NIDDK NIH HHS · P60 DK020541 · United States
NCI NIH HHS · P30 CA013330 · United States
NIGMS NIH HHS · T32 GM007491 · United States
NIGMS NIH HHS · T32 GM07491 · United States
NIDDK NIH HHS · DK565701 · United States
NIDDK NIH HHS · P30 DK020541 · United States
External Links
PubMed source DOI: 10.1091/mbc.e09-09-0756 PMC Full Text View journal details
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