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PMID: 24529379 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome.

Cell ·Vol. 156 ·No. 4 ·2014-02-13 ·Pages 771-85

Menon S, Dibble CC, Talbott G, Hoxhaj G, Valvezan AJ, Takahashi H, Cantley LC, Manning BD

Abstract

mTORC1 promotes cell growth in response to nutrients and growth factors. Insulin activates mTORC1 through the PI3K-Akt pathway, which inhibits the TSC1-TSC2-TBC1D7 complex (the TSC complex) to turn on Rheb, an essential activator of mTORC1. However, the mechanistic basis of how this pathway integrates with nutrient-sensing pathways is unknown. We demonstrate that insulin stimulates acute dissociation of the TSC complex from the lysosomal surface, where subpopulations of Rheb and mTORC1 reside. The TSC complex associates with the lysosome in a Rheb-dependent manner, and its dissociation in response to insulin requires Akt-mediated TSC2 phosphorylation. Loss of the PTEN tumor suppressor results in constitutive activation of mTORC1 through the Akt-dependent dissociation of the TSC complex from the lysosome. These findings provide a unifying mechanism by which independent pathways affecting the spatial recruitment of mTORC1 and the TSC complex to Rheb at the lysosomal surface serve to integrate diverse growth signals.

MeSH Terms
Amino Acids/metabolism Animals Cell Line GTP Phosphohydrolases/metabolism Humans Insulin/metabolism Lysosomes/metabolism Mechanistic Target of Rapamycin Complex 1 Mice Multiprotein Complexes/metabolism Phosphatidylinositol 3-Kinases/metabolism Phosphorylation TOR Serine-Threonine Kinases/metabolism Tuberous Sclerosis Complex 2 Protein Tumor Suppressor Proteins/metabolism
Chemicals
Amino Acids Insulin Multiprotein Complexes TSC2 protein, human Tsc2 protein, mouse Tuberous Sclerosis Complex 2 Protein Tumor Suppressor Proteins Mechanistic Target of Rapamycin Complex 1 TOR Serine-Threonine Kinases GTP Phosphohydrolases
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Menon Suchithra
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Dibble Christian C
Department of Systems Biology, Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Electronic address: ccdibble@bidmc.harvard.edu.
Talbott George
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Hoxhaj Gerta
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Valvezan Alexander J
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Takahashi Hidenori
Department of Systems Biology, Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Cantley Lewis C
Department of Systems Biology, Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Manning Brendan D
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA. Electronic address: bmanning@hsph.harvard.edu.
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2013.11.049
Email
ccdibble@bidmc.harvard.edu
bmanning@hsph.harvard.edu
Published
2014-02-13
Pages
771-85
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC4030681
Subset
IM
Grants
NCI NIH HHS · P01 CA120964 · United States
NIGMS NIH HHS · R01 GM041890 · United States
NHLBI NIH HHS · T32 HL007893 · United States
NCI NIH HHS · R01 CA122617 · United States
NCI NIH HHS · P01-CA120964 · United States
NHLBI NIH HHS · T32-HL007893 · United States
NCI NIH HHS · R01-CA122617 · United States
Corrections
CommentIn
PMID: 24529368
External Links
PubMed source DOI: 10.1016/j.cell.2013.11.049 PMC Full Text View journal details
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