title: Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome.
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.
authors: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors: Suchithra
authors: S
authors: Menon
authors: 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.
authors: Christian C
authors: CC
authors: Dibble
authors: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors: George
authors: G
authors: Talbott
authors: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors: Gerta
authors: G
authors: Hoxhaj
authors: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors: Alexander J
authors: AJ
authors: Valvezan
authors: Department of Systems Biology, Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors: Hidenori
authors: H
authors: Takahashi
authors: 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.
authors: Lewis C
authors: LC
authors: Cantley
authors: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA. Electronic address: bmanning@hsph.harvard.edu.
authors: Brendan D
authors: BD
authors: Manning
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D000596:Amino Acids; D020558:GTP Phosphohydrolases; D007328:Insulin; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse