TY - JOUR
T1 - Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome
AU - Menon, Suchithra
AU - Dibble, Christian C.
AU - Talbott, George
AU - Hoxhaj, Gerta
AU - Valvezan, Alexander J.
AU - Takahashi, Hidenori
AU - Cantley, Lewis C.
AU - Manning, Brendan D.
N1 - Funding Information:
We thank J. Howell for critical comments on the manuscript, S.G. Kim and J. Blenis for antibody advice, L. Bar-Peled and D.M. Sabatini for the p18-N-terminal construct, D.J. Kwiatkowski for the Tsc2 −/− MEFs, and P.P. Pandolfi for the Pten −/− MEFs. This work was supported by NIH grants T32-HL007893 (C.C.D.), R01-CA122617 (B.D.M.), and P01-CA120964 (B.D.M. and L.C.C.) and by The Ellison Medical Foundation (B.D.M.).
PY - 2014/2/13
Y1 - 2014/2/13
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2013.11.049
DO - 10.1016/j.cell.2013.11.049
M3 - Article
C2 - 24529379
AN - SCOPUS:84894114029
SN - 0092-8674
VL - 156
SP - 771
EP - 785
JO - Cell
JF - Cell
IS - 4
ER -