Spatial Control of the TSC Complex Integrates Insulin and Nutrient Regulation of mTORC1 at the Lysosome

By Suchithra Menon, Christian C. Dibble, G. Talbott, Gerta Hoxhaj, Alexander J. Valvezan, Hidenori Takahashi, Lewis C. Cantley, B. Manning. Cell, 2014

771 citations recorded by the source corpus.

SUMMARY 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.

Subfields: Cell Biology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/a615abafe51caa40af7be16317620cdb4f922512

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Citations in the corpus

mTOR: a pharmacologic target for autophagy regulation. (2015, positive): “In addition, it has been shown that the insulin/ AKT signaling axis regulates lysosomal localization of TSC1/2, demonstrating that the lysosome is the signaling hub of mTORC1 activation (24).”
Regulation of mTORC1 by amino acids (2014, positive): “Given the number of signals upstream of mTORC1 that converge on TSC complex phosphorylation, it is likely that other pathways, like the AMPK pathway, also affect TSC shuttling to and from the lysosome (74).”
Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease (2023, background): “39 Importantly, the environmental/extracellular and intracellular stresses are sensed by the mTORC1 and modulate cellular growth and survival under hypoxia, lower levels of ATP, and DNA damage conditions.”
Nutrient sensing and TOR signaling in yeast and mammals (2017, positive): “We note that yeast contains a protein, termed Rhb1 (Urano et al , 2000), that resembles RHEB, but is not a functional RHEB homolog. mTORC1 inactivation is an active process that requires translocation of TSC2 to the lysosome to inhibit RHEB upon growth factor deprivation (Menon et al , 2014; Fawal e”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “This phosphorylation inhibits TSC by dissociating it from the lysosomal membrane, where at least some fraction of cellular Rheb localizes (Menon et al., 2014).”
mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “This phosphorylation inhibits TSC by dissociating it from the lysosomal membrane, where at least some fraction of cellular Rheb localizes (Menon et al., 2014).”
The Neurology of mTOR (2014, positive): “One exception is the recently described TBC1D7, a TSC1-dependent component of the TSC1/2 complex that functions similarly to TSC1 and TSC2 on a cellular level (Dibble et al., 2012; Menon et al., 2014).”
The CASTOR proteins are arginine sensors for the mTORC1 pathway (2016, positive): “The lysosome is a critical organelle for mTORC1 activation, and amino acids promote the translocation of mTORC1 to its surface where its kinase activator Rheb, a small GTPase, resides (Buerger et al., 2006; Dibble et al., 2012; Menon et al., 2014; Saito et al., 2005; Sancak et al., 2008).”