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

Abstract

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.

Rheb in neuronal degeneration, regeneration, and connectivity

“…Rheb is localized to multiple endo-membrane compartments including lysosomes due to the farnesylation of the C-terminal CAAX motif (Buerger et al, 2006). This localization of Rheb is not affected by insulin or amino acid levels (Inoki et al, 2002;Zhang et al, 2003;Li et al, 2004a,b;Tee et al, 2005;Menon et al, 2014). Although some studies suggest that Akt mediates the disassembly of the TSC complex, others suggest that Akt-mediated phosphorylation of TSC2 causes its degradation (Inoki et al, 2002;Menon et al, 2014).…”

“…The TSC2 within the intact TSC complex has a strong binding preference for Rheb-GDP. In the presence of insulin, Akt-mediated phosphorylation of TSC complex causes its dissociation from the lysosomes, hence promoting Rheb and mTORC1 activation ( Benjamin and Hall, 2014;Menon et al, 2014;Dibble and Cantley, 2015). Interestingly, mTORC1 can also be activated at other endo-membranes including peroxisomes and Golgi complex (Flinn et al, 2010;Zhang et al, 2013).…”

“…This localization of Rheb is not affected by insulin or amino acid levels (Inoki et al, 2002;Zhang et al, 2003;Li et al, 2004a,b;Tee et al, 2005;Menon et al, 2014). Although some studies suggest that Akt mediates the disassembly of the TSC complex, others suggest that Akt-mediated phosphorylation of TSC2 causes its degradation (Inoki et al, 2002;Menon et al, 2014). However, recently it was found that in the absence of insulin or growth factors, the TSC complex resides at the lysosomes in a Rheb-dependent manner and inactivates the Rheb at the lysosomes by acting as a Rheb-GAP.…”

“…Hence, the GTP/GDP loading state of Rheb is highly regulated by its GAP, which is controlled by the presence of growth factors ( Figure 1). Rheb binds to its effector 'mammalian target of rapamycin' (mTOR) (Long et al, 2005) and GTPloaded Rheb is required for the activation of mTOR (Inoki et al, 2003;Long et al, 2005;Menon et al, 2014;Dibble and Cantley, 2015). A guanine nucleotide exchange factor (GEF) for Rheb has been identified but the biochemical and cellular relevance is still under discussion (Rehmann et al, 2008;Schöpel et al, 2017).…”

“…The localization of TSC complex, Rheb and mTORC1 at the lysosomes is critical for the regulation of mTORC1 and downstream pathway activation (Demetriades et al, 2014;Menon et al, 2014). Rheb is localized to multiple endo-membrane compartments including lysosomes due to the farnesylation of the C-terminal CAAX motif (Buerger et al, 2006).…”