Regulation of the mTOR/S6K pathway by cellular energy

The mammalian target of rapamycin (mTOR) signaling pathway integrates positive and negative signals that control cellular growth, metabolism and survival. mTOR exists in two different complexes, mTOR Complex1 and mTOR Complex2. mTOR Complex1, which is rapamycin-sensitive, phosphorylates ribosomal S6 kinase 1 (S6K1) and initiation factor 4E binding proteins (4E-BPs). mTOR Complex2, which is rapamycin-insensitive, phosphorylates and activates protein kinase B (PKB/Akt). Both mTOR complexes are stimulated by mitogens, but only mTOR Complex1 is under the control of nutrients and cellular energy status. With respect to cellular energy status, mTOR Complex1 signaling is sensitive to inhibition of both glycolytic flux and mitochondrial oxidative phosphorylation. In brief, energy deprivation affects mTOR Complex1 through two routes: an acute rapid response and a chronic long lasting response. Here we describe the mechanisms by which energy depletion influences mTOR Complex1 signaling, largely focusing on the acute response. Previous studies, mainly based on correlative evidence, argued that the acute energy deprivation response is mediated by adenosine mono phosphate-dependent protein kinase (AMPK) through the activation of the tumor suppressor, Tuberous Sclerosis Complex 1 and 2 (TSC1/2). We used specific knockout cell lines to address this issue and, unexpectedly, found that TSC1/2, recognized as a point of convergence for a number of specific signals, is dispensable for the regulation of mTOR Complex1 by acute energy depletion. Strikingly, neither the inhibitory acute nor the chronic energy-deprivation response towards mTOR Complex1 requires AMPK. Moreover, the upstream activator of AMPK, the serine/threonine protein kinase 11 (STK11/LKB1) is also dispensable for the acute energy depletion response to mTOR Complex1 signaling. The results demonstrate that acute energy depletion signals operate independently of the LKB1-AMPK-TSC2 axis on mTOR Complex1, revealing a novel autonomous energy-dependent mTOR Complex1 signaling pathway. Importantly, we find that metformin, a widely prescribed drug for the treatment of diabetes mellitus type II, which is thought to operate through the LKB1-AMPK-TSC2 axis, affects mTOR Complex1 signaling through this same autonomous energy-dependent pathway, independent of AMPK and TSC. The significance of these findings is underscored by recent clinical studies showing that patients using metformin have a lower incidence of tumor development.