mTOR Signaling in Growth, Metabolism, and Disease

Abstract

The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

Keywords: aging; cancer; cell growth; diabetes; mTOR; mTORC1; mTORC2; metabolism; nutrients; signaling.

Figure 1. mTORC1 and mTORC2

(A) The mTORC1 and mTORC2 signaling pathways. (B) mTORC1 subunits and respective binding sites on mTOR. The FKBP12-rapamycin. The 5.9 Å cryo-EM structure of mTORC1 (without DEPTOR and PRAS40, PDB ID: 5FLC) from is depicted as a space filling model and colored by subunit. (C) mTORC2 subunits and respective binding sites on mTOR.

Figure 2. The mTOR Signaling Network

(A) The signaling pathways upstream of mTORC1 and mTORC2. Positive regulators of mTORC1 signaling are shown in yellow, while negative regulators are shown in blue. mTORC1 and mTORC2 are shown in green and red, respectively. (B) The major signaling pathways downstream of mTORC1 signaling in mRNA translation, metabolism, and protein turnover. (C) mTORC1 controls the activity of several transcription factors that can also be independently regulated by cell stress. (D) The major signaling pathways downstream of mTORC2 signaling.

Figure 3. Evolutionary Conservation of the mTOR Pathway

(A) The nutrient sensing pathway upstream of mammalian mTORC1 (left) and yeast TORC1 (right). (B) Phylogenetic tree depicting the presence (green box) of key mTORC1 regulators in various model organisms.

Figure 4. Physiological Roles of mTOR

(A) mTORC1 controls the balance between anabolism and catabolism in response to fasting and feeding. (B) The effect of cumulative mTORC1 activity on overall health. (C) The effect of mTORC1 hyperactivation in pancreatic β-cells on glucose tolerance over time. (D) The normal functions of mTORC1 in the liver, muscle, pancreas, and adipose tissue (left), and the consequences of chronic mTORC1 inhibition (middle) or activation (right). (E) Deregulation of mTORC1 signaling in insulin resistance/diabetes, and the effect of rapamycin or a theoretical mTORC1 specific inhibitor.

Figure 5. mTOR in Cancer and Aging

(A) The common tumor suppressors and oncogenes upstream of mTORC1 leading to increased mTORC1 signaling in a wide variety of cancers. (B) The varying effects of rapalogs, catalytic mTOR inhibitors, a combination of an mTOR inhibitor and autophagy inhibitor on cancer proliferation and survival. (C) The role of mTORC1 signaling in aging.