Regulation and metabolic functions of mTORC1 and mTORC2

Abstract

Cells metabolize nutrients for biosynthetic and bioenergetic needs to fuel growth and proliferation. The uptake of nutrients from the environment and their intracellular metabolism is a highly controlled process that involves crosstalk between growth signaling and metabolic pathways. Despite constant fluctuations in nutrient availability and environmental signals, normal cells restore metabolic homeostasis to maintain cellular functions and prevent disease. A central signaling molecule that integrates growth with metabolism is the mechanistic target of rapamycin (mTOR). mTOR is a protein kinase that responds to levels of nutrients and growth signals. mTOR forms two protein complexes, mTORC1, which is sensitive to rapamycin and mTORC2, which is not directly inhibited by this drug. Rapamycin has facilitated the discovery of the various functions of mTORC1 in metabolism. Genetic models that disrupt either mTORC1 or mTORC2 have expanded our knowledge on their cellular, tissue as well as systemic functions in metabolism. Nevertheless, our knowledge on the regulation and functions of mTORC2, particularly in metabolism, has lagged behind. Since mTOR is an important target for cancer, aging and other metabolism-related pathologies, understanding the distinct and overlapping regulation and functions of the two mTOR complexes is vital for the development of more effective therapeutic strategies. This review will discuss the key discoveries and recent findings on the regulation and metabolic functions of the mTOR complexes. We highlight findings from cancer models, but also discuss other examples of the mTOR-mediated metabolic reprogramming occurring in stem and immune cells, type 2 diabetes/obesity, neurodegenerative disorders and aging.

Rapalink-1 Increased Infarct Size in Early Cerebral Ischemia–Reperfusion With Increased Blood–Brain Barrier Disruption

“…In our previous studies, we reported an increase in the mTORC1 and mTORC2 activity in cerebral ischemia-reperfusion where there is a shortage of energy and an imbalance between energy demand and metabolism (Chi et al, 2016a(Chi et al, , 2020Weiss et al, 2018). In this study, the phosphorylation of Akt ( Ser473) is increased during ischemiareperfusion of the brain of the rat, which is consistent with the role of mTORC2 in responding to starvation conditions and neuronal survival through FOX03a (Brunet et al, 2001;Szwed et al, 2021). The elevated phosphorylation of Akt (Ser473) during ischemia-reperfusion is accompanied by increased mTORC1 signaling.…”

“…Mechanistic target of rapamycin (mTOR), as a catalytic subunit of two distinct protein complexes, namely, rapamycin-sensitive mTORC1 and rapamycin-insensitive mTORC2, is a protein kinase and an integral regulator of cellular proliferation, apoptosis, growth, metabolism, and autophagy (Murugan, 2019 ; Szwed et al, 2021 ). Both mTORCs are involved in maintaining metabolic homeostasis by responding to intracellular and environmental nutrient conditions.…”

The innate immune kinase TBK1 directly increases mTORC2 activity and downstream signaling to Akt

“…This observation agrees with other studies ( 14 , 15 , 16 , 17 , 18 ), several of which reported that TBK1 phosphorylates Akt S473 directly ( 16 , 17 , 18 ). As Akt S473 represents an established target of mTOR complex 2 (mTORC2) ( 19 , 20 , 21 , 22 ), we investigated more fully the mechanism by which TBK1 promotes Akt phosphorylation, testing the hypothesis that TBK1 directly activates mTORC2 and its downstream signaling to Akt.…”

“…mTOR comprises the catalytic kinase core of two known multisubunit mTOR complexes (mTORCs) ( 21 , 22 , 23 ). The scaffolding protein Raptor (regulatory-associated protein of mTOR) defines mTORC1 ( 24 , 25 ), whereas the scaffolding protein Rictor (rapamycin-insensitive companion of mTOR) defines mTORC2 ( 26 , 27 ).…”

“…These mTORCs sense and integrate a diverse array of environmental cues to control cell physiology appropriate for cell type and context. Indeed, aberrant mTORC function contributes to pathologic states including oncogenesis and obesity-linked metabolic disorders ( 21 , 22 , 23 , 28 ). Despite the physiological importance of mTOR, our knowledge of the upstream regulation of mTORCs remain incompletely defined, in particular mTORC2.…”