An emerging role for TOR signaling in mammalian tissue and stem cell physiology

Abstract

SummaryThe mammalian target of rapamycin (mTOR) is a kinase that responds to a myriad of signals, ranging from nutrient availability and energy status, to cellular stressors, oxygen sensors and growth factors. The finely tuned response of mTOR to these stimuli results in alterations to cell metabolism and cell growth. Recent studies of conditional knockouts of mTOR pathway components in mice have affirmed the role of mTOR signaling in energy balance, both at the cell and whole organism levels. Such studies have also highlighted a role for mTOR in stem cell homeostasis and lifespan determination. Here, we discuss the molecular mechanisms of TOR signaling and review recent in vitro and in vivo studies of mTOR tissuespecific activities in mammals. Key words: mTOR, TORC1, Stem cells, Rapamycin, TSC IntroductionThe ability of cells to respond appropriately to nutrient flux is essential for maintaining energy homeostasis. From yeast to humans, nutrient deprivation activates a highly conserved cellular program that acts to prune back energy-intensive processes while promoting energy-producing catabolic activities. Target of rapamycin (TOR) is a key regulatory kinase that acts at the nexus of a vast array of nutrient-sensitive signals to regulate cellular metabolism. TOR exists in two complexes, TOR complex 1 (TORC1) and TOR complex 2 (TORC2), which are functionally conserved in eukaryotes. TORC1 is the primary effector for the nutrient-sensitive functions of TOR, whereas TORC2 has been implicated in cytoskeletal reorganization and cell survival. During periods of nutrient deprivation, TORC1 activity in vitro is drastically reduced, resulting in the modulation of several key processes, including translational initiation, ribosome and tRNA biogenesis, and autophagy. Key upstream regulators of TORC1 include AKT (a serine/threonine protein kinase) and the tuberous sclerosis complex (TSC). More recently, the activity of Rag GTPases in concert with Ras homolog enriched in brain (Rheb) has been described in the promotion of TORC1 activity in vitro by amino acids. These studies have filled in a major gap in our understanding of how intracellular nutrients regulate TOR activity. However, our understanding of TOR signaling in vivo has progressed more slowly. Deletion of TOR is lethal in all eukaryotic model systems, making the study of TOR signaling in vivo more challenging. Deletion of mTOR in mice, for example, is early embryonic lethal; however, conditional knockouts of mTOR or TORC components in mice have begun to reveal exciting functions for mTOR in metabolically sensitive organs. In this review, we introduce our current understanding of TOR signaling in vitro and highlight recent advances in this field. Moreover, we review recent genetic studies in mice that explore perturbation of mTOR pathway components. Finally, we discuss several recent studies that have identified a role for TOR signaling in various stem cell models. TOR kinaseThe discovery of TOR kinases arose from the study of the antifungal agent rapamycin. Additi...

Staying alive

“…273 The TOR signaling pathway is frequently regulated with quiescence and can allow the cell to respond to extracellular nutritional conditions by modulating the rate of protein synthesis and growth. 19 In yeast, lymphocytes and HSCs, downregulation of the TOR pathway occurs with quiescence. In yeast, inhibiting TOR is sufficient to recapitulate a quiescence-like phenotype.…”

“…21 In mammals, there are two TOR proteins, mTORC1, which is sensitive to rapamycin, and mTORC2, which is not. 19,22 mTORC1 plays an important role in promoting translation and two important targets of its kinase activity are 4E-BP1 and S6 kinase. 23 Phosphorylation of 4E-BP1 releases its inhibition of eIF-4E, 24 which can, in turn, recruit the translation initiation complex to 5' caps and increase cap-dependent translation rates.…”

Metabolic Adaptation of Neutrophils in Cystic Fibrosis Airways Involves Distinct Shifts in Nutrient Transporter Expression

“…The CREB pathway is commonly induced in stress responses, as expected in the inflammatory environment of CF airways (6). However, the mTOR pathway is the main anabolic switch in eukaryotes and is generally associated with cell survival and growth (7). Therefore, its activation in catabolic neutrophils is rather perplexing.…”

Protein Phosphorylation as a Key Mechanism of mTORC1/2 Signaling Pathways

“…Other mTORC1 functions include autophagy inhibition, promotion of the ribosome biogenesis and of the tRNA production. The main known mTORC2 activity is the phosphorylation and activation of AKT and of the related kinases -serum/glucocorticoid regulated kinase (SGK) and protein kinase C (PKC) [35]. It is also involved in cytoskeletal organization.…”

“…mTOR can associate with general transcription factor III C (TFIIIC) and relieve its inhibitor Maf1, leading to increased tRNA production. mTORC1 activity also promotes association between transcription initiation factor 1A (TIF-1A) and polymerase I (PolI), thereby promoting rRNA synthesis [35]. The activity of several other transcription factors, such as signal transducer and activator of transcription-1 and -3 (Stat-1 and Stat-3) is also suggested to be regulated by mTORC1-mediated phosphorylation in a rapamycinsensitive manner [196].…”