mTORC1 signaling and the metabolic control of cell growth
Introduction
Cellular metabolic homeostasis requires the coordinated conversion of nutrients (e.g., glucose and amino acids) and energy (ATP) into macromolecules (e.g., proteins, nucleic acids, and lipids) through anabolic processes and the recycling of these macromolecules back into their nutrient components, which can be further catabolized to produce energy (Figure 1a). With a continuous input of nutrients, this interconversion of nutrients and macromolecules can, theoretically, be self-sustaining. However, cells and organisms possess distinct systems to sense fluctuations in nutrients and energy to properly adapt their metabolic state to nutrient availability (feast) or depletion (famine) [1]. At the cellular level, these nutrient sensing mechanisms involve transcription factors, such as hypoxia-inducible factor 1 (HIF1) and sterol regulatory element-binding protein (SREBP), which can alter the metabolic program of the cell through the expression of nutrient transporters and metabolic pathway-specific enzymes. In addition, acute adaptations to changes in intracellular nutrients and energy can be achieved through nutrient sensing signaling proteins, such as the protein kinases glucose non-fermenting 2 (GCN2) and AMP-activated protein kinase (AMPK). Here, we discuss the mechanistic (or mammalian) target of rapamycin (mTOR) complex 1 (mTORC1) as a nutrient sensing protein kinase that acts as a master regulator of cellular metabolism. Through a network of upstream signaling pathways, mTORC1 integrates signals from intracellular nutrients and energy with endocrine and paracrine signals reflecting the status of the system or tissue, in the form of exogenous growth factors, hormones, and cytokines, to reciprocally regulate a variety of anabolic and catabolic processes (Figure 1b). Through its control of cellular metabolism, mTORC1 promotes the production of biomass to support growth and proliferation or the stable storage of energy in highly reduced macromolecules, such as lipids. The importance of coordinated regulation of distinct biosynthetic processes and metabolic pathways that support anabolic metabolism downstream of mTORC1 is discussed below.
Section snippets
An upstream signaling network regulates mTORC1 through the Rag and Rheb (Ras homology enriched in brain) GTPases
The activation state of mTORC1 is tightly controlled by numerous upstream signaling pathways that respond to either exogenous growth factors through cell surface receptors or changes in intracellular nutrients and energy through cytosolic sensors. These mTORC1 regulatory pathways, which have been extensively reviewed in recent years [2, 3], impinge on two systems of small G proteins and their regulators that reside, at least in part, on the cytosolic face of lysosomes (Figure 2). The Rag
mTORC1 activation promotes anabolic metabolism
Through a variety of transcriptional, translational, and post-translational mechanisms, mTORC1 stimulates an increase in biosynthetic processes that are otherwise maintained at basal, homeostatic states. As such, it should be emphasized that mTORC1 is not required for the anabolic processes described below, but serves as an essential link between growth signals and heightened biosynthetic activities.
Autophagy and lysosomal degradation
Autophagy is a highly conserved catabolic pathway that is activated in response to nutrient and energy deprivation, at least in part, through the inhibition of mTORC1 signaling. The process of autophagy serves to recycle cytosolic components, such as proteins and organelles, into their nutrient components through engulfment in a membranous structure called the autophagosome, which subsequently fuses with the lysosome for degradation of its components. The autophagy pathway is made up of several
Conclusions and impact on human diseases
It is now evident that mTORC1 serves as a key molecular link between signals that control cell growth and the metabolic processes that underlie growth (Figure 2). It should be emphasized that, while mTORC1 is essential for the survival of organisms from yeast to mammals [104, 105], it is not generally required for the basal activity of the metabolic pathways it controls. As such, inhibition of mTORC1 is not equal to direct inhibition of a metabolic enzyme in the given pathway. However, the
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank Gerta Hoxhaj and Alexander Valvezan for discussions and critical comments. Studies in the Manning laboratory on this topic were supported by grants from the LAM Foundation (I.B.-S.), Tuberous Sclerosis Alliance (B.D.M.), Ellison Medical Foundation (B.D.M.), and NIH grants K99/R00-CA194192 (I.B.-S.) and P01-CA120964 and R35-CA197459 (B.D.M.).
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Current address: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.