The mTOR pathway integrates a diverse set of environmental cues, such as growth factor signals and nutritional status, to direct eukaryotic cell growth. Over the past two and a half decades, mapping of the mTOR signalling landscape has revealed that mTOR controls biomass accumulation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Given the pathway’s central role in maintaining cellular and physiological homeostasis, dysregulation of mTOR signalling has been implicated in metabolic disorders, neurodegeneration, cancer and ageing. In this Review, we highlight recent advances in our understanding of the complex regulation of the mTOR pathway and discuss its function in the context of physiology, human disease and pharmacological intervention.
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The authors thank all members of the Sabatini laboratory for helpful discussions, with particular gratitude to K. J. Condon and J. M. Orozco for their insightful comments on this manuscript and K. Shen for his assistance with Fig. 1. This work was supported by grants from the National Institutes of Health (NIH) (R01 CA103866, R01 CA129105 and R37 AI047389) and the Lustgarten Foundation to D.M.S and by fellowship funding from the NIH (T32 GM007287 and F31 CA232340) to G.Y.L. D.M.S. is an Investigator at the Howard Hughes Medical Institute and an American Cancer Society Research Professor.
D.M.S. is a founder and a member of the scientific advisory board for Navitor Pharmaceuticals, which targets the mTORC1 pathway for therapeutic benefit.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
A double-membraned vesicle that forms during the early stages of autophagy to engulf cellular cargo (organelles and macromolecules). The autophagosome fuses with the lysosome to degrade macromolecules into constituent amino acids or fatty acids, enabling their reuse elsewhere in the cell.
A non-selective endocytic process in which cells take up soluble nutrients and macromolecules from the extracellular medium. These molecules are eventually degraded and recycled in the lysosome.
- Endoplasmic reticulum unfolded protein response
A stress pathway activated by unfolded proteins in the endoplasmic reticulum lumen that upregulates chaperones, selectively degrades the mRNA of secretory proteins and reduces global protein synthesis.
- GTP exchange factor
A factor that catalyses the loading of GTP in place of GDP to activate a given small G protein.
A condition in which the head is abnormally small owing to a brain that fails to grow and fully develop. Microcephaly is often coupled to developmental abnormalities and cognitive deficits.
- Brain-derived neurotrophic factor
(BDNF). A member of the neurotrophin growth factor family that binds to tropomyosin receptor kinase B (Trkb) to stimulate the growth and differentiation of new neurons and synapses. BDNF may regulate synaptic plasticity, learning and memory.
- Dendritic spines
Small protrusions on dendrites that receive excitatory synaptic inputs and undergo morphological alterations to modulate synaptic strength. Because these spines are structured by the actin cytoskeleton, they are sensitive to mTOR complex 2 activity, such that mice lacking Rictor in the brain fail to convert early long-term potentiation into long-term memory.
- Long-term potentiation
A process in which synapses in neurons become selectively stronger in response to frequent activation. Long-term potentiation and long-term depression (the weakening of a synapse after persistent or patterned activation) may underlie neuronal plasticity by allowing the brain to change after an experience.
- NMDA receptor
An ionotropic glutamate receptor found at many excitatory synapses. Upon binding to the neurotransmitter glutamate, this receptor opens a cation channel, allowing calcium ions to flow into the neuron. Ketamine binds the NMDA receptor and antagonizes its activation by glutamate.
- Synaptic pruning
A regulated process in which axons and dendrites are eliminated to remove unnecessary synapses in an experience-dependent fashion. In humans, pruning occurs primarily during childhood and after adolescence.
- Senescent cells
Cells that have arrested in a quasi-G0 state and no longer divide. Often induced by insults associated with cellular ageing, the senescent state is also accompanied by morphological and metabolic changes that induce chromosomal remodelling, constitutive autophagy and secretion of inflammatory factors.
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