The mammalian target of rapamycin (mTOR) is a highly conserved kinase that belongs to the phosphoinositide 3-kinase-related protein kinases (PIKK) family. mTOR participates in two distinct complexes, mTOR complex 1 (mTORC1) and mTORC2.
mTORC1 integrates energy, nutrients, stress and growth factors and, in response to these stimuli, it drives the growth of cells, organs and whole organisms. mTORC2, which is activated by growth factors, promotes cell proliferation and survival.
mTOR signalling maximizes energy storage and consumption. Upon chronic activation, mTORC1 drives insulin resistance by suppressing insulin receptor signalling and promoting fat accumulation.
mTORC1 and mTORC2 are tightly linked with signalling pathways that lead to cancer. mTORC1 drives tumorigenesis by boosting translation of oncogenes, promoting anabolism and angiogenesis and suppressing autophagy. mTORC2 activates Akt and other AGC family kinases that promote cell proliferation and survival. Therapeutic strategies that are based on novel catalytic mTOR inhibitors have shown promising preclinical results.
Our increasing knowledge of the molecular mechanisms underlying ageing is revealing a major role for mTOR in this process. Thus, understanding mTORC1 and mTORC2 biology is crucial for the development of novel drugs that can stave off ageing and age-related diseases.
In all eukaryotes, the target of rapamycin (TOR) signalling pathway couples energy and nutrient abundance to the execution of cell growth and division, owing to the ability of TOR protein kinase to simultaneously sense energy, nutrients and stress and, in metazoans, growth factors. Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt. In the past few years, a significant advance in our understanding of the regulation and functions of mTOR has revealed the crucial involvement of this signalling pathway in the onset and progression of diabetes, cancer and ageing.
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The authors acknowledge support from the US National Institutes of Health, the Howard Hughes Medical Institute and the Whitehead Institute for Biomedical Research. R.Z. is supported by a Jane Coffin Childs Memorial Fund postdoctoral fellowship. A.E. is supported by a Human Frontier Science Program postdoctoral fellowship.
The authors declare no competing financial interests.
A naturally occurring drug, generally an antibiotic, that is composed of a large lactone carbon ring.
- WD40 domain
A protein domain that comprises a 40-amino-acid- long protein motif that contains a Trp–Asp (W–D) dipeptide at its carboxyl terminus. Several WD40 repeats are often arranged in a β-propeller configuration, forming a protein–protein interaction surface.
- DEP domain
(Dishevelled, EGL-10 and pleckstrin domain). A domain of unknown function that is present in signalling proteins.
- PDZ domain
(Postsynaptic density of 95 kDa, Discs large and zona occludens 1 domain). A protein-interaction domain that often occurs in scaffolding proteins and is named after the founding members of this protein family.
A transient membrane vesicle that engulfs and digests cellular components.
- Guanine nucleotide exchange factor
(GEF). A protein that promotes the loading of GTP onto G proteins, resulting in their activation.
A set of chemical reactions that build complex molecules from simpler units, consuming energy in the process.
- GTPase activating protein
(GAP). A protein that promotes hydrolysis of GTP to GDP by G proteins, resulting in their inactivation.
The breakdown of fatty acids that occurs in the mitochondria and generates acetyl CoA, which is the entry substrate for the tricarboxylic acid cycle.
A lipid that is formed by the esterification of fatty acids with glycerol. Triglycerides are the most abundant form of lipid storage.
The chain of enzymatic reactions, mainly occurring in the liver, which leads to the de novo production of glucose from more simple carbon precursors and ATP.
An almost irreversible stage of permanent G0–G1 cell-cycle arrest that is linked to morphological changes, metabolic changes and changes in gene expression (for example, of the gene encoding β-galactosidase).
Cells in this state have exited the cell cycle and are in the G0 ('resting') phase, but can re-enter the cell cycle.
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Zoncu, R., Efeyan, A. & Sabatini, D. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12, 21–35 (2011). https://doi.org/10.1038/nrm3025
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