mTOR at the nexus of nutrition, growth, ageing and disease

Abstract

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.

Fig. 1:. Structure and function of mTORC1 and mTORC2.

A. mTOR complex 1 (mTORC1) and mTORC2 have distinct signalling roles in the cell. mTORC1 integrates information about nutritional abundance and environmental status to tune the balance of anabolism and catabolism in the cell, while mTORC2 governs cytoskeletal behaviour and activates several pro-survival pathways. Unlike mTORC1, which is acutely inhibited by rapamycin, mTORC2 responds only to chronic rapamycin treatment. B. Components of mTORC1 (left). The domain structure of the mTOR kinase (green) is annotated with binding sites for the other mTORC1 subunits. The N-terminus of mTOR contains clusters of huntingtin, elongation factor 3, a subunit of protein phosphatase 2A and TOR1 (HEAT) repeats, followed by a FRAP, ATM and TRRAP (FAT) domain; the FKBP12–rapamycin binding (FRB) domain; the catalytic kinase domain; and the C-terminal FATC domain. mTOR binds mammalian lethal with SEC13 protein 8 (mLST8), a core component of the complex, and DEP-domain-containing mTOR-interacting protein (DEPTOR), an endogenous inhibitor of mTORC1 activity. Regulatory-associated protein of mTOR (Raptor), the defining subunit of mTORC1, binds mTOR with its own HEAT repeats and is required for lysosomal localization of the complex. Raptor also recruits proline-rich AKT substrate 40 kDa (PRAS40), an insulin-regulated inhibitor of mTORC1 activity. A 5.9-Å reconstruction of mTORC1 (without PRAS40 and DEPTOR) complexed with FKBP12–rapamycin is shown as a surface representation (Protein Database (PDB) ID: 5FLC) (right). C. Components of mTORC2 (left). The mTOR kinase (green) is annotated with the binding sites for the other constituent subunits of mTORC2. These subunits include mLST8, DEPTOR and RICTOR, the defining component of mTORC2. As a scaffolding protein, RICTOR recruits protein associated with rictor 1 or 2 (PROTOR1/2) to the complex, along with MAPK-interacting protein (mSIN1), which contains a pleckstrin homology domain. A 4.9-Å reconstruction of mTORC2 (without DEPTOR and PROTOR) is shown as a surface representation (PDB: 5ZCS) (right).

Fig. 2:. Targets of mTORC1 and mTORC2 signalling.

A. mTOR complex 1 (mTORC1) activation initiates a downstream anabolic programme that enhances the production of proteins, lipids, nucleotides and other macromolecules while inhibiting catabolic processes, such as autophagy and lysosome biogenesis. B. By regulating the expression or nuclear localization of transcription factors, mTORC1 and mTORC2 control the expression of genes that promote organelle biogenesis or alter metabolic flux through biosynthetic pathways. Although these transcription factors can be independently activated by specific, acute cellular stress signals (for example, hypoxia inducible factor 1α (HIF1α) can be directly activated by hypoxia and ATF4 can be directly activated by endoplasmic reticulum stress), mTORC1 and mTORC2 toggle the activation of these factors in a coordinated manner to support growth and proliferation. Thus, activation of mTORC1 can simultaneously activate ATF4, the sterol regulatory element binding proteins (SREBPs), HIF1α and yin–yang 1 (YY1)−peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1α (PGC1α) to drive diverse processes involved in cellular growth, all while blocking lysosomal biogenesis through transcription factor EB (TFEB). C. mTORC2 activates the AGC family kinases protein kinase C (PKC), Akt and serum- and glucocorticoid-induced protein kinase (SGK) to regulate the cytoskeleton, metabolism and ion transport and promote cell survival. CAD, carbamoyl-phosphate synthetase 2, apartate transcarbamoylase, dihydroorotase; 4E-BP, 4E-binding protein; eIF4, eukaryotic translation initiation factor 4; GSK3b, glycogen synthase kinase 3b; MTHFD2, methylenetetrahydrofolate dehydrogenase 2; PDCD4, programmed cell death 4; Pol I/Pol III, RNA polymerase I/RNA polymerase III; S6K1, p70 S6 kinase 1; TFE3, transcription factor E3; TIF-1A, transcription initiation factor 1A; TSC2, tuberous sclerosis complex 2; UBF, upstream binding factor; ULK1, unc-51-like autophagy-activating kinase 1.

Fig. 3:. Upstream regulators of the mTOR signalling pathway.

mTOR complex 1 (mTORC1) and mTORC2 integrate upstream environmental information to gate their own activation. Because mTORC1 controls cellular entry into an anabolic state that requires copious amounts of energy and macromolecules, activation of the complex should only occur when amino acids, insulin/growth factors, ATP and oxygen are all readily available. To ensure that all of these requirements are satisfied, mTORC1 must translocate to the lysosome by anchoring onto the Rag GTPases, which are only competent to recruit mTORC1 in the presence of amino acids. Once localized to the lysosomal surface, mTORC1 can be then be activated by the small GTPase Rheb in its GTP-bound state. Importantly, GTP loading of Rheb is promoted by growth factors and opposed by energetic stress or hypoxia. All of these inputs converge on tuberous sclerosis complex (TSC), which acts as a GAP for Rheb. mTORC2 is thought to be primarily regulated by growth factors. Although it is not clear where mTORC2 activation occurs, the pleckstrin homology domain on MAPK-interacting protein 1 (mSIN1) may recruit mTORC2 to the plasma membrane. Positive regulators of the mTORC1 pathway are shown in green, while negative regulators of mTORC1 are shown in blue. AMPK, AMP-activated protein kinase; CASTOR, cellular arginine sensor for mTORC1; EGFR, epidermal growth factor receptor; FLCN, folliculin; GATOR, GAP activity towards the Rags; Grb2, growth factor receptor-bound protein 2; GSK3, glycogen synthase kinase 3; IGF, insulin-like growth factor; IKKβ, inhibitor of nuclear factor κB kinase β; IRS, insulin receptor substrate; LKB1, liver kinase B1; Mek, MAPK/ERK kinase; NF1, neurofibromatosis type 1; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PTEN, phosphatase and tensin homologue; RSK, p90 ribosomal S6 kinase; SAM, S-adenosylmethionine; SAMTOR, S-adenosylmethionine sensor; Sos, son of sevenless; TNF, tumour necrosis factor.

Fig. 4:. mTOR signalling in metabolism.

A. mTOR coordinates feeding and fasting with nutrient storage and mobilization. In the liver, skeletal muscle and adipose tissue, rising insulin levels after feeding activate both mTOR complex 1 (mTORC1) and mTORC2, promoting lipogenesis, glycogen synthesis and protein synthesis (left). During fasting, the nutrient, growth factor and insulin levels drop precipitously, tilting the metabolic balance in favour of gluconeogenesis, ketogenesis and lipolysis (right). B. Dysregulation of mTOR signalling in metabolic syndrome. Although the negative feedback loop between mTORC1 and mTORC2 is carefully balanced under physiological conditions (left), chronic hyperactivation of mTORC1 by excessive nutrients and mitogens can shut off PI3K–mTORC2 signalling, leading to insulin resistance, ectopic accumulation of lipids in the muscle and liver, and type 2 diabetes (middle). Rapamycin-based therapies have not been effective in diabetes patients with hyperactive mTORC1 signalling because prolonged rapamycin treatment also inhibits mTORC2 (right). Grb10, growth factor receptor-bound protein 10; IGF, insulin-like growth factor; IRS, insulin receptor substrate; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; S6K1, p70 S6 kinase 1.

Fig. 5:. mTOR signalling in the brain.

A. In the brain, mTOR complex 1 (mTORC1) signalling is activated not just by nutrients and insulin but also by several tissue-specific inputs, including the neurotransmitter glutamate and the neurotrophic growth factor brain-derived neurotrophic factor (BDNF). Dysregulation of the mTORC1 pathway is associated with a set of characteristic neurodevelopmental diseases, collectively termed ’mTORopathies’. Patients with mTORopathies suffer from severe epilepsy and may also display focal cortical dysplasia, macrocephaly or megalencephaly, cognitive and social defects, and benign tumours. Proteins from genes bearing mutations in neurodevelopmental diseases are shown in blue. B. Roles of mTORC1 and mTORC2 during neuronal development. Ablation of mTORC1 or mTORC2 in the nervous system perturbs cell and organ size and disrupts the cortical architecture of the brain. mTORC1 deletion also causes early postnatal lethality. C. Roles of mTORC1 and mTORC2 in postnatal maintenance of synaptic plasticity and homeostasis. mTORC1 regulates activity-dependent synaptic translation through its substrates eukaryotic initiation factor 4E-binding protein 2 (4E-BP2) and p70 S6 kinase 1 (S6K1) to strengthen or weaken a given neuronal circuit; moreover, it also promotes synaptic plasticity by pruning obsolete synapses through autophagy. Autophagy may additionally play a neuroprotective role by degrading misfolded proteins and damaged organelles. mTORC2 remodels the actin cytoskeleton in response to neuronal signal transmission and helps convert transient excitatory events into long-term memory. AMPK, AMP-activated protein kinase; ASD, autism spectrum disorder; GATOR, GAP activity towards the Rags; IRS, insulin receptor substrate; LKB, liver kinase B1; NF1, neurofibromatosis type 1; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PKC, protein kinase C; PMSE, polyhydramnios, megalencephaly and symptomatic epilepsy; PTEN, phosphatase and tensin homologue; STRADα, STE20-related kinase adapter protein-α; TSC, tuberous sclerosis complex.

Fig. 6:. mTOR in cancer and ageing.

A. mTOR complex 1 (mTORC1) and mTORC2 participate in cancer pathogenesis by underwriting biosynthetic programmes and promoting proliferation and survival. Emerging evidence also implicates mTORC2 activity in metastatic transformations. B. Modulation of mTORC1 signalling in ageing cells may enable us to slow the molecular clock. mTORC1 activates processes that may accelerate cellular and tissue ageing, including protein synthesis, mitochondrial energy production and entry into senescence. Chronic mTORC1 activation also blocks autophagic clearance of damaged cellular components. Inhibition of this pathway — by either rapamycin treatment, genetic inactivation of mTORC1 or dietary restriction — has been shown to extend lifespan and improve physiological performance across a range of model organisms. 4E-BP, 4E-binding protein; HIF1α, hypoxia inducible factor 1α; PKC, protein kinase C; ROS, reactive oxygen species; SGK, serum- and glucocorticoid-induced protein kinase; S6K1, p70 S6 kinase 1; SREBP, sterol regulatory element binding protein.