mTORC1
mTOR Complex 1; regulates protein synthesis, autophagy, and growth in response to nutrients and growth factors.
The growth decision itself. The first of the two mTOR complexes, and the one most people mean when they just say 'mTOR.' It controls protein-building, cellular cleanup, and growth in response to nutrients and growth-factor signals.
Coincidence detector: nutrients supply location via the Rags, growth factors supply activation via Rheb. Neither alone is sufficient – the central idea of the amino-acid route.
TL;DR. mTORC1 appears in 208 curated studies in Oliver's mTOR Atlas: 14 in people (14 human studies); 54 in animal models; 109 at the molecular level (cells, biochemistry, structure); 27 reviews; 4 preprints, not peer-reviewed. It has 41 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| mTORC1 inhibits 4E-BP1 mechanism: phosphorylation · this link in full · on the map table | mTORC1 tags 4E-BP1 so it lets go of another protein, freeing up protein-building – but the standard drug (rapamycin) only partly blocks this step. Holds under: Cell and in vitro evidence (human and mouse cells, with C. elegans RNAi in one study). Rapamycin blocks this phosphorylation only partly, and individual sites differ in how sensitive they are (KAN2013). Not shown in people by these studies. plausible in people, not shown directly · settled in the literature | M | BUR1998, HARA2002, FEL2009, GIN1999, KAN2013, HAR1998, BRU1997, NOJ2003, SAT2010 |
| mTORC1 activates Grb10 mechanism: stabilization · this link in full · on the map table | mTORC1 stabilises Grb10, kicking off a feedback loop that talks back to the insulin receptor. Holds under: Two mammalian cell studies (HSU2011, YUX2011). Cell culture only; not tested in whole animals or in people. plausible in people, not shown directly · settled in the literature | M | HSU2011, YUX2011 |
| mTORC1 inhibits Longevity mechanism: functional-consequence · this link in full · on the map table | Turning mTORC1 down extends lifespan in yeast, worms, flies and mice – one of the best-replicated anti-ageing effects in laboratory animals. In mice, how big the effect is depends on sex, strain, diet and when treatment starts, and it has not been shown in people. Holds under: No human hard-endpoint evidence. This is the Atlas's flagged 'human endpoint desert'. Strongly modified by sex, strain, diet and the age at which inhibition starts. Effect direction is reproducible; effect size is not transferable between models. not tested in people · settled in the literature | A | HAR2009, LAM2012, ROB2012, VEL2003, HAN2008, POW2006, WAN2026 |
| mTORC1 inhibits ERK / RSK (MAPK) mechanism: signal-relay · this link in full · on the map table | Blocking mTORC1 can backfire by releasing a brake on a different growth pathway (MAPK) – one reason mTOR-blocking drugs alone often aren't enough. Holds under: Single-study edge in this corpus. CAR2008 includes tumour biopsies from patients with advanced solid tumours treated with RAD001 (everolimus), in which MAPK activation depended on the dosing schedule, plus a mouse prostate cancer model, xenografts and cell lines. shown in people · settled in the literature | M | CAR2008 |
| mTORC1 activates Mitochondrial biogenesis mechanism: signal-relay · this link in full · on the map table | mTORC1 boosts the cell's mitochondria – its power plants – two ways at once: through a gene-activating complex, and by freeing up 4E-BP. Holds under: Shown in cultured cells and skeletal muscle (CUN2007) and mammalian cell lines (MOR2013). One organismal result points the other way: adipose-specific Raptor deletion raised mitochondrial respiration (POL2008), see MTORC1-OXPHOS. plausible in people, not shown directly · emerging, few independent studies | A | CUN2007, MOR2013, BEN2008 |
| mTORC1 activates Nucleotide synthesis mechanism: signal-relay · this link in full · on the map table | mTORC1 turns on the machinery for building DNA/RNA building blocks, so a growing cell can actually copy its DNA. Holds under: Cancer cell and mammalian cell studies, including xenograft tumours (VAL2017, BEN2016, ALI2022). The evidence comes mostly from dividing or tumour cells; whether non-dividing tissues use the same route is not shown. plausible in people, not shown directly · settled in the literature | M | VAL2017, BEN2016, ALI2022 |
| mTORC1 activates Prostate cancer mechanism: functional-consequence · this link in full · on the map table | Blocking mTOR reversed early, pre-cancerous prostate changes in mice caused by an overactive growth signal. Holds under: Scope: the lesion was prostatic intraepithelial neoplasia, a pre-cancerous stage, driven by transgenic human AKT1 in mice, and the drug (RAD001) inhibits mTORC1 allosterically. Mouse only in this corpus. Not a demonstration in established prostate cancer. plausible in people, not shown directly · emerging, few independent studies | A | MAJ2004 |
| mTORC1 associated-with Renal cell carcinoma (RCC) mechanism: association · this link in full · on the map table | Many kidney cancers carry changes that leave mTORC1 stuck "on", which is why this cancer responds to mTOR-blocking drugs at all. In one large trial, people with advanced kidney cancer lived longer on temsirolimus; in another, everolimus slowed the cancer's growth for a few months. Responding to the drug is not proof that mTORC1 started the cancer. Holds under: Correlative, plus two randomised human trials showing the tumour responds to mTOR inhibitors: overall survival in poor-prognosis first-line RCC with temsirolimus (HUD2007), progression-free survival only after VEGF-targeted therapy with everolimus (MOT2008). This is response to treatment, not a demonstration that mTORC1 activation initiates RCC. The bladder-cancer responder case IYE2012 was removed from this edge on 2026-10-09 as a citation-population mismatch (it describes bladder, not kidney). shown in people · emerging, few independent studies | H | MOT2008, HUD2007 |
| mTORC1 activates S6K1 mechanism: phosphorylation · this link in full · on the map table | mTORC1 switches on S6K1, which turns on the cell's protein-building machinery – the classic effect most studies of this drug class measure. Holds under: Caution: p-S6K is a proxy, not the phenotype. Many 'mTORC1 activity' claims rest on this single band. Standard mTORC1 readout, but a readout is not the whole output. S6K1 phosphorylation is fully rapamycin-sensitive while 4E-BP1 is not, so 'mTORC1 activity' measured by S6K1 alone systematically overstates how much rapamycin inhibits mTORC1. plausible in people, not shown directly · settled in the literature | A | BUR1998, CHU1992, HOL2005, KAN2013, HAR1998, NOJ2003, POD2001, JEF1997, RAO2010 |
| mTORC1 activates Senescence-associated secretory phenotype (SASP) mechanism: functional-consequence · this link in full · on the map table | mTORC1 keeps old, "senescent" cells pumping out inflammatory signals, and blocking it calms that output down without making those cells young again. Whether mTORC1 also helps push cells into senescence in the first place is a separate question this arrow does not answer. Holds under: Three studies, all in cells or a rat disease model. LAB2015 and NAR2011 measure the secretory output of cells that are already senescent (IL1A translation; IL-6/IL-8 production fuelled by mTOR at the TASCC). CHEN2026C (human disc cells, rat needle-puncture model) shows mTORC1 hyperactivation after TSC2 loss together with senescence and SASP, both blocked by rapamycin - a disease-model result, not a general demonstration that mTORC1 drives cells into senescence. That is why this arrow lands on the secretory programme and not on senescence itself. plausible in people, not shown directly · emerging, few independent studies | A | LAB2015, CHEN2026C, NAR2011, WAN2017 |
| mTORC1 activates SREBP1 / SREBP2 mechanism: signal-relay · this link in full · on the map table | mTORC1 switches on SREBP, the genes that build fat and cholesterol – a growing cell needs membrane material, not just protein. Holds under: Mammalian cell studies (POR2008, PET2011) and an emerging rather than settled consensus. Cultured cells; the size of the effect in whole animals and in people is not measured by these studies. KID2013 adds primary mouse T cells: rapamycin blocked SREBP processing and nuclear entry after T-cell activation, and Scap-deleted T cells could not raise sterol synthesis. Still no human tissue data. plausible in people, not shown directly · emerging, few independent studies | M | POR2008, PET2011, DUV2010, KID2013 |
| mTORC1 inhibits TFEB mechanism: phosphorylation · this link in full · on the map table | Active mTORC1 tags TFEB and traps it outside the nucleus; switch mTORC1 off and TFEB moves in. Holds under: RagD specifically (more than RagC) promotes TFEB/TFE3 phosphorylation via tighter LAMTOR binding — GOL2022 shows this is paralogue-specific, not a generic Rag-dimer property. Substrate-selective. Depends on FLCN/FNIP RagC/D status, so mTORC1 can be active on S6K1 while not phosphorylating TFEB. plausible in people, not shown directly · settled in the literature | M | ROC2012, SET2012, MAR2012, SET2011, GOL2022, CUI2023, MAR2013 conflicting: ZHANG2026, PEN2011 |
| mTORC1 activates Tumor growth mechanism: functional-consequence · this link in full · on the map table | In mouse tumour models and cancer cells where the pathway is already over-active, hyperactive mTORC1 pushes cells to build a specific set of growth- and spread-promoting proteins, and the tumour becomes dependent on that programme. Holds under: Context-dependent: shown in genetically driven mouse tumour models and cancer cell lines with hyperactive mTORC1 (PTEN loss, TSC loss), not as a general property of tumours. OKI2021 (mouse AML) is not cited as support: mTORC1 activity fell as the leukaemia progressed and rose during the chemotherapy response, so it bears on when to inhibit mTORC1, not on mTORC1 driving growth. plausible in people, not shown directly · settled in the literature | A | HSI2010, HSI2012, VAL2017, INO2006, FER2026, NES2001, POD2001 |
| mTORC1 inhibits ULK1 mechanism: phosphorylation · this link in full · on the map table | Active mTORC1 tags ULK1 to hold it back, keeping the cell's self-cleanup process (autophagy) switched off while nutrients are plentiful. Holds under: Mammalian and human/mouse cell studies (HOS2009, GAN2009, KIM2011, NAZ2013). Cell-culture biochemistry; the whole-animal and human consequence is not shown by these sources. plausible in people, not shown directly · settled in the literature | M | HOS2009, GAN2009, KIM2011, NAZ2013 |
| mTORC1 activates Oxidative phosphorylation mechanism: signal-relay · this link in full · on the map table | mTORC1 boosts how much energy mitochondria can produce, through both gene activation and protein-building. One mouse experiment points the other way – removing mTORC1 from fat tissue RAISED respiration – so this direction is not settled in a living animal. Holds under: Effect size varies strongly by tissue; the transcriptional and translational arms have not been cleanly separated in vivo. OVERLAP (audit 2026-09-04): this edge and MTORC1-MITO assert overlapping biology from overlapping citations (CUN2007, MOR2013) at different tiers and different consensus levels. Read them together; they are not independent support. plausible in people, not shown directly · emerging, few independent studies | M | CUN2007, MOR2013, SCH2006 conflicting: POL2008 |
| mTORC1 activates PGC-1α / YY1 mechanism: binding · this link in full · on the map table | mTOR works together with a gene-activating team to switch on mitochondrial genes – a rare example of this pathway acting inside the nucleus rather than at the cell's outer edges. The direct interaction rests on a single study in this Atlas. Holds under: Single-study support in this corpus for the direct interaction; the downstream respiratory phenotype is better replicated than the binding itself. plausible in people, not shown directly · emerging, few independent studies | M | CUN2007 |
| mTORC1 activates Reactive oxygen species mechanism: functional-consequence · this link in full · on the map table | Switching mTORC1 on too much pushes resting stem cells to start dividing and floods them with reactive, damaging molecules; giving them antioxidants restores their normal function. Holds under: Demonstrated in haematopoietic stem cells, where quiescence is the baseline state. Cell types that are already cycling need not behave this way. plausible in people, not shown directly · emerging, few independent studies | A | CHE2008 |
| mTORC1 activates HIF-1α mechanism: signal-relay · this link in full · on the map table | In one specific setting (prostate cells), mTORC1 turns on a factor usually associated with low oxygen – here it's mTORC1 driving it, not the other way around. Holds under: Mouse prostate model with pharmacological mTOR inhibition; HIF-1α is one of several pathways implicated in the same experiment. DUV2010 adds cultured-cell evidence (Tsc2-null fibroblasts with rapamycin) that mTORC1 drives HIF1α target genes such as glycolytic enzymes; still no human tissue data. plausible in people, not shown directly · emerging, few independent studies | A | MAJ2004, DUV2010 |
| mTORC1 activates S-adenosylmethionine (SAM) mechanism: transcriptional · this link in full · on the map table | mTORC1 tells the cell to make more SAM. Holds under: Human cell lines and mouse xenograft tumours; acts through c-MYC on MAT2A. Together with SAM-SAMTOR this forms a loop whose behaviour in normal tissue is untested. Single study. plausible in people, not shown directly · emerging, few independent studies | M | VIL2021 |
| mTORC1 activates Ribosome biogenesis mechanism: functional-consequence · this link in full · on the map table | A growing cell needs more ribosomes, not just busier ones, and mTORC1 has a say in how many get built. That was followed through the cell cycle in yeast, and in mammalian cells the programme mTORC1 controls turns out to be dominated by the ribosome's own parts. The link runs in both directions: block ribosome building and the cell turns mTOR down to cope. Holds under: The two polymerase steps that carry most of this output are NOT measured by any study in this corpus. mTOR controls rRNA transcription through RNA polymerase I via TIF-IA (Mayer 2004, PMID 15004009, outside this corpus) and tRNA and 5S transcription through RNA polymerase III via Maf1 (Shor 2010, PMID 20233713, outside this corpus). Until those are curated here the edge rests on a yeast cell-cycle study, a mammalian ribosome-profiling study and a reverse-direction survival study, so read it as the existence of the output rather than as its mechanism. plausible in people, not shown directly · emerging, few independent studies | M | GUE2022, HSI2012, FAN2026 |
| mTORC1 activates 5'TOP mRNA mechanism: functional-consequence · this link in full · on the map table | When mTORC1 is on, the cell does not simply make more of every protein. It preferentially makes the parts of its own protein-making machinery, from a particular class of messages marked at one end. Holds under: The selectivity is from ribosome profiling in cancer cell lines (HSI2012); the lifespan link is Drosophila only (WAN2026); PLEDGER2026 shows the same arm being repressed in chronically activated human CD8+ T cells. No human in vivo measurement of 5'TOP translation under an mTOR inhibitor in this corpus. Which of the 5'TOP transcripts matter for which phenotype is not resolved. plausible in people, not shown directly · settled in the literature | A | HSI2012, WAN2026, PLEDGER2026, JEF1997 |
| AMPK inhibits mTORC1 mechanism: phosphorylation · this link in full · on the map table | AMPK also hits mTORC1 directly, adding a second, energy-based checkpoint on top of TSC. Holds under: Cell biochemistry in human and mouse cells (GWI2008) plus one study in aged mice (YAN2026B). Direct Raptor phosphorylation is shown in cells; how much it adds beside the TSC route in living tissue, and in people, is not shown. The Raptor arm is the TSC2-independent route, which is why it is measurable in TSC-null cells. Its relative contribution versus the TSC2 arm varies by cell type and by how deep the energy stress is. plausible in people, not shown directly · settled in the literature | A | GWI2008, YAN2026B |
| Everolimus inhibits mTORC1 mechanism: allosteric-inhibition · this link in full · on the map table | Everolimus is rapamycin with a small chemical tweak that makes it easier to take as a pill – same mechanism, better drug. Holds under: Clinical evidence from phase 3 trials of everolimus in specific diseases (kidney cancer, breast cancer, pancreatic neuroendocrine tumours, TSC and LAM) at the doses used for those diseases. It does not speak to low-dose use in healthy ageing. shown in people · settled in the literature | H | MOT2008, YAO2011, BAS2012, KRU2010, BIS2013, IYE2012, MEI2008 |
| FKBP12 binds mTORC1 mechanism: binding · this link in full · on the map table | Only when it carries rapamycin does FKBP12 dock on mTORC1; the pair then blocks some, but not all, of what mTORC1 does. FKBP12 on its own does nothing to mTORC1. Holds under: Biochemical and structural work on rat and bovine brain extracts, rodent and T cells, and a cryo-EM structure of human mTORC1. It defines how the drug-bound complex docks. FKBP12 alone does not inhibit mTORC1, and effects in whole animals are carried by the rapamycin edges, not this one. plausible in people, not shown directly · settled in the literature | M | SAB1994, SAB1995, CHU1992, BRO1994, AYL2015, YIP2010 |
| Lysosome required-for mTORC1 mechanism: localisation · this link in full · on the map table | In the amino-acid route, mTORC1 has to travel to the lysosome before it can work, because its activator Rheb waits there. Getting it there and switching it on are two different steps: when researchers glued mTORC1 to the lysosome so it no longer had to be delivered, amino acids stopped making any difference, but the activator was still needed. Holds under: Scoped to amino-acid-driven activation. Live BRET imaging in this corpus (BOU2020) resolves mTOR activity in the cytosol, at the lysosome, in the nucleus and near mitochondria, so mTOR signalling is measurably not one pool. This map draws the lysosomal route and keeps the other localisations declared as open rather than asserting there are none. FER2024 refines this further: lysosomal mTORC1 (fed by local lysosomal proteolysis) and cytoplasmic mTORC1 (fed by exogenous amino acids) phosphorylate distinct downstream substrates — the lysosome is required for one regulatory sub-pool of mTORC1, not for all of it. plausible in people, not shown directly · settled in the literature | M | SAN2010, ZON2011, FER2024, KOR2011, CUI2025 |
| Metformin inhibits mTORC1 mechanism: signal-relay · this link in full · on the map table | Metformin can also block mTORC1 through a separate route that doesn't need AMPK – a route often left out of the simple "metformin works via AMPK" story. This was shown in cells and mice, often at doses higher than patients take, and how much each route matters in people is not known. Holds under: Runs in parallel with METFORMIN-AMPK, not instead of it. The relative weight of the two routes in humans is unresolved. Dose is the whole argument. Concentrations used in cell culture are typically far above plasma levels achieved at clinical doses, so in vitro mechanism may not describe what metformin does in a patient. plausible in people, not shown directly · disputed: at least one study points the other way | M | KAL2010 |
| PRAS40 inhibits mTORC1 mechanism: competitive-inhibition · this link in full · on the map table | Untagged PRAS40 sits inside mTORC1 and blocks it, like a built-in plug. Holds under: Human cell biochemistry and a cryo-EM structure (SAN2007, YAN2017). Shows the plug mechanism in cells and in structure; its effect in whole animals and in people is not tested here. plausible in people, not shown directly · settled in the literature | M | SAN2007, YAN2017 |
| Rag GTPases recruits mTORC1 mechanism: recruitment · this link in full · on the map table | The switched-on Rag proteins grab mTORC1 and drag it to the lysosome. This moves it into place; it doesn't turn it on by itself. Holds under: Rag paralogues are not interchangeable: RagC/D sets substrate specificity downstream (RagD favors TFEB/TFE3 phosphorylation via tighter LAMTOR binding, while both Rags are involved for non-lysosomal substrates like S6K), and RagA/B sets the response to amino acid withdrawal (RagB-expressing cells keep mTORC1 lysosomal and active even when starved) — GOL2022. plausible in people, not shown directly · settled in the literature | A | SAN2008, SAN2010, LAW2018, GOL2022, EFE2012, CUI2025, NAR2011, KIM2008, ANA2019, KIM2012 |
| Raptor required-for mTORC1 mechanism: complex-assembly · this link in full · on the map table | Raptor is the piece that makes mTORC1 what it is, and hands it the targets it needs to act on. Holds under: Mostly cell and in vitro work (human cells, C. elegans RNAi, rodent cell lines). One muscle-specific knockout in mice (BEN2008) shows lifelong total loss, which is not the same as partial inhibition by a drug. Not tested in people. plausible in people, not shown directly · settled in the literature | A | HARA2002, KIM2002, BEN2008, SEN2010, NOJ2003 |
| Rheb activates mTORC1 mechanism: allosteric-activation · this link in full · on the map table | Switched-on Rheb docks onto mTORC1 and physically reshapes it into its working form – the actual "on" switch. Holds under: Cryo-EM structures, in vitro biochemistry, Drosophila and one mouse study (INOK2003, SAU2003, YAN2017, CUI2025, DEL2011). Defines how Rheb activates mTORC1 in reconstituted and cellular systems; not measured directly in human tissue. Rheb must be GTP-loaded and co-located with mTORC1. Rheb is also distributed across the ER and Golgi, and which pool supplies the activating Rheb is unresolved. plausible in people, not shown directly · settled in the literature | A | INOK2003, SAU2003, YAN2017, CUI2025, DEL2011 |
| Spalt-related (Salr) inhibits mTORC1 mechanism: signal-relay · this link in full · on the map table | This stress-induced protein suppresses mTORC1-driven growth once stress signalling turns it on. Holds under: One Drosophila study (DEN2026). Fly only and a single study; no mammalian or human data are cited for this edge. not tested in people · emerging, few independent studies | A | DEN2026 |
| Temsirolimus inhibits mTORC1 mechanism: allosteric-inhibition · this link in full · on the map table | Temsirolimus is the IV version of rapamycin and, as far as we know, the first mTOR-blocking drug shown to help patients live longer in a controlled trial (in advanced kidney cancer). Holds under: HUD2007 shows the clinical effect (overall survival in poor-prognosis metastatic kidney cancer). It did not measure mTORC1 activity; that temsirolimus inhibits mTORC1 rests on the FKBP12-dependent mechanism it shares with rapamycin. shown in people · settled in the literature | H | HUD2007 |
| TSC1/TSC2 inhibits mTORC1 mechanism: signal-relay · this link in full · on the map table | The TSC brake is the pathway's main tumour-suppressor. Inherit one broken copy of the gene and growths appear wherever the second copy is also lost. (This arrow skips a step for simplicity – TSC actually acts through Rheb first.) Holds under: Human cell lines, Drosophila, mouse and cell studies, one open-label human trial (KRU2010) and human disease genetics. The human evidence comes from disease caused by TSC loss, not from healthy tissue. Deliberately compressed: TSC acts on Rheb rather than directly on mTORC1. Kept as one link so the overview reads cleanly. shown in people · settled in the literature | H | TEE2003, INOK2003, KRU2010, CHEN2026C, ZHANG2026, DEM2014, SEN2010, GAO2002, TEE2002, KWI2002, DEY2008, POL2015, TSA2012, BAT2013, ZEN2008 |
| Rapamycin inhibits mTORC1 mechanism: allosteric-inhibition · this link in full · on the map table | Rapamycin, carried by its helper protein FKBP12, jams part of mTORC1 – it blocks some of what mTORC1 does but not all of it. Holds under: Directness is graded indirect because the mechanism requires FKBP12, as for everolimus and the bi-sterics. Acute effect only; the chronic effect on mTORC2 is the separate RAPA-MTORC2 edge. plausible in people, not shown directly · settled in the literature | A | CHU1992, BRO1994, SAB1994, SAB1995, CHO1996, MEI2008, KAN2013, FIN2002, BRU1997, SAT2010, YIP2010, RAO2010, MAR2014, BAT2013 |
| Glutamine activates mTORC1 mechanism: signal-relay · this link in full · on the map table | Some experiments say glutamine has a second way in that skips the Rag proteins entirely. If that is right, the lysosome story is not the whole story – which is a big claim resting on thin evidence. Holds under: Cell-type dependent and not uniformly reproduced across labs. The Rag-dependent route is the separate GLN-RAG edge; neither edge should be read as covering the other. not tested in people · disputed: at least one study points the other way | M | JEW2015 |
| Resistance exercise / mechanical load activates mTORC1 mechanism: signal-relay · this link in full · on the map table | Working a muscle raises mTORC1 activity in it. When volunteers took rapamycin, the early rise in muscle protein building after one workout was blocked, so in people, and not only in cell dishes, rapamycin-sensitive signalling takes part in that response. The drug also dampened a second signal (ERK1/2), so this does not prove that mTORC1 alone does the job. The map draws one arrow, but load reaches mTORC1 by several routes, and the study did not measure muscle growth. Holds under: Compressed: load reaches mTORC1 through several routes, only some of which need IGF-1, and the map draws one arrow. The human evidence (DRU2009) is one acute bout, measured 1-2 h later: it shows that rapamycin-sensitive signalling takes part in the early rise in protein synthesis. It does not show that mTORC1 is the only required mediator, which upstream route carries the signal, or that muscle growth changes; muscle growth was not measured. shown in people · settled in the literature | H | DRU2009, BOD2001 |
| Fasting / caloric restriction inhibits mTORC1 mechanism: signal-relay · this link in full · on the map table | Eating less is expected to turn mTORC1 down, because the cell's fuel and amino-acid sensors both report scarcity. But this has not been measured here. The one study behind this arrow let mice eat freely on 25 different diets and found that the ratio of protein to carbohydrate, not the number of calories, went with health and lifespan, and lower-protein diets went with lower mTOR activity in the liver. So what has support is eating less protein, not eating less, and it is a correlation, not a test. Holds under: Supporting evidence is thinner than the claim's reputation. ROM2016 (two-year caloric restriction is tolerable in non-obese humans) and MAT2017 (rhesus survival) were removed as support in the 2026-09-21 audit because neither measured mTORC1; they belong to the CR-LONGEVITY edge. That leaves SOL2014, which is an ad-libitum 25-diet study whose own title states that the ratio of macronutrients, not caloric intake, dictates the outcome, and whose mTOR observation is correlative and confined to liver. Re-audit 2026-10-10: consensus was downgraded from established to emerging and the evidence kind from genetic epistasis to correlative, because neither matched what SOL2014 actually did. The edge is retained because the mechanistic expectation is sound and well motivated by the sensor arms, but it is an expectation, not a measured result in this corpus. 2026-10-18: YIL2012 added. In mouse intestine, calorie restriction lowered mTORC1 activity in Paneth cells, and rapamycin or Paneth-cell genetics reproduced the stem-cell effect, so the corpus now has one direct mTORC1 measurement under restriction. It is a single tissue in mice and does not show the same in people. plausible in people, not shown directly · emerging, few independent studies | A | SOL2014, YIL2012 |
| ATP-competitive mTOR inhibitors inhibits mTORC1 mechanism: competitive-inhibition · this link in full · on the map table | Torin sits in the spot where mTOR holds its energy molecule ATP, so it shuts the kinase down whatever the kinase is about to modify. Rapamycin leaves part of mTORC1's work running; Torin does not, which is how researchers learned how much rapamycin had been missing. This comes from cell-culture work, not from patients. Holds under: Cell-line pharmacology. Clinical development of this class has been limited by toxicity attributed to simultaneous mTORC2 inhibition, which is precisely what the bi-steric design tries to avoid. plausible in people, not shown directly · settled in the literature | A | THO2009, FEL2009, CHR2009, JAN2010, ROD2011, GAR2009, MAR2014 |
| Bi-steric mTORC1-selective inhibitors inhibits mTORC1 mechanism: competitive-inhibition · this link in full · on the map table | A two-part drug grips mTORC1 at two places at once, which blocks it more completely than rapamycin-type drugs. So far only a first safety trial in people with advanced tumours has reported on it. Holds under: Phase 1 in advanced solid tumours – a safety and pharmacodynamic result, not an efficacy verdict. Directness is graded indirect because, like rapalogs, the mechanism requires FKBP12. Consensus is emerging: one trial. plausible in people, not shown directly · emerging, few independent studies | H | SCH2025 |
| Mitochondrial dysfunction inhibits mTORC1 mechanism: signal-relay · this link in full · on the map table | When mitochondria – the cell's power plants – are damaged, at least two separate alarm signals reach mTORC1 to shut it down. Holds under: CRISPR screening in cell lines; the relative weight of the AMPK and HRI arms in tissue is untested. plausible in people, not shown directly · emerging, few independent studies | M | CON2021 |
| Reactive oxygen species activates mTORC1 mechanism: signal-relay · this link in full · on the map table | Oxidative damage can itself switch on mTORC1 through a chain of signals, closing a feedback loop that can turn a brief stress into a lasting one. Holds under: One cell-line study in a multidrug-resistance context; whether the loop runs in normal physiology at these ROS levels is untested. not tested in people · emerging, few independent studies | M | JIN2026 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| H | Human study | 14 |
| A | Animal model | 54 |
| M | Molecular — cells, biochemistry, structure | 109 |
| PP | Preprint, not peer-reviewed | 4 |
| R | Review — secondary literature, not a new result | 27 |
Human studies in the Atlas
Studies
| Year | Evidence | Study |
|---|---|---|
| 2026 | H | Association of rapamycin treatment with the modulation of purine metabolism, reduced microglial inflammatory responses, improved mitochondrial energy metabolism, and alleviation of fatigue symptoms in ME/CFS subjects: pilot findings from phase-II observational study GIL2026 In an uncontrolled phase-II pilot (no placebo), low-dose rapamycin was associated with reduced fatigue in ME/CFS. In plasma from responders, purine intermediates shifted, consistent with lower IMP dehydrogenase activity in PBMCs. Lab assays suggest that altered purines can impair mitochondrial metabolism and promote microglial inflammation; these links were not measured in patients. |
| 2026 | H | EVERolimus effectiveness after proGREssion on ENdocrine therapy plus CDK4/6 inhibitor for ER-positive/HER2-negative advanced breast cancer: EVERGREEN study MAR2026 Everolimus added to endocrine therapy provided modest but statistically significant PFS benefit (5.0 vs 4.3 months; HR 0.68) in ER+/HER2- advanced breast cancer post-CDK4/6 inhibitor progression, without demonstrable OS benefit, supporting selective use. Retrospective and non-randomised, so treatment-selection bias cannot be excluded. |
| 2026 | H | Sexual Dimorphism in Placental mTORC1 Signaling, Amino Acid Transport, and Mitochondrial Respiration at Term. SHIMADA2026 In 46 term placentas, male placentas showed higher mTORC1 signalling (increased S6RP phosphorylation, reduced 4E-BP1), greater System A amino acid transport and higher mitochondrial respiratory capacity than female placentas, and male pregnancies had a higher birth-weight-to-placental-weight ratio. Observational: a cross-sectional association at a single timepoint, with no intervention and no randomisation, so the direction of the relationship between mTORC1 signalling and growth is not established here and residual confounding by maternal and obstetric factors cannot be excluded. |
| 2025 | H | The Bi-steric, mTORC1-Selective Inhibitor, RMC-5552, in Advanced Solid Tumors: A Phase 1 Trial SCH2025 First-in-human, open-label dose-escalation trial (n=57, advanced solid tumors, no comparator arm) of a bi-steric mTORC1-selective inhibitor. Treatment-related hyperglycemia was low (4%) and not dose-limiting, alongside a 64% disease control rate. Because the trial was uncontrolled and made no head-to-head comparison against rapamycin or an ATP-site inhibitor, this is encouraging early clinical evidence consistent with the hypothesis that sparing mTORC2 reduces metabolic toxicity -- it does not establish mTORC2 sparing as the cause. |
| 2021 | H | Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials MAN2021 This paper reports two trials of RTB101, a drug that blocks mTOR, taken once a day for 16 weeks by adults over 65. In the phase 2b trial (652 people), fewer people on 10 mg had a lab-confirmed respiratory infection than on placebo (19% against 28%), but that result comes from a pooled analysis the authors did not correct for multiple testing, and the corrected analysis did not reach significance. The phase 3 trial (1,024 people) used a different main endpoint, set with the FDA: symptoms with or without a lab test. It found no difference (26% against 25%, p = 0.65), although blood tests still showed more antiviral genes switched on in both trials. In phase 2b, twice-daily dosing and a combination with everolimus did not reach significance, which the authors read as a hint that on-off inhibition may beat constant inhibition. Those numbers are "data not shown" in the paper. Boundary: RTB101 is not rapamycin or everolimus, the phase 3 group was healthier (no COPD, no smokers), and that trial was too small to test the lab-confirmed endpoint. The only everolimus arm (RTB101 plus everolimus 0.1 mg daily) was a combination and did not reach significance, which is why this paper is listed against the everolimus and immune function link on the pathway map. It cannot show what everolimus alone does. |
| 2019 | H | Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial CHU2019 A small human trial testing whether rapamycin can slow aging in a tissue you can actually see and biopsy - skin. Topical rapamycin significantly lowered the senescence marker p16 and raised collagen VII, with visible improvement in skin appearance. Early, small-scale evidence (17 of 36 completed) that topical rapamycin can reduce a senescence marker in human skin. |
| 2018 | H | TORC1 inhibition enhances immune function and reduces infections in the elderly MAN2018 A phase 2a RCT in 264 older adults: 6 weeks of a low-dose combination of BEZ235 (a catalytic PI3K/mTOR inhibitor) and everolimus (RAD001) was associated with fewer reported infections over the following year, plus higher antiviral gene expression and a better flu-vaccine response. The later phase 3 trial of RTB101 (BEZ235) alone (MAN2021) did not confirm a clinical benefit. |
| 2018 | H | A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. KRA2018 A safety-first pilot RCT (n=25, ages 70-95) asking the basic question before any longevity trial: is daily rapamycin safe in healthy older people? Over 8+ weeks it was well tolerated with only minor red-blood-cell changes and - importantly - NO rise in blood glucose or insulin resistance in this short window. Groundwork for larger aging trials like PEARL. |
| 2013 | H | Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial BIS2013 The companion phase 3 RCT (n=118) to EXIST-1, targeting kidney tumors (angiomyolipomas) in tuberous sclerosis and LAM. Everolimus shrank them by >=50% in 42% of patients versus 0% on placebo. Together EXIST-1 and -2 sealed everolimus as a disease-modifying therapy across multiple TSC tumor types. |
| 2013 | H | Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial FRA2013 Phase 3 RCT (n=117) in tuberous sclerosis, the disease where mTOR is stuck ON by a genetic fault. Everolimus shrank brain tumors (SEGA) by >=50% in 35% of patients versus 0% on placebo. Because the underlying cause here is direct mTOR overactivation, this is arguably the cleanest randomised human evidence that blocking mTOR works in a genetically defined mTORopathy -- which does not extend to mTOR inhibition in people without such a mutation. |
| 2012 | H | Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer (BOLERO-2) BAS2012 A phase 3 RCT (n=724) proving mTOR matters in a common cancer. Resistance to hormone therapy in breast cancer is associated with mTOR activation. Adding everolimus more than doubled progression-free survival (10.6 vs 4.1 months by central review) - leading to FDA approval. Main toxicity was stomatitis. |
| 2011 | H | Everolimus for advanced pancreatic neuroendocrine tumors (RADIANT-3) YAO2011 A phase 3 RCT (n=410) that made everolimus a standard treatment for pancreatic neuroendocrine tumors. It more than doubled progression-free survival (11.0 vs 4.6 months, a 65% reduction in risk of progression/death) with mostly mild side effects. Another FDA-approved indication built on blocking mTOR. |
| 2011 | H | Efficacy and safety of sirolimus in lymphangioleiomyomatosis (MILES) MCC2011 MILES was a 12-month placebo-controlled trial of sirolimus in 89 women with lymphangioleiomyomatosis (LAM), a rare lung disease driven by overactive mTOR. On placebo, lung function (FEV1) fell by about 12 ml a month. On sirolimus it held steady (+1 ml a month), a 153 ml difference over the year. In the next year nobody took the drug, and the sirolimus group's decline resumed in parallel with placebo, so the benefit lasted only while the drug was taken. Walking distance and gas-transfer capacity did not improve. Boundary: patients had fairly advanced disease (average FEV1 about 48% of predicted), many dropped out of the observation year, and mouth ulcers and rashes may have revealed who was on the drug. Sirolimus was held at a blood level of 5 to 15 ng/ml, so this was continuous dosing, not intermittent. |
| 2009 | H | Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis DRU2009 Rapamycin given before resistance exercise blocked the early (1–2 h) post-exercise rise in human muscle protein synthesis, which was about 40% in the control group. Rapamycin also blocked the rise in ERK1/2 phosphorylation and blunted MNK1, so the authors conclude that mTORC1 drives the response only in part. The study measured acute protein synthesis, not muscle growth. |
| 2026 | A | Spalt-related is an inhibitor of mTORC1-mediated growth activated by the integrated stress response DEN2026 Transcription factor Spalt-related (Salr) is a novel mTORC1 inhibitor in Drosophila activated by the integrated stress response, restricting anabolic growth and lipid storage during nutrient stress. Salr responds to a distinct, ISR-driven cue, acting convergently with FoxO rather than downstream of it. |
| 2026 | A | SLC15A3-mediated dipeptide metabolism confers antimetabolite resistance in lymphoma via mTORC1 activation. YAN2026 SLC15A3-mediated dipeptide import sustains mTORC1 activation in B cell lymphomas, enabling resistance to antimetabolite chemotherapy. Silencing SLC15A3 lowered mTORC1 activity and restored sensitivity to 6-mercaptopurine, and the resistant lymphomas, but not the parental tumours, were selectively sensitive to rapamycin in culture and in vivo. |
| 2026 | A | Rapamycin-induced fatty liver in mice is attenuated by chloroquine co-treatment in an ERRα-dependent manner BCH2026 Chloroquine co-treatment attenuates rapamycin-induced hepatic steatosis (a known mTORC1-inhibitor side effect) in mice, and this rescue depends on the nuclear receptor ERRα; RNA-seq shows chloroquine reverses rapamycin-driven upregulation of lipid-metabolism genes, with ERRα identified as a top transcriptional regulator of the effect. |
| 2026 | A | Enforcing mTORC1 activity in therapeutic CD4+ T cells promotes persistence but eventual immune exhaustion SIL2026 Enforced RHEB overexpression (mTORC1 hyperactivation) in therapeutic CD4+ T cells boosts initial proliferation/persistence after adoptive transfer, but drives cells toward an exhausted phenotype (co-inhibitory receptors, impaired re-proliferation on rechallenge) -- a double-edged sword for CAR/TCR-T cell engineering, distinct from the CD8 response to the same manipulation. |
| 2026 | A | Impaired Chaperone-Mediated Autophagy Accelerates Intervertebral Disc Degeneration by Inducing MIDN Accumulation to Target TSC2 for Proteasomal Degradation CHEN2026C Loss of chaperone-mediated autophagy lets its substrate midnolin (MIDN) accumulate; MIDN binds TSC2 and drives its proteasomal degradation independently of ubiquitination, de-repressing mTORC1 and causing senescence, SASP and matrix loss in disc cells. MIDN knockdown, LAMP2A overexpression or rapamycin each blocked the degeneration - a new upstream route to mTORC1 hyperactivation. |
| 2026 | A | Nutrient/TOR signaling controls adipose mitochondrial transcription factor A (TFAM) to regulate organismal growth in Drosophila SRI2026 In Drosophila larvae, nutrient/TOR signaling in the fat body (a key nutrient-sensing tissue) post-transcriptionally suppresses the mitochondrial transcription factor TFAM, and this TOR→TFAM axis in fat-body tissue controls whole-body developmental growth — a mechanistic link between nutrient sensing and interorgan growth control via mitochondrial bioenergetics. |
| 2026 | A | Anticipatory metabolic regulation drives the distinct and improved metabolic state of caloric restriction compared to Fasting-Refeeding cycles. VEL2026 Comparing caloric restriction (CR, one meal/day) to a fasting-refeeding-fasting (FRF) regimen with matched food intake and fasting duration, CR engages anticipatory, circadian-clock-aligned metabolic control (hepatic mTOR signaling, ketogenesis, metabolic gene coordination), whereas FRF responses track direct nutrient/gastric-emptying cues and disrupt circadian rhythmicity. CR improved glucose and fatty-acid metabolism; FRF caused glucose intolerance and hepatic fat accumulation. |
| 2026 | A | Hepassocin prevents age-related liver senescence and facilitates liver regeneration by activating AMPK YAN2026B Hepassocin (HPS/FGL1), a hepatokine, activates AMPK via an ANXA2-ERK-p90RSK-LKB1 cascade, restraining mTOR activity. Aged HPS-knockout mice show reduced LKB1/AMPK activation and elevated mTOR activity, impaired autophagy, exacerbated cellular senescence, and severely compromised liver regeneration after partial hepatectomy. AMPK agonist AICAR or exogenous HPS rescued the aging/regeneration phenotype. |
| 2026 | A | Dietary protein governs the role of insulin signaling in the postprandial regulation of hepatic mTORC1. KAL2026 In liver-specific mouse genetic models, AKT-mediated TSC2 phosphorylation is the main route by which insulin induces hepatic mTORC1, but is dispensable for feeding-induced activation; postprandial mTORC1 activation instead requires dietary protein, and hepatic mTORC1 signalling is not elevated in diet-induced obesity despite impaired insulin/glucose homeostasis. |
| 2026 | A | Non-canonical mTORC1-TFEB activation promotes hepatocyte plasticity and high-grade malignancy in hepatocellular carcinoma. ZHANG2026 TSC1 loss drives non-canonical mTORC1-mediated TFEB nuclear translocation, promoting hepatocyte-to-biliary plasticity and spontaneous aggressive HCC in mice; Tsc1/Tfeb double knockout rescues the phenotype. |
| 2026 | A | Novel mTORC1 Booster LAPTM4A Potentiates Pathological Cardiac Hypertrophy HU2026 Identifies LAPTM4A, a lysosomal transmembrane protein, as a novel booster of mTORC1 signaling in cardiomyocytes: LAPTM4A binds NEDD4L, driving K63-linked ubiquitination of AKT and downstream mTORC1-p70S6K/4EBP1-mediated protein synthesis, without affecting lysosomal autophagy. Cardiomyocyte-specific LAPTM4A deletion attenuated TAC-induced hypertrophy/fibrosis in mice; an FDA-approved-drug screen identified magnolol as a LAPTM4A suppressor with cardioprotective effect in vivo. |
| 2026 | A | LncRNA DLX6-AS1 promotes necroptosis through PI3K/AKT/mTOR signaling pathway in myocardial ischemia/reperfusion injury mice SU2026 LncRNA DLX6-AS1 activates PI3K/AKT/mTOR signaling to promote necroptosis in myocardial ischemia-reperfusion injury; inhibiting DLX6-AS1 suppresses necroptosis and protects cardiomyocytes. |
| 2026 | A | mTORC1-TFEB/TFE3 signaling is associated with bile acid diversification during hepatic metabolic adaptation ZAU2026 Establishes a new mTORC1-TFEB/TFE3 signaling axis controlling hepatic bile acid metabolism. Depending on mTORC1 signaling state, mice show coordinated shifts in bile-acid species (non-12-OH vs 12-OH) via altered enzyme expression and cholesterol trafficking; these shifts are reversed by mTORC1 pathway deletion or rapamycin treatment. Dietary protein restriction (which inhibits mTORC1) produces a similar bile-acid shift in mice and correlates with improved metabolic outcomes in human MASLD patients, linking mTORC1 nutrient sensing directly to bile-acid homeostasis and fatty liver disease. |
| 2026 | A | Synergistic role of TFEB/TFE3 and mTORC1 in kidney cystogenesis and tumorigenesis FER2026 Using kidney-specific mouse models that genetically uncouple mTORC1 activity from TFEB/TFE3 activity (Depdc5-KO, RagC-KO, and Flcn/RagC double-KO), the authors show mTORC1 hyperactivation -- not TFEB/TFE3 activation alone -- is the primary driver of kidney cystogenesis and tumorigenesis in Birt-Hogg-Dube and Tuberous Sclerosis Complex models. Constitutive TFEB/TFE3 activity further accelerates disease on top of mTORC1-driven pathology. |
| 2026 | A | Constitutive mTORC1 Activation in Skeletal Muscle Increases Inflammation but is not Sufficient to Impair Glucose Tolerance. MARCHANT2026 Constitutive mTORC1 activation in mouse skeletal muscle (via GATOR1 complex KO) increases inflammatory markers but is not sufficient to impair glucose tolerance, indicating that additional metabolic inputs beyond muscle mTORC1 hyperactivation are required to drive glucose intolerance. |
| 2026 | A | D-Amino Acid Prodrug DLMEH Activates mTORC1 via Sestrin2 to Restore Muscle Protein Synthesis in Sarcopenia. SHIM2026 DLMEH, a D-leucine ester prodrug, binds Sestrin2 with leucine-like potency (Kd 28.3 uM, equivalent to L-leucine) and activates mTORC1 in a Sestrin2-dependent way. It restored protein synthesis in human myotubes and preserved muscle mass, grip strength and endurance in a rat dexamethasone-induced atrophy model (not an ageing sarcopenia model). |
| 2026 | A | Lsp2 links mTORC1 to TOP mRNA translation and lifespan in Drosophila WAN2026 Identifies Lsp2, a Drosophila fat-body storage protein, as an amino-acid-induced feedback activator of mTORC1 that specifically boosts translation of TOP-motif mRNAs (mostly ribosomal proteins) via 4E-BP — a rapamycin-resistant arm of mTORC1 output. Genetic loss of Lsp2 reduces TOP mRNA translation and robustly extends lifespan without cost to reproduction, revealing a rapamycin-independent route from mTORC1 activity to organismal longevity. |
| 2026 | A | Feeding-Induced Muscle mTORC1 Signaling Regulates Postprandial Protein Synthesis and Endurance but Not Muscle Size LAP2026 Using a mouse model expressing an AKT-nonphosphorylatable TSC2 mutant specifically in skeletal muscle, the Manning lab genetically separated feeding-induced from contraction-induced mTORC1 activation. AKT-mediated TSC2 phosphorylation is required for feeding (but not contraction) to activate muscle mTORC1 and drive postprandial protein synthesis — yet mice lacking this feeding-induced signal have normal muscle mass and myofiber size, and instead show improved maximal endurance capacity with a modest rise in mitochondrial content. The finding dissociates mTORC1's role in postprandial anabolism from its role in maintaining steady-state muscle mass, and is a directly relevant data point for whether the pattern/source of mTORC1 activation (feeding vs. mechanical) — not just its average level — shapes downstream outcomes. |
| 2026 | A | SLC4A7/NBCn1 maintains intracellular pH to support mTORC1 activity and antibody-secreting cell differentiation HU2026B SLC4A7/NBCn1, a Na/HCO3 cotransporter, maintains intracellular pH needed for mTORC1 activity during B-cell differentiation into antibody-secreting cells; its loss causes intracellular acidification, lysosomal alkalinization, impaired mTORC1 function, and blunted antibody responses in vivo. |
| 2023 | A | A bi-steric mTORC1-selective inhibitor overcomes drug resistance in breast cancer MEN2023 RMC-6272, a bi-steric molecule with >25-fold selectivity for mTORC1 over mTORC2, completely suppresses mTORC1 (hitting the rapamycin-resistant substrate 4E-BP1) and overcomes hormone- and CDK4/6-inhibitor resistance in breast cancer cell lines and PDX -- the preclinical basis for the RMC-5552 selective-inhibitor clinical program. |
| 2021 | A | Imaging dynamic mTORC1 pathway activity in vivo reveals marked shifts that support time-specific inhibitor therapy in AML OKI2021 Fluorescent probes imaged in the bone marrow of live mice show mTORC1 activity in AML cells falls as the disease progresses but is high at the moment of maximal chemotherapy response, where it is induced rather than selected; inhibiting mTORC1 at that time improved killing of AML cells. |
| 2018 | A | In Vivo Decoding Mechanisms of the Temporal Patterns of Blood Insulin by the Insulin-AKT Pathway in the Liver KUB2018 The in-vivo follow-up to KUB2012. In rat liver, all temporal patterns of blood insulin were encoded at the insulin receptor, and downstream molecules decoded them selectively through AKT: S6K read the additional (pulse-like) secretion, G6Pase the basal secretion via FoxO1, GSK3-beta all of it. Modelling tied the selectivity to network structure, sensitivity and time constants. Shows that pattern decoding is not only a cell-culture effect. |
| 2017 | A | Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy LIP2017 In mouse models of tuberous sclerosis, where mTOR is stuck on, the circadian clock ran abnormally: poor timekeeping in constant conditions and exaggerated responses to phase resetting. mTOR raised BMAL1 levels by changing its translation, degradation and location; genetically lowering BMAL1 rescued the behavioural rhythm defects. Constant, unpatterned mTOR activity disturbs a rhythm downstream. |
| 2015 | A | The Circadian Protein BMAL1 Regulates Translation in Response to S6K1-Mediated Phosphorylation LIP2015 S6K1, a main output of mTORC1, phosphorylates the clock protein BMAL1 rhythmically, and that phosphorylation lets BMAL1 join the translation machinery and drive protein synthesis. Protein synthesis rates oscillated over the day in a BMAL1-dependent way. A direct molecular bridge between mTORC1 output and the 24-hour clock. |
| 2015 | A | mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation POL2015 By deleting Tsc2, Rheb or Rictor in T cells, this work split the CD8 response between the two mTOR complexes. Tsc2 loss left mTORC1 constitutively active: the cells were strongly glycolytic (high ECAR, high Slc2a1 and Pfk1, low spare respiratory capacity), made more IFN-gamma, TNF and granzyme B, cleared EL4 thymoma and slowed B16-OVA growth, but stayed terminally differentiated and were about two-fold fewer than wild type at day 30, with no memory. Rheb loss removed mTORC1 activity with mTORC2 intact: those cells failed as effectors but kept memory-like features and were about two-fold more numerous at day 30, yet did not respond to rechallenge, which the authors trace to metabolic defects. Rapamycin from day 5 (100 ug/kg daily) rescued survival of Tsc2-deficient cells, raised CD127 and Eomesodermin, lowered KLRG1 and T-bet and restored a recall response. Losing mTORC2 by Rictor deletion left effector function intact but increased memory cells that still responded 133 days after infection, and the Tsc2/Rictor double knockout showed that the hyperactive effector phenotype needs mTORC2. Boundary: mouse genetics with TCR-transgenic transfers and transplantable tumours; the comparison rests on genetic extremes (no TSC2, no Rheb, no Rictor) rather than graded physiological signalling, and nothing here is measured in people. |
| 2014 | A | The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice SOL2014 Lifespan and cardiometabolic health were determined not by caloric intake but by the protein:carbohydrate ratio; a low protein ratio was associated with lower hepatic mTOR activation. |
| 2014 | A | BMAL1-dependent regulation of the mTOR signaling pathway delays aging KHA2014 Loss of the clock protein BMAL1 raised mTORC1 activity in mice and in cultured cells, and rapamycin extended the lifespan of Bmal1-/- mice by 50%. Places the circadian clock upstream of mTORC1 as a brake, and links that brake to ageing. |
| 2014 | A | The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells MAR2014 This study separated two arms of IL-15 signalling in NK cells by dose: low IL-15 mainly phosphorylated STAT5 (EC50 about 1.5 ng/ml), while higher IL-15 was needed to switch on mTOR (EC50 about 5.3 ng/ml for S6 phosphorylation), and IL-15 was the only one of many tested stimuli that strongly raised pS6. Deleting mTOR in NK cells left bone-marrow numbers normal but blocked the CD11b-low to double-positive transition, cut proliferation about three-fold and left almost no mature NK cells in the periphery, with lower CD71, glucose uptake and about half the surface CD122 and CD132, so the receptor feedback is itself mTOR-dependent. In activation, mTOR-deficient NK cells failed to grow or raise nutrient uptake after poly(I:C) and made about half as much granzyme B, while IFN-gamma production in response to IL-12 plus IL-18 stayed normal. Oral rapamycin lowered pS6 and granzyme B in vivo and made rejection of MHC-class-I-negative target cells significantly less efficient, and mTOR inhibitors also blocked IL-2-driven granzyme B induction in human NK cells. Boundary: mouse genetics and mouse in vivo pharmacology, with the human arm limited to healthy-donor NK cells stimulated in culture; the clinical implication for patients on rapalogs is inference, not a measured patient outcome. |
| 2014 | A | Testing efficacy of administration of the antiaging drug rapamycin in a nonhuman primate, the common marmoset. TAR2014 First description of dosing, pharmacokinetics, biochemical action and tolerability of rapamycin in the common marmoset. Eudragit-encapsulated rapamycin given orally at roughly 1.0 mg/kg/day gave mean trough blood levels of 5.2 ng/mL (range 1.93-10.73), comparable to rodent studies and within the human therapeutic range. In long-term animals (6 of 8) the phospho-rpS6 to total rpS6 ratio fell after 2 weeks, and rapamycin was detectable in liver and adipose tissue with reduced mTOR signalling there. There was no evidence of clinical anemia, fibrotic lung changes or mouth ulcers, and the death rate in the 14-month study was as expected for the animals' ages. Boundary: small cohort (6 of 8 long-term animals showed the pS6 drop), a 3-week and a 14-month study, pharmacology and tolerability only; no lifespan or healthspan outcome was measured, and nothing here is tested in people. |
| 2013 | A | Late-life rapamycin treatment reverses age-related heart dysfunction FLY2013 Striking evidence that in mice mTOR inhibition doesn't just SLOW aging - it can partly reverse an established age-related phenotype. Giving rapamycin to already-old (24-month) female mice for 3 months improved aged heart function, reversing or attenuating age-related cardiac changes, with RNA-seq changes suggesting anti-hypertrophic and anti-inflammatory effects. Started late, still worked. |
| 2013 | A | Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation SIN2013 Antigen-receptor-driven System-L (SLC7A5) amino-acid transport controls mTORC1 and T-cell differentiation. |
| 2013 | A | mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function ZEN2013 mTORC1 couples immune signals and metabolism to establish regulatory T-cell function. |
| 2013 | A | Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression WUX2013 Genetically reduced mTOR increases mouse lifespan with tissue-specific slowing of aging. |
| 2012 | A | Rapamycin slows aging in mice WIL2012 Answered a crucial objection: does rapamycin really slow AGING, or just prevent the cancers that kill mice? By showing slower age-related change across many tissues (heart, liver, tendon, activity), it argued for genuine slowing of aging. Honestly reported harms too - more cataracts and testicular degeneration - making it a balanced landmark, not hype. |
| 2012 | A | Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. HAL2012 Asked whether the lifespan-extending dose of rapamycin harms or helps the aging BRAIN. Reassuringly, it enhanced learning and memory in young mice, prevented age-related cognitive decline in old ones, and even reduced anxiety and depression-like behavior - linked to boosted brain monoamines. Cognitive benefit, not cost. |
| 2012 | A | Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival EFE2012 Rag-GTPase control of mTORC1 is essential for neonatal autophagy and survival to fasting. |
| 2012 | A | Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice TSA2012 Deleting one or both copies of Tsc1 only in cerebellar Purkinje cells raised phospho-S6 (a readout of mTORC1) in those cells. Both heterozygous and homozygous mutants showed autism-like behaviour: no preference for a mouse over an object or for a new mouse, more self-grooming, more pup ultrasonic calls and poorer reversal learning in a water T-maze. Purkinje cells fired fewer action potentials, both spontaneously and when driven, in a gene-dose-dependent way, while their synaptic inputs looked largely normal; homozygous mutants also lost Purkinje cells from about 2 months of age and became ataxic. Rapamycin (6 mg/kg intraperitoneally, three times a week from postnatal day 7) prevented the Purkinje cell loss and enlargement and the social, learning and motor deficits. Boundary: mouse, cell-type-specific genetic deletion; rapamycin given from early postnatal life, so this is prevention, not reversal; relevance to human autism is by analogy with TSC patients. |
| 2011 | A | The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2 DEL2011 mTORC1 and mTORC2 selectively program distinct CD4 helper T-cell lineages. |
| 2010 | A | Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster BJE2010 Feeding rapamycin extended fly lifespan through autophagy and reduced translation, and worked even in flies already on a lifespan-maximizing diet. |
| 2010 | A | Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease SPI2010 Connected the longevity drug to a specific age-related disease. Long-term rapamycin prevented memory deficits and lowered toxic amyloid-beta in an Alzheimer's mouse model - and the benefit tracked with INCREASED autophagy in neurons. Suggested that the same autophagy boost that may slow aging could also help clear disease-causing proteins. |
| 2010 | A | Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. CAC2010 Revealed a vicious cycle: amyloid-beta RAISES mTOR activity, and high mTOR in turn blocks the autophagy needed to clear amyloid and tau - so the disease feeds itself. Rapamycin broke the loop in 3xTg-AD mice, rescuing memory and lowering BOTH amyloid and tau, with autophagy induction shown to be necessary for the reduction in amyloid levels. |
| 2009 | A | Rapamycin fed late in life extends lifespan in genetically heterogeneous mice HAR2009 Rapamycin fed from 600 days of age extended median and maximal lifespan in both sexes; age at 90% mortality rose 14% in females and 9% in males. |
| 2009 | A | Ribosomal protein S6 kinase 1 signaling regulates mammalian life span SEL2009 Deleting S6K1 (a direct mTORC1 effector) extended lifespan in FEMALE mice (+19% median); the effect was not significant in males. It also protected against age-related bone, immune and motor decline. One of the clearest cases of the sex dimorphism catalogued in gap H6 - and a reminder that a single downstream branch, not mTORC1 as a whole, can carry much of the ageing signal. |
| 2009 | A | 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila ZID2009 Connected the dots between diet, mTOR, and lifespan. 4E-BP, an mTOR target, is upregulated on dietary restriction and here was shown to be REQUIRED for the lifespan boost, working by selectively boosting translation of mitochondrial genes. A rare case pinning a specific mTOR effector to the longevity benefit of eating less. |
| 2009 | A | Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice ZHO2009 In neural Pten-knockout mice, rapamycin prevented and reversed neuronal hypertrophy and improved a subset of the PTEN-associated abnormal behaviours. |
| 2008 | A | TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species CHE2008 Showed why blood stem cells must keep mTOR LOW. Deleting TSC1 (which unleashes mTOR) drove resting stem cells into rapid division, flooded them with reactive oxygen species, and burned out their ability to self-renew. An antioxidant rescued them. A key link between mTOR, stem-cell exhaustion, and tissue aging. |
| 2008 | A | Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy BEN2008 In mice, muscle-specific raptor loss (not rictor) causes dystrophy, showing mTORC1 is essential for muscle homeostasis. |
| 2008 | A | Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function MEI2008 mTOR inhibition rescues a neuronal tuberous-sclerosis model, supporting rapamycin for TSC neurology. |
| 2008 | A | Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex ZEN2008 Mice lacking Tsc1 mainly in glial cells (Tsc1 GFAP conditional knockout) develop glial overgrowth, progressive epilepsy and early death. Rapamycin started at postnatal day 14, before symptoms, prevented epilepsy and premature death; started at 6 weeks, after seizures had begun, it suppressed seizures and prolonged survival. In the brain, rapamycin reversed the abnormal mTOR pathway activation (measured as phospho-S6), the astrogliosis and the neuronal disorganisation, and increased brain size, compared with vehicle-treated knockouts. The study provided evidence in mice that mTOR inhibition can act on epilepsy itself in TSC, not only on tumours, and it is part of the rationale for the later EXIST-3 seizure trial in patients. Boundary: mouse model with Tsc1 deleted mainly in glia, not the human germline mutation; seizure and survival outcomes in mice only; abstract does not state dose or schedule. |
| 2004 | A | Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway KAP2004 Genetically reducing TOR pathway activity extends fruit fly lifespan, overlapping with dietary restriction effects. |
| 2004 | A | Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease RAV2004 Induced autophagy cleared toxic clumped proteins and improved symptoms in fly (rapamycin) and mouse (the rapalog CCI-779) models of Huntington's disease. |
| 2002 | A | A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells KWI2002 The authors built a Tsc1 knockout mouse to model tuberous sclerosis. Embryos lacking both copies of Tsc1 died at mid-gestation because the liver failed to develop. Mice with one copy often developed kidney cystadenomas and liver hemangiomas; the hemangiomas were more common, more severe and more often fatal in females. Fibroblasts lacking Tsc1 showed persistent phosphorylation of S6K and its substrate S6 that rapamycin could reverse, and S6 phosphorylation was also high in kidney tumours from the mice. The authors suggested that blocking this pathway might help control TSC tumours. Boundary: mouse model and mouse cells; the rapamycin result is in cultured cells, and treatment of the mouse tumours was not tested here. |
| 2001 | A | Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR NES2001 Tested whether tumour cells that have lost PTEN depend more on mTOR. The rapamycin analogue CCI-779 (temsirolimus) blocked growth of PTEN-null cells and tumours preferentially, and reversed the extra tumour growth caused by constitutively active Akt, placing mTOR downstream of Akt in tumour formation. PTEN loss went with higher S6 kinase activity and S6 phosphorylation. Sensitivity was not explained by how well the drug blocked S6 phosphorylation, since S6 was inhibited in sensitive and resistant lines alike. Boundary: worked from the abstract only (scanned PMC record); mouse and human cell lines and mouse tumour models, not patients. |
| 2001 | A | An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice POD2001 Transformed cells in Pten+/- mice showed raised phosphorylated Akt and active p70 S6 kinase together with faster proliferation. Treating the mice with an mTOR inhibitor reduced neoplastic proliferation, tumour size and S6 kinase activity without changing Akt status. The authors concluded that S6K and possibly other mTOR targets contribute to tumour development downstream of PTEN loss. Boundary: worked from the abstract only (scanned PMC record); mouse model. The abstract does not name the inhibitor. |
| 2026 | R | Biological limits of lifespan extension: evidence for a shift from pathway leverage to system-level buffering across species PIR2026 mTOR/TOR pathway interventions achieve large lifespan extensions in simple organisms but face declining efficacy in mammals due to distributed multi-tissue buffering, redundancy, and pharmacokinetic complexity - proposing a unifying framework for the translational challenge of aging pathway targeting. |
| 2026 | M | FLCN loss is characterized by SQSTM1/p62 accumulation despite functional autophagy flux in Birt-Hogg-Dubé syndrome-associated kidney cancer ULL2026 In BHD patient-derived kidney cancer cells, FLCN loss causes constitutive nuclear TFEB localization and mTORC1 hyperactivation, but leaves bulk autophagy flux and LC3 lipidation unaffected; however, the autophagy receptor SQSTM1/p62 accumulates in enlarged puncta, a finding replicated in a Norwegian cohort of BHD patient kidney tumors, showing p62 accumulation is dissociable from bulk autophagic flux. |
| 2026 | M | mTOR inactivation governs adaptive survival to ribosome biogenesis deficiency FAN2026 mTORC1 inhibition does not restore ribosome biogenesis but redistributes limited ribosomes away from highly-translated 5'TOP mRNAs toward survival-essential transcripts, defining a 'translational fitness' mechanism that lets cancer cells survive ribosome biogenesis deficiency. |
| 2026 | M | Firefox, a protein encoded by circular PVT1, is essential for MYC-driven oncogenesis. TIW2026 A micropeptide (Firefox/FFX) encoded by the circular RNA circPVT1 stimulates AKT-mTORC1 signaling and cap-dependent translation to sustain MYC protein abundance and transcriptional output. FFX depletion reduces MYC levels and impairs tumor growth in MYC-amplified xenograft models, identifying an mTORC1-linked vulnerability in MYC-driven cancers. |
| 2026 | M | mTORC1 inhibition upregulates CD20 and enhances anti-CD20 antibody efficacy in B-cell precursor acute lymphoblastic leukemia DAB2026 mTORC1 inhibitors upregulate CD20 via the AKT-FOXO1 axis and promote B-lineage maturation in B-cell precursor ALL, enhancing the antitumor efficacy of anti-CD20 monoclonal antibodies -- including in high-risk IKZF1-deleted disease -- providing a rationale for combining mTORC1 inhibition with CD20-directed immunotherapy. |
| 2026 | M | Fluorescent protein ticker tape (FPTT): Multiplexed recording of transcriptional dynamics in living cells and in vivo WANG2026C Engineered a multiplexed fluorescent-protein 'ticker tape' biosensor platform (self-assembling protein fibers + multispectral fluorescent proteins) for longitudinal, single-cell recording of signaling-pathway transcriptional histories (mTOR, NF-κB, STAT3, NFAT, cAMP). Applying the mTOR-FPTT reporter, the authors independently observed cell-cycle-dependent OSCILLATING mTOR activity dynamics -- a new, orthogonal tool corroborating that mTOR signaling is patterned over time rather than static, consistent with JOS2024's cell-cycle oscillation finding. |
| 2026 | M | CASTOR1 regulates humoral immune responses and contributes to the pathogenesis of systemic lupus erythematosus KUS2026 Gives the arginine sensor CASTOR1 a defined physiological job upstream of mTORC1: losing it de-represses mTORC1 in B cells and drives plasma-cell expansion, IgG and anti-dsDNA autoantibodies, and lupus-like glomerulonephritis. In human SLE, CASTOR1 expression in plasmablasts was inversely correlated with disease activity (r = -0.32, p = 0.00031). One of the few studies to tie a specific upstream amino-acid sensor to a human autoimmune phenotype rather than to cancer or growth. |
| 2026 | M | Amino acid homeostasis by CORVET/HOPS: A metabolic and stress resilience checkpoint for T cells WANG2026 Identifies the CORVET and HOPS endolysosomal tethering complexes as upstream suppliers of intracellular amino acids in activated T cells, acquired via macropinocytosis. Loss of the core subunits VPS18 or VPS11 starves the cell of amino acids, switches on the integrated stress response and shuts down mTORC1; enforced mTORC1 activity rescues the proliferative defect while BIM deletion rescues survival, separating the two failure modes. Places vesicular nutrient acquisition upstream of the canonical lysosomal amino-acid-sensing arm of mTORC1. |
| 2026 | M | "Trojan" Methionine Probe Reveals PKM2 as a Methionine-Sensing Protein in the mTORC1 Pathway SANG2026 Identifies PKM2 as a direct methionine sensor for mTORC1. A photoaffinity methionine analogue plus chemoproteomics showed that PKM2 binds free methionine through a distinct recognition pocket — independently of its glycolytic enzyme activity — and transduces methionine availability to mTORC1 via the GATOR2 complex. Complements SAMTOR (GU2017), which reads the methionine metabolite SAM rather than methionine itself, and suggests a route to a pharmacological "methionine pseudostarvation" state. |
| 2026 | M | TCR-mTORC1 signaling promotes epigenetic stabilization of Foxp3 expression in regulatory T cells via TET protein translation KIN2026 Sustained TCR signaling activates mTORC1, which boosts translation of the TET2 (and likely TET3) DNA-demethylation enzymes; this demethylates the Foxp3 TSDR enhancer and epigenetically locks in stable Foxp3 expression in regulatory T cells. In vivo mTORC1 inactivation increases methylated-TSDR Foxp3+ T cells, confirming the pathway's physiological relevance. |
| 2026 | R | The hallmarks of protein and amino acid restriction in aging and longevity KNO2026 Defines the "hallmarks" of dietary protein restriction (PR) through the lens of aging: PR and restriction of specific essential amino acids — especially methionine, isoleucine and valine — improve metabolic health, healthspan and lifespan across organisms, with amino-acid composition (not just protein quantity) acting as a key determinant via nutrient-sensing pathways including mTORC1. |
| 2026 | M | Structure and function of TM6SF1 reveals role in mTORC1 signaling HON2026 Cryo-EM structure of TM6SF1 identifies it as a lysosomal cholesterol-binding protein that directly engages LAMTOR1 (Ragulator) to regulate mTORC1 signaling in a cholesterol-dependent manner. |
| 2026 | M | mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis LI2026C Using human brain organoids carrying TSC2 loss-of-function mutations plus patient-derived cortical tuber tissue, shows that hyperactive mTORC1 signaling drives neural progenitors to differentiate into enlarged, pro-inflammatory reactive astrocytes in a cell-autonomous manner (downregulated glutamate transporters, elevated inflammatory cytokines and AD-risk genes APOE/CLU) — independent of seizure activity. Positions glial dysfunction as a primary driver of TSC pathology, not merely a downstream consequence. |
| 2026 | M | IGF2BP3-Mediated m6A Modification of OLR1 mRNA Promotes Immune Evasion in CRC via the PI3K/AKT/mTOR Pathway CHEN2026B IGF2BP3 stabilizes OLR1 via m6A RNA modification, activating PI3K/AKT/mTOR signaling which suppresses CD8+ T cell anti-tumor activity and drives immune evasion in colorectal cancer. |
| 2026 | M | ATF4 activates a transcriptional program that chronically suppresses mTOR activity and promotes neurodegeneration in Parkinson disease models DEMMINGS2026 Chronic integrated-stress-response signalling through ATF4 coordinately upregulates SESN2, DDIT4 and Trib3, which together suppress BOTH mTORC1 and mTORC2; this sustained mTOR inhibition drives dopaminergic neuron death via the pro-apoptotic BCL-2 family protein PUMA. Defines a maladaptive ISR/ATF4-to-mTOR axis in Parkinson disease models — a case where LESS mTOR activity is harmful, opposite to the usual longevity framing. |
| 2026 | R | Substrate-selective mTORC1 regulation and gene dosage-dependent tissue divergence in Birt-Hogg-Dubé syndrome CAO2026 Reframes Birt-Hogg-Dube (BHD) syndrome beyond the classic 'global mTORC1 hyperactivation' model: FLCN acts as a GAP for RagC/D, giving substrate-selective (not global) mTORC1 control. Biallelic FLCN loss drives kidney tumors via MiT/TFE nuclear accumulation, while haploinsufficiency alone is sufficient for lung and skin lesions -- resolving the 'mTORC1 paradox' via gene dosage and signaling timing. Narrative synthesis of human genetics and mouse mechanistic data. |
| 2026 | M | Collagen I promotes cancer cell survival via amino acid import and mTORC1/S6 activation NAZ2026 Collagen I drives alpha2beta1 integrin-dependent mTORC1/S6 activation and membrane localization of the LAT1-4F2hc amino acid transporter, sustaining essential amino acid supply and cancer cell survival in nutrient-poor, collagen-rich tumor stroma; LAT1-4F2hc is upregulated in basal-like breast/pancreatic tumors and correlates with poor prognosis. |
| 2026 | M | IDH3 regulates citrate homeostasis to control metabolic fitness and venetoclax resistance of AML stem cells DEM2026 IDH3A loss in AML leukemic stem cells reduces TCA cycle flux and raises intracellular citrate, activating AMPK and suppressing mTORC1 (lowering translation), which sensitizes cells to BCL2 inhibition by venetoclax - nominating the IDH3A-citrate-AMPK-mTORC1 axis as a target to overcome venetoclax/azacitidine resistance. |
| 2026 | M | Inferring feedback regulation from static snapshots of a single signal GIN2026 Introduces AoF (Assay of Feedback), a perturbation-free single-cell imaging method that reconstructs how a signal CHANGES OVER TIME from fixed-cell snapshots, using DNA content and Geminin to order cells along the cell cycle. Applied to Akt phosphorylation, it uncovers a negative feedback loop that is active only in a narrow window at the G1/S transition; biochemistry points to mTORC1/S6K1-dependent inhibitory phosphorylation of IRS1 as the likely source, though the authors state this edge is not uniquely established. Directly relevant to the question of whether mTOR pathway activity is better described as a time-varying pattern than a fixed level. |
| 2026 | R | Molecular switches of SQSTM1: the impact of post-translational modifications on autophagy and neurodegeneration ABR2026 Comprehensive review of how post-translational modifications (phosphorylation, ubiquitination, acetylation, S-acylation, S-nitrosylation) tune SQSTM1/p62's role as the autophagy cargo-receptor hub -- relevant to neurodegenerative disease (Alzheimer's, ALS, Huntington's) where SQSTM1 regulation goes awry. |
| 2026 | M | Mathematical Modeling of Dietary Timing- and Protein Quality-Responsive Liver Circadian Clock and its Function on Ribosome Biogenesis LU2026 Builds a semi-mechanistic model in which liver mTORC1 and GCN2-ISR signalling are driven by RHYTHMS in dietary essential amino acid availability rather than by a fixed nutrient level. Simulations show the two pathways jointly set metabolic entrainability and are required to keep the peripheral clock and ribosome biogenesis synchronised under nutrient stress, and predict individualised recovery trajectories after a transient dietary disruption. A worked example of treating mTORC1 activity as a time-varying pattern whose shape — not just its average — determines the downstream growth output. |
| 2025 | R | mTORC1, the maestro of cell metabolism and growth HE2025 Comprehensive current review of how nutrients and growth signals are integrated by mTORC1 and the metabolic programs it commands, plus the clinical outlook for mTORC1-targeted therapy across cancer, neurodegeneration, obesity, diabetes and aging -- anchor reference for the pathway map. |
| 2025 | M | Structural basis for mTORC1 activation on the lysosomal membrane CUI2025 Resolves how mTORC1 flips from 'parked on the lysosome' to 'catalytically switched on'. Reconstituting the whole assembly on membranes from purified Rheb, Rag GTPases, Ragulator and mTORC1, cryo-EM shows the kinase reaches full activity only after two separate anchoring steps: Rag-Ragulator first pulls it to within about 100 angstroms of the membrane, then Rheb pulls it to within about 40 angstroms, and only when Raptor and mTOR itself also touch the membrane directly do the catalytic residues line up for full activity. Growth-factor input (via Rheb) and nutrient input (via the Rags) are shown converging on the same physical docking event rather than acting through separate switches. Boundary: reconstituted on synthetic membranes from purified components — a structural/biochemical model, not a measurement inside a living cell. |
| 2024 | M | mTORC1 activity oscillates throughout the cell cycle, promoting mitotic entry and differentially influencing autophagy induction JOS2024 mTORC1 activity oscillates across the cell cycle (lowest in mitosis/G1, highest in S/G2) via the TSC complex, independent of Akt/Mek-Erk; low mTORC1 in G1 sensitizes cells to autophagy induction from the same partial inhibition or nutrient drop -- direct evidence that the TIMING/pattern of mTORC1 activity, not just its average level, shapes autophagy outcome. |
| 2024 | M | Spatial and functional separation of mTORC1 signalling in response to different amino acid sources FER2024 mTORC1 regulation and downstream substrate phosphorylation are spatially separated: lysosomal mTORC1 (fed by local lysosomal proteolysis) and cytoplasmic mTORC1 (fed by exogenous amino acids) phosphorylate distinct substrates depending on amino acid source, challenging the single lysosomal-hub model. |
| 2023 | M | Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex CUI2023 First structural view of how mTORC1 actually reaches TFEB to phosphorylate it: two full Rag-Ragulator complexes present a single TFEB molecule to the mTOR active site, one in the normal Raptor-docking arrangement and a second, non-canonical one that grips TFEB's own first helix. Mutating that grip point drives TFEB straight into the nucleus (turning on autophagy/lysosome genes) without disturbing where mTORC1 itself sits. Explains, at the level of atoms, why TFEB phosphorylation needs the tumour suppressor FLCN and the GDP-loaded state of RagC in a way the authors report for no other mTORC1 substrate. Boundary: cryo-EM of a complex reconstituted from purified human proteins — a static structural snapshot, not a live cell or a real-time measurement. |
| 2023 | R | The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease GOU2023 Authoritative review of the molecular basis of nutrient sensing and signalling by mTORC1 in disease. |
| 2023 | M | Continuous sensing of nutrients and growth factors by the mTORC1-TFEB axis SPA2023 Live imaging of single MCF10A cells shows mTORC1-TFEB signalling adjusts continuously to amino acids and insulin, given alone, one after another or together; at physiological amino acid levels TFEB, AMPK and AKT activity fluctuate in step, and these graded changes track protein synthesis rate through a distributed set of mTORC1 effectors. |
| 2023 | M | Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor NIC2023 Malonyl-CoA, an intermediate of fatty-acid biosynthesis, binds the mTOR catalytic pocket directly and acts as a conserved ATP-competitive inhibitor of mTORC1; when fatty acid synthase is downregulated, rising malonyl-CoA feeds back to dampen mTORC1 activity, linking lipogenic capacity to overall biosynthetic output. |
| 2022 | R | mTOR substrate phosphorylation in growth control BAT2022 Review cataloguing direct mTOR substrates and how mTORC1/2 achieve substrate specificity. |
| 2022 | M | TORC1 and PKA activity towards ribosome biogenesis oscillates in synchrony with the budding yeast cell cycle GUE2022 Tracking the localisation of two TORC1 and PKA targets by time-lapse microscopy in hundreds of yeast cells shows that TORC1/PKA activity towards ribosome biogenesis rises and falls in step with the cell cycle even when outside conditions stay constant; mutations in upstream regulators suggest internal metabolic signals partly drive the oscillation. |
| 2022 | M | A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids GOL2022 The four mammalian Rag GTPase paralogues are not functionally interchangeable: RagC/D determines substrate specificity (RagD favors TFEB/TFE3 phosphorylation via tighter LAMTOR binding), while RagA/B determines the response to amino acid withdrawal (RagB-expressing cells keep mTORC1 lysosomal and active even upon starvation). Author correction issued 2023 (PMID 36536178, no change to conclusions). |
| 2022 | M | The mTORC1-SLC4A7 axis stimulates bicarbonate import to enhance de novo nucleotide synthesis ALI2022 Building a nucleotide needs a carbon donor, and cells get it from bicarbonate dissolved in their surroundings. This study shows mTORC1 does not just switch on the nucleotide enzymes - it also arranges the delivery of the raw material. Through S6K and the translation factor eIF4B, mTORC1 selectively increases translation of the mRNA for SLC4A7, a sodium-bicarbonate cotransporter, so more bicarbonate is pulled into the cell. Removing SLC4A7 from cells with hyperactive mTORC1 cut flux through both de novo purine and pyrimidine synthesis and slowed cell and tumor growth, without changing intracellular pH - so the transporter matters as a supply line, not as a pH regulator. A fourth distinct route by which mTORC1 feeds nucleotide synthesis, alongside CAD (BEN2013), the mitochondrial folate cycle (BEN2016) and demand coupling (VAL2017). |
| 2021 | M | mTORC1 stimulates cell growth through SAM synthesis and m6A mRNA-dependent control of protein synthesis VIL2021 SAMTOR (GU2017) showed the cell can sense S-adenosylmethionine and report it to mTORC1. This study runs the arrow the other way: mTORC1 controls how much SAM the cell makes. Downstream of mTORC1, c-MYC binds intron 1 of MAT2A and raises expression of the enzyme that produces SAM, the cell's main methyl donor; mTORC1 separately increases the protein level of WTAP, the regulatory subunit of the m6A RNA methyltransferase complex. Together these raise m6A methylation of mRNA, which primes the translation machinery for growth. Blocking MAT2A lowers SAM, m6A, protein synthesis rate and tumor growth. |
| 2021 | R | Regulation and metabolic functions of mTORC1 and mTORC2 SZW2021 Comprehensive review of the regulation and metabolic functions of mTORC1 and mTORC2. |
| 2021 | M | G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling PRE2021 Adds a physical brake upstream of mTORC1. G3BP1 and G3BP2, known until then as core stress-granule proteins, also sit on the cytoplasmic face of the lysosome and are what holds the TSC complex there; without them TSC cannot reach its target and mTORC1 becomes over-responsive to amino acids and insulin. Loss of G3BP1 reproduces TSC-like hyperactivity phenotypes: faster mTORC1-driven motility in breast cancer cells, with low G3BP1 correlating with worse patient outcome, and disturbed neuronal development in zebrafish. Relevant to the Atlas because it is a lysosomal tethering step that the canonical Rheb/TSC diagram does not show. |
| 2020 | R | mTOR at the nexus of nutrition, growth, ageing and disease LIU2020 The flagship modern review of the whole field, from Sabatini's own lab (Nature Reviews Molecular Cell Biology). Maps 25+ years of mTOR biology - how it senses nutrients, controls growth and autophagy, and goes wrong in cancer, neurodegeneration, metabolic disease and aging. The single best orientation document for the entire Atlas. |
| 2020 | M | Crosstalk dynamics between the circadian clock and the mTORC1 pathway GUE2020 A mathematical model of how mTORC1 could tune the circadian clock. It suggests mTORC1 raises clock amplitude by controlling BMAL1 translation and shortens the period by controlling where BMAL1 sits in the cell, and that both levels are needed for robust oscillation. A model, not a measurement - it proposes mechanisms for RAM2018's observations rather than testing them. |
| 2019 | M | Structural basis for the docking of mTORC1 on the lysosomal surface ROG2019 3.2-angstrom cryo-EM structure of Raptor bound to Rag-Ragulator, showing how Raptor reads out the nutrient-dependent nucleotide state of the Rag GTPases: one part of Raptor senses RagA's nucleotide state, a separate 'claw' senses RagC's, and both have to be in the correct nutrient-signalling combination before Raptor is allowed to dock. Mutating the contact points blocks mTORC1 from reaching the lysosome and inhibits its signalling, which is the functional evidence behind the structural claim. Combined with a separate structure of mTORC1 bound to its activator Rheb, the paper builds a model of the complete, active mTORC1 sitting on the lysosome. Boundary: cryo-EM of a complex reconstituted from purified human proteins, not a live-cell measurement. |
| 2019 | R | mTOR as a central hub of nutrient signalling and cell growth KIM2019 Review: mTOR as a central hub of nutrient signalling and cell growth. |
| 2019 | R | Molecular logic of mTORC1 signalling as a metabolic rheostat VAL2019 Review framing mTORC1 as a metabolic rheostat coupling growth signals to metabolism. |
| 2019 | M | Architecture of human Rag GTPase heterodimers and their complex with mTORC1 ANA2019 Structures of Rag GTPase heterodimers with mTORC1 explain nucleotide-state-dependent recruitment. |
| 2019 | R | The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism HOX2019 Review of the PI3K-AKT-mTOR network at the interface of oncogenic signalling and metabolism. |
| 2018 | M | Architecture of the human GATOR1 and GATOR1-Rag GTPases complexes SHE2018 Cryo-EM structures of GATOR1 and GATOR1-Rag complexes reveal GAP and inhibitory-clamp mechanisms. |
| 2018 | M | NUFIP1 is a ribosome receptor for starvation-induced ribophagy WYA2018 The authors purified lysosomes from human cells and measured how their protein content changes when mTORC1 is switched off by nutrient starvation or by the mTOR inhibitor Torin1, defining 828 lysosome-associated proteins. One responder, NUFIP1 (with its partner ZNHIT3), moved from the nucleus to autophagosomes and lysosomes after mTORC1 inhibition, bound ribosomes from Torin1-treated cells, and bound LC3B directly through a motif lost in the W40A mutant. Without NUFIP1 or its LC3B-binding ability, starvation or Torin1 no longer depleted ribosomal proteins and rRNA, while bulk autophagy and ferritin degradation were unaffected. In cells lacking the GATOR1 subunit DEPDC5, where mTORC1 ignores amino-acid loss, starvation no longer depleted ribosomal proteins but Torin1 still did, which points to mTORC1 inhibition as the trigger. NUFIP1 loss reduced survival under starvation (rescued by nucleosides) and blunted mTORC1 reactivation after long arginine deprivation. Boundary: Human and mouse cell lines over hours of starvation; Torin1 inhibits both mTOR complexes. No tissue or whole-animal data. |
| 2017 | R | mTOR Signaling in Growth, Metabolism, and Disease SAX2017 Comprehensive synthesis of mTORC1/mTORC2 signaling, growth regulation, metabolism, and disease relevance. |
| 2017 | M | SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway GU2017 Extended nutrient sensing beyond amino acids to METABOLITES: SAMTOR reads S-adenosylmethionine (SAM), the cell's methyl-donor currency, linking methionine and one-carbon metabolism to mTORC1. Relevant to why methionine restriction affects aging. |
| 2017 | M | Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex HOW2017 Pinned down HOW the diabetes drug metformin - a major longevity candidate - actually reaches mTOR. In the liver, metformin lowers cellular energy, and at low doses this shuts down mTORC1 specifically through AMPK and the TSC complex. Direct mechanistic bridge between a widely-used drug, energy sensing, and the mTOR pathway. |
| 2017 | M | Hybrid Structure of the RagA/C-Ragulator mTORC1 Activation Complex SUX2017 Hybrid structural model of the RagA/C-Ragulator mTORC1 activation complex. |
| 2017 | R | The Dawn of the Age of Amino Acid Sensors for the mTORC1 Pathway WOLF2017 Review of the newly discovered amino-acid sensors feeding into mTORC1. |
| 2017 | M | Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing CAR2017 Explains why mTORC1 stays switched on in senescent cells. In human fibroblasts rendered senescent three different ways, mTORC1 is constitutively active and no longer responds to serum or amino acid withdrawal. The defect is upstream, not in mTORC1 itself: it is driven in part by depolarisation of the senescent plasma membrane, which leads to primary cilia defects and a failure to shut off growth-factor signalling, while increased autophagy and high intracellular amino acid levels may act to support the nutrient arm. Correcting these inputs restored sensitivity of the pathway and killed the cells, which frames persistent mTORC1 signalling as a survival dependency of senescent cells rather than a by-product of senescence. |
| 2016 | M | The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway CHA2016 Identified CASTOR1 as the direct arginine sensor: when arginine binds CASTOR1, it lets go of GATOR2, switching mTORC1 on. Together with Sestrin2 (leucine) this built the picture of mTORC1 as a cell that literally tastes individual amino acids. |
| 2016 | R | The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging KEN2016 A Cell Metabolism review framing mTOR as the 'grand conductor' that coordinates whole-body metabolism, tissue by tissue. Especially valuable for its clear-eyed section on WHY rapamycin causes metabolic side effects (the mTORC2 problem) - which is the main barrier to using it against aging. Pairs perfectly with Lamming's own 2012 mechanism paper. |
| 2016 | M | A systems study reveals concurrent activation of AMPK and mTOR by amino acids DAL2016 Adding amino acids back to starved cells switched on AMPK, PI3K and mTORC2 acutely and independently of mTORC1, at the same time as mTOR. AMPK activation ran through CaMKK-beta and, under amino acid sufficiency, AMPK kept autophagy going via ULK1. So the textbook picture of AMPK and mTORC1 as simple opposites does not hold in the first minutes after feeding - which matters for how the AMPK-ULK1 feedback arm behaves over time. |
| 2016 | M | Dynamics of mTORC1 activation in response to amino acids MAN2016 Live imaging shows mTORC1 moves to lysosomes within 2 minutes of amino acid addition and peaks by 5 minutes, in step with leucine arriving in lysosomes; phosphorylation of classic mTORC1 targets lags behind, suggesting mTORC1 passes briefly through the lysosome before acting on substrates elsewhere. |
| 2016 | R | Amino Acid Sensing by mTORC1: Intracellular Transporters Mark the Spot GOB2016 Review: intracellular amino-acid transporters mark the site of mTORC1 activation. |
| 2015 | M | Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway SAX2015 Solves the crystal structure of Sestrin2 bound to leucine, revealing the molecular pocket that lets it act as mTORC1's dedicated leucine sensor. |
| 2015 | M | mTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation LAB2015 Explained HOW rapamycin calms 'inflammaging'. Senescent cells spew inflammatory signals (the SASP) that damage surrounding tissue and even feed tumors. mTOR powers this by translating IL1A, the cytokine at the top of the cascade. Rapamycin selectively shuts it down - and blocked senescent cells from fueling prostate tumor growth in mice. |
| 2015 | M | Dynamic Visualization of mTORC1 Activity in Living Cells ZHO2015 TORCAR, described by its authors as the first genetically encoded FRET reporter of mTORC1 activity, lets mTORC1 be watched in living cells as it changes. It showed mTORC1 activity not only at the lysosome but also in the cytosol, nucleus and at the plasma membrane; growth factor spread activity widely, while a leucine surrogate kept it at the lysosome and nucleus. A growth-factor-induced calcium transient contributed to mTORC1 activity. The earliest live reader of mTORC1 held in the atlas. |
| 2015 | M | Architecture of human mTOR complex 1 AYL2015 Cryo-EM architecture of human mTORC1 reveals its dimeric organization and active site access. |
| 2014 | R | Mammalian target of rapamycin signaling in cardiac physiology and disease SCI2014 Review of mTOR signalling in cardiac physiology and disease. |
| 2014 | M | Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2 DEM2014 Amino-acid starvation recruits TSC2 to the lysosome to inhibit Rheb and TORC1. |
| 2013 | M | A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1 BAR2013 Found the OFF switch for amino acid signaling: the GATOR1 complex is a GAP that shuts the Rag GTPases (and thus mTORC1) down when amino acids run low, while GATOR2 opposes it. GATOR1 genes are mutated in cancers, making those tumors 'blind' to starvation and hypersensitive to rapamycin. |
| 2013 | R | mTOR is a key modulator of ageing and age-related disease JOH2013 The landmark Nature review that put mTOR at the center of aging biology. Lays out the case that inhibiting mTOR extends lifespan across species and guards against a growing list of age-related diseases - while being candid that side effects currently block its use in healthy people. Excellent orientation map for the whole field. |
| 2013 | R | Where is mTOR and what is it doing there? BETZ2013 Review of where mTOR localizes and its compartmentalized functions. |
| 2013 | R | Signal integration by mTORC1 coordinates nutrient input with biosynthetic output DIB2013 Review: mTORC1 integrates nutrient input with biosynthetic output. |
| 2013 | M | mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin KAN2013 Each mTORC1 phosphorylation site has its own intrinsic 'substrate quality'. Good substrates stay phosphorylated when mTORC1 is partly inhibited by rapamycin or starvation, poor ones drop out first, and changing a few residues around a site shifts its sensitivity in cells. One level of mTORC1 activity can therefore produce different output profiles. |
| 2013 | M | Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1 PAN2013 The SEACIT complex is a GAP for the Rag/Gtr GTPases mediating amino-acid inhibition of TORC1. |
| 2013 | M | Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes MAR2013 The authors asked how TFEB reaches the lysosome, where mTORC1 phosphorylates it. In human cells, depleting Raptor inactivated mTORC1 and sent TFEB to the nucleus but did not stop TFEB binding lysosomes (82.5% of cells still showed lysosomal TFEB), whereas depleting the Rag GTPases or the Ragulator subunit p18 abolished it (under 4% of Rag-depleted cells kept the S211A mutant on lysosomes, against about 80% of controls). TFEB bound only active Rag heterodimers through its first 30 amino acids, and active Rags were enough to bring TFEB to lysosomes; TFEB mutants that could not bind Rags lost S211 phosphorylation and stayed in the nucleus. Endogenous TFEB accumulated in the nucleus after Torin1 or amino-acid starvation and moved back to the cytosol and lysosomes when amino acids were added again. Some MITF isoforms behaved the same way. Boundary: Human cell lines, mostly with overexpressed or mutant proteins; not tested in tissues or whole animals. |
| 2013 | M | Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity KID2013 Activating T cells switch on cholesterol and fatty acid synthesis genes within hours, and this paper showed the switch runs through PI3K and mTOR to SREBP: 100 nM rapamycin given 30 minutes before stimulation blocked the induction of the lipogenic programme, prevented processing of full-length SREBP and its accumulation in the nucleus, and reduced SREBP1 and SREBP2 occupancy at lipogenic promoters to background. Deleting Scap in T cells, which removes both SREBP1 and SREBP2 activity, left thymic and peripheral T-cell numbers normal but the cells could not blast: they entered G1 and stalled, failed to raise cholesterol and fatty acids after activation, and increased ECAR and OCR only modestly where controls rose about ten-fold and four-fold. Adding cholesterol conjugated to methyl-beta-cyclodextrin roughly doubled survival at 48 hours (21 to 45 percent) and restored growth, cell-cycle entry and ER expansion, which points to cholesterol as the limiting step. After LCMV-Armstrong infection the Scap-deficient mice had fewer virus-specific CD8 T cells with lower IFN-gamma and TNF, while homeostatic proliferation was unaffected. Boundary: mouse genetics and mouse cells; the mTOR step is shown with rapamycin pretreatment in cultured T cells, and the in vivo arm measures the consequence of losing SREBP activity rather than of inhibiting mTOR. |
| 2013 | M | Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis BAT2013 Deleting Tsc1 from cultured mouse hippocampal neurons raised phospho-S6 and made the network fire more than twice as much as controls by day 14, in an epilepsy-like bursting pattern; four days of rapamycin brought activity back to control levels. Many gene-expression and synaptic changes in the knockout cultures, such as high Arc and fewer surface AMPA receptors, turned out to be secondary responses to the high activity, not direct effects of mTOR. In hippocampal CA1, Tsc1 loss in single pyramidal neurons weakened the inhibitory synaptic input they received and raised their excitation/inhibition ratio, while their intrinsic excitability was lower, not higher. Forebrain Tsc1 knockout mice had more severe kainate-induced seizures (80% died, while all controls survived), and seven days of rapamycin in vivo restored inhibition and normalised the E/I ratio. Boundary: mouse neurons, cultures and brain slices; Tsc1 deleted in excitatory neurons only; seizure test used a chemical convulsant. |
| 2012 | M | A unifying model for mTORC1-mediated regulation of mRNA translation THO2012 Used ribosome profiling with the complete inhibitor Torin1 to address a long-standing debate: in these cells, mTORC1's translational control runs largely through the 4E-BP family acting on a specific class of mRNAs (TOP motifs). Losing just the 4E-BPs makes translation of TOP mRNAs resistant to mTOR inhibition - naming them the master effectors. |
| 2012 | M | The translational landscape of mTOR signalling steers cancer initiation and metastasis HSI2012 Showed WHY mTOR-driven translation matters for cancer: in prostate cancer, oncogenic mTOR selectively translates a specific set of pro-invasion mRNAs that drive metastasis. An ATP-competitive mTOR inhibitor (INK128) reversed that signature - an early preclinical rationale from mouse models and cell lines, not a clinical result. |
| 2012 | M | MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB MAR2012 Showed mTORC1-dependent TFEB Ser211 phosphorylation: mTORC1 (docked at the lysosome via Ragulator) phosphorylates TFEB on Ser211, which traps it in the cytosol via 14-3-3 proteins. Inhibit mTORC1 and TFEB rushes to the nucleus to switch on autophagy - explaining how mTORC1 controls recycling at the level of gene transcription. |
| 2012 | R | mTOR signaling in growth control and disease LAP2012 The classic 2012 Cell review that became the standard reference for mTOR signaling. Comprehensive yet readable synthesis of how mTOR integrates environmental cues to control growth, and how its deregulation drives cancer, obesity, diabetes and neurodegeneration. A perfect companion to the newer 2020 review. |
| 2012 | M | Temporal coding of insulin action through multiplexing of the AKT pathway KUB2012 The same pathway can carry different messages in the shape of its signal over time. A short insulin pulse produced transient AKT phosphorylation and a sustained dose produced sustained AKT phosphorylation. S6K read only the transient part, G6Pase only the sustained part and GSK3-beta both. Which output responds depends on the pattern, not just the amount - the clearest cell-level case in the atlas that timing carries information in this pathway. |
| 2012 | M | A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation DAL2012 A time-resolved, data-fitted model of the whole core insulin-mTOR network, including the mTORC1 negative feedback loop onto PI3K. Perturbing it in silico and in cells showed that TSC1-TSC2 is not a regulator of mTORC2, directly or through the feedback loop, and that mTORC2 activation runs through a PI3K variant insensitive to that loop. One of the few places where the feedback loops in the atlas are treated as a dynamical system rather than a diagram. |
| 2012 | M | SH3BP4 is a negative regulator of amino acid-Rag GTPase-mTORC1 signaling KIM2012 SH3BP4 negatively regulates amino-acid-Rag-GTPase-mTORC1 signalling. |
| 2012 | M | Leucyl-tRNA synthetase controls TORC1 via the EGO complex BON2012 In budding yeast, the leucyl-tRNA synthetase Cdc60 bound the Rag GTPase Gtr1, part of the EGO complex that activates TORC1, and this binding depended on leucine. The authors reported that the interaction was both necessary and sufficient to pass the leucine signal on to TORC1. When Cdc60 was busy editing wrongly charged tRNA(Leu), the interaction with Gtr1 was lost. The model is that TORC1 reads how well tRNA(Leu) is being charged as a stand-in for how much leucine the cell has. Together with Han et al. 2012 in human cells, it was one of the early papers to propose a tRNA synthetase as a leucine sensor upstream of the Rags. Boundary: Yeast only. The mammalian leucine sensor most widely accepted today is Sestrin2, and this yeast mechanism has not been reconciled with it. Drafted from the abstract only. |
| 2012 | M | Distinct perturbation of the translatome by the antidiabetic drug metformin LAR2012 The authors compared genome-wide changes in mRNA translation caused by metformin with those caused by the mTOR inhibitors rapamycin and PP242 in cancer cells. Metformin changed gene expression at the level of translation to an extent comparable to the classic mTOR inhibitors. Its antiproliferative effect could be explained by selective suppression of translation of mRNAs encoding cell-cycle regulators, acting through the mTORC1 / 4E-BP pathway. The paper provided evidence that metformin's effect on cell growth in vitro goes through selective translational control rather than a general drop in protein synthesis. Boundary: Cultured cancer cells at drug concentrations used in vitro; does not show that metformin at clinical doses acts this way in patients. Drafted from the abstract only. |
| 2012 | M | mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake YIL2012 Mice kept on calorie restriction (60% of normal intake) had more intestinal stem cells and Paneth cells, the cells that form the stem-cell niche (Lgr5+ stem cells 5.6% vs 4.3% of crypt cells, Paneth cells 9.8% vs 6.7%), and their crypts were nearly twice as likely to form organoids. In co-culture, Paneth cells from restricted mice, not stem cells, carried the boost. Restriction lowered S6 and S6K1 phosphorylation in crypts, and feeding or insulin switched on mTORC1 in Paneth cells but not in stem cells; forcing mTORC1 back on during restriction (Rheb induction or Tsc1 deletion) cancelled the effect, while one week of rapamycin copied it and did not add to restriction. The niche signal ran through higher Bst1 in Paneth cells, an enzyme that makes the paracrine messenger cyclic ADP ribose, and knocking down Bst1 removed the restriction effect in culture. Boundary: Mouse intestine and ex vivo organoid assays; restriction started in young adult mice, and no lifespan or human tissue was studied. |
| 2011 | M | mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase ZON2011 Showed amino acid sensing starts INSIDE the lysosome: amino acids accumulate in the lumen and the v-ATPase relays that signal outward ('inside-out') to Ragulator-Rag. A surprising twist on where the cell measures its nutrient status. |
| 2011 | M | TFEB links autophagy to lysosomal biogenesis SET2011 Showed that TFEB drives a coordinated autophagy and lysosomal gene programme during starvation. In this paper TFEB was regulated by ERK2 phosphorylation; its control by mTORC1 at the lysosome was established in later work (SET2012). |
| 2011 | M | AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1 KIM2011 Revealed the tug-of-war over ULK1: the energy sensor AMPK phosphorylates ULK1 at activating sites to turn autophagy ON when energy is low, while mTORC1 phosphorylates a different site (Ser757) to keep it OFF and even blocks AMPK from reaching ULK1. Two opposing kinases wired to the same switch. |
| 2011 | M | Lysosomal positioning coordinates cellular nutrient responses KOR2011 Where the lysosome sits inside the cell helps decide whether mTORC1 is on. With nutrients available, lysosomes move to the cell periphery, physically close to the plasma-membrane signalling modules, and mTORC1 is active there; starvation changes intracellular pH and pulls lysosomes into a cluster around the nucleus, where mTORC1 output falls and autophagy is released. Lysosomal position also sets the rate of autophagosome-lysosome fusion, so one variable acts at both the initiation and the termination end of autophagic flux. This added a spatial axis to mTORC1 regulation that Rag/Ragulator recruitment alone does not account for. |
| 2011 | M | Rac1 regulates the activity of mTORC1 and mTORC2 and controls cellular size SAC2011 Rac1 binds and regulates both mTORC1 and mTORC2, controlling their localization and cell growth. |
| 2011 | M | mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling ROD2011 mTOR kinase inhibition triggers feedback-dependent biphasic AKT reactivation, informing resistance. |
| 2011 | M | Regulation of TFEB and V-ATPases by mTORC1 PEN2011 Using Tsc2-null and wild-type mouse fibroblasts with and without rapamycin, the authors looked for genes whose expression follows mTORC1 activity and found 75 genes, enriched for subunits of the lysosomal proton pump (V-ATPase). mTORC1 also raised V-ATPase expression in mouse liver after Tsc1 deletion and in a prostate tumour model, through a transcriptional mechanism that needed the transcription factor TFEB: knocking down Tfeb cut the number of mTORC1-induced genes from 1146 to 424 probes, and about a quarter of mTORC1-induced genes depended on Tfeb. mTORC1 promoted albumin uptake (endocytosis) in a Tfeb- and V-ATPase-dependent way. In these serum-deprived cells, active mTORC1 (TSC loss) increased nuclear TFEB and rapamycin or Raptor knockdown reduced it, which is the opposite direction to the TFEB inhibition reported by later studies in fed or starved cells. Boundary: Mostly mouse and human cell lines under low serum; liver and prostate data are expression measurements. The direction of mTORC1 control over TFEB localisation here differs from later work and is condition-dependent. |
| 2010 | M | Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids SAN2010 Established WHERE mTORC1 gets switched on: the lysosome surface. Identified Ragulator as the lysosomal dock that recruits the Rag GTPases and drags mTORC1 to the membrane where its activator Rheb lives. Amino acids work by controlling this translocation. |
| 2010 | R | Extending healthy life span--from yeast to humans FON2010 Influential review proposing that dietary restriction and reduced nutrient-sensing signalling (mTOR, GH/IGF-1) may slow ageing through similar, evolutionarily conserved mechanisms. Lifespan extension is shown in yeast, invertebrates, rodents and rhesus monkeys; in humans the evidence is limited to protective biomarker changes and genetic associations. |
| 2010 | M | Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor JAN2010 The ATP-competitive TORC1/2 inhibitor PP242 selectively kills leukemia cells, with much weaker effects on the proliferation and function of normal lymphocytes. |
| 2010 | M | Termination of autophagy and reformation of lysosomes regulated by mTOR YUX2010 Reactivation of mTOR terminates autophagy and drives autophagic lysosome reformation (ALR). |
| 2010 | R | mTOR: from growth signal integration to cancer, diabetes and ageing ZON2010 Authoritative review of mTOR from growth-signal integration to disease. |
| 2010 | M | mTORC1 controls fasting-induced ketogenesis and its modulation by ageing SEN2010 mTORC1 controls fasting-induced hepatic ketogenesis via PPARalpha, and this is blunted with age. |
| 2010 | M | Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner KAL2010 Metformin inhibits mTORC1 even in cells lacking AMPK or TSC1/TSC2, and the effect requires the Rag GTPases instead. Together with Foretz 2010 this places a large part of metformin's action outside the AMPK axis it is usually credited to. |
| 2010 | M | ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS ALE2010 Described a cytoplasmic job for the DNA-damage kinase ATM. In response to raised ROS, ATM activated TSC2 through LKB1 and AMPK, which repressed mTORC1 and induced autophagy. ATM-deficient cells had high ROS and poorly controlled mTORC1, and rapamycin lowered both and delayed lymphoma formation in Atm-deficient mice. Boundary: worked from the abstract only (PMC record without retrievable text); cell lines and mice. Note that the Atlas edge ROS-MTORC1 describes the opposite sign in another context, so the effect of ROS on mTORC1 depends on source and setting. |
| 2010 | M | Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer SAT2010 Screened point mutations from cancer genome databases and found two, S2215Y (large intestine adenocarcinoma) and R2505P (renal cell carcinoma), that kept mTOR signalling on even under nutrient starvation. mTORC1 purified from starved cells carrying the mutants still phosphorylated 4E-BP1 in vitro. Mutant cells had more S-phase cells (42.0% vs 28.2% for S2215Y) and resisted the shrinkage caused by amino-acid withdrawal. The mutants stayed sensitive to rapamycin. Boundary: overexpressed mutants in cultured cells; the mutations were found in tumour databases, their driver role in patients was not tested. |
| 2010 | M | Activation of a metabolic gene regulatory network downstream of mTOR complex 1 DUV2010 Used cells with constitutively active mTORC1 (TSC2 loss) and rapamycin to map what mTORC1 switches on besides protein synthesis. Gene expression and metabolite profiling showed that mTORC1 activation is enough to drive glycolysis, the oxidative pentose phosphate pathway and de novo lipid synthesis. This ran through a transcriptional program of HIF1alpha and SREBP1/2 target genes; SREBP1 and 2 were needed for proliferation downstream of mTORC1, and their activation required S6K1. Boundary: cultured cells, mostly mouse fibroblasts with genetic mTORC1 activation; tissue and human relevance not tested here. |
| 2010 | M | Structure of the human mTOR complex I and its implications for rapamycin inhibition YIP2010 The authors purified intact, active human mTORC1 and solved its shape by cryo-electron microscopy at about 26 angstrom resolution. The complex is an obligate dimer with a rhomboid outline and a central cavity, held together by interlocking contacts between mTOR and Raptor; antibody labelling placed mLST8 at the outer 'feet' and PRAS40 next to Raptor. Exposing purified mTORC1 to FKBP12-rapamycin first added a bound density in about 10% of particles, then broke the complex apart, with virtually no intact particles left after one hour, while the ATP-competitive inhibitor Torin1 left it intact. In matching kinase assays, FKBP12-rapamycin blocked S6K1 phosphorylation quickly but 4E-BP1 phosphorylation only after at least 60 minutes, and Raptor-free mTOR still phosphorylated S6K1 (rapamycin-sensitively) but not 4E-BP1. The authors proposed that rapamycin inhibits the two substrates by different mechanisms. Boundary: Purified protein and low-resolution EM; the authors note that in cells rapamycin neither fully blocks 4E-BP1 phosphorylation nor dismantles mTORC1, so the disassembly model is an in vitro result. |
| 2009 | M | The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment DEL2009 T cells lacking mTOR fail to become normal effector cells and default toward regulatory T cells, showing mTOR is a master switch for immune cell fate. |
| 2009 | M | DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival PET2009 Identified DEPTOR as a built-in brake on BOTH mTOR complexes. The twist: in some multiple myelomas DEPTOR is overexpressed, which by relieving a feedback loop actually keeps pro-survival Akt signaling ON - a neat example of how an 'inhibitor' can be co-opted by cancer. |
| 2009 | M | Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy HOS2009 Showed the DIRECT brake mTORC1 uses on autophagy: when nutrients are plentiful, mTORC1 physically joins the ULK1-Atg13-FIP200 complex (the autophagy-starter kinase) and phosphorylates ULK1 to keep it off. Starvation or rapamycin releases this brake and autophagy begins. |
| 2009 | M | An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1 THO2009 Dropped a bombshell: rapamycin does NOT fully block mTORC1. Using Torin1 (which jams the active site directly), the authors showed rapamycin leaves important mTORC1 jobs running - notably 4E-BP1 phosphorylation and autophagy suppression. This reframed a decade of rapamycin experiments and launched the search for complete inhibitors. |
| 2009 | M | Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2 FEL2009 The parallel discovery to Thoreen 2009 (same year), from the Shokat lab. Their TORKinibs (PP242, PP30) block mTOR's active site, hitting both complexes and shutting down cap-dependent translation that rapamycin misses. Together these two papers established a whole new drug class beyond rapamycin. |
| 2009 | M | Rapamycin decelerates cellular senescence DEM2009 Blagosklonny's key experiment behind his 'hyperfunction' theory of aging. When a cell's division is blocked but mTOR keeps driving growth, the cell tips into permanent senescence. Rapamycin uncouples the two - keeping arrested cells reversible instead of senescent. Direct evidence that mTOR actively drives the senescent state, not just passively accompanies it. |
| 2009 | M | Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR) GAR2009 Ku-0063794 is a specific ATP-competitive mTOR inhibitor blocking mTORC1 and mTORC2. |
| 2009 | R | Translational control of long-lasting synaptic plasticity and memory COS2009 This review gathers evidence that long-lasting synaptic plasticity and long-term memory depend on new protein synthesis, and that the step where mRNA translation starts is a main control point. It covers two arms: the mTORC1 arm (4E-BP2, eIF4E, S6K) that controls cap-dependent translation, and the eIF2alpha arm (GCN2, PKR, ATF4) that controls general translation and specific mRNAs. It also discusses how faulty translational control is linked to disorders such as fragile X syndrome and tuberous sclerosis. It is a summary of work by many labs and gives the field a shared framework rather than new data. Boundary: narrative review; the cited evidence is mainly from rodent slices, rodent behaviour and invertebrate models, not from people. |
| 2008 | M | The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1 SAN2008 Identifies the Rag GTPase family as the missing link that lets mTORC1 sense amino acids by controlling whether mTOR is positioned near its activator Rheb. |
| 2008 | M | AMPK phosphorylation of raptor mediates a metabolic checkpoint GWI2008 Found a SECOND way the energy sensor AMPK shuts mTORC1 down. Besides acting through TSC2, AMPK directly phosphorylates Raptor - the core mTORC1 subunit - to halt growth when energy runs low. This 'metabolic checkpoint' is exactly the switch that drugs like metformin and exercise tap into. |
| 2008 | M | Regulation of TORC1 by Rag GTPases in nutrient response KIM2008 Rag GTPases mediate amino-acid signalling to TORC1 (parallel discovery to Sancak 2008). |
| 2008 | M | Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling DEY2008 Explains how low oxygen turns mTORC1 off. Growth factors keep TSC2 bound to inhibitory 14-3-3 proteins; under hypoxia REDD1 releases TSC2 from 14-3-3, which frees TSC2 to inhibit mTORC1. REDD1-null cells failed to release TSC2 or to switch mTORC1 off in hypoxia, and REDD1 mutants that cannot bind 14-3-3, or TSC2 mutants that cannot bind it, broke the signal. REDD1-null cells grew into far larger tumours in mice, and REDD1 was low in a subset of human breast carcinomas (8 of 27). Boundary: cell lines and mouse xenografts under acute hypoxia (hours); the human data are expression correlations only. |
| 2008 | M | p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling BUD2008 Connected DNA damage to mTOR. Two p53 target genes, Sestrin1 and Sestrin2, bound and activated AMPK and steered it to phosphorylate TSC2, which raised TSC2 GAP activity and lowered mTOR signalling. Sesn2-deficient mice failed to inhibit mTOR signalling after genotoxic challenge. This describes the stress-induced arm of Sestrin biology; the later leucine-sensing role of Sestrin2 through GATOR2 is a separate mechanism. Boundary: cell lines and mice under acute genotoxic stress; no human data. |
| 2008 | M | Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34 GUL2008 In cultured human cells, adding amino acids raised the free calcium level inside the cell, and this rise was needed for amino acids to switch on mTORC1 and the lipid kinase hVps34. Calcium-bound calmodulin bound directly to a conserved motif in hVps34, and the authors showed this motif was needed for hVps34 lipid kinase activity and for the increase in mTORC1 signalling. The paper proposed a route from amino acids to mTORC1 that runs through class III PI3K (hVps34) rather than the class I PI3K used by insulin and growth factors. Boundary: Human cell lines only. The calcium/hVps34 route was proposed before the Rag-Ragulator-GATOR model and is not part of the current consensus amino-acid pathway. Drafted from the abstract only. |
| 2007 | R | Defining the role of mTOR in cancer GUE2007 Comprehensive review arguing mTOR signaling is commonly deregulated in human cancers, laying out the rationale for rapalog trials in oncology. |
| 2007 | M | PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase SAN2007 Identified PRAS40 as the missing insulin-controlled brake INSIDE mTORC1. When insulin is absent PRAS40 clamps the complex shut; insulin makes Akt phosphorylate PRAS40, releasing the brake so Rheb can fully switch mTORC1 on. Explained how hormone signals set the exact strength of mTORC1 activity. |
| 2007 | M | mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex CUN2007 Showed mTOR isn't just about building proteins - it also runs the cell's POWER plants. mTORC1 drives mitochondrial gene expression and oxygen consumption through a YY1-PGC-1alpha transcriptional program; block mTOR with rapamycin and mitochondrial output falls. Explains part of why mTOR inhibition reshapes metabolism. |
| 2006 | R | Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition BLA2006 Proposes the 'hyperfunction theory' of aging: TOR signaling, useful in youth, stays switched on into old age and becomes actively damaging. |
| 2006 | M | Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1 GUE2006 The foundational genetic 'dissection' of the two complexes in living mice. Deleting Raptor was lethal early (mTORC1 essential); deleting Rictor or mLST8 selectively knocked out mTORC2 signaling to Akt and PKCalpha but spared S6K1. This cleanly assigned jobs to each complex and showed mLST8 is an mTORC2-specific requirement in mice. |
| 2006 | M | mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt ORE2006 mTORC1 inhibition relieves feedback and activates upstream RTK-PI3K-Akt signalling. The Akt activation was demonstrated both in cancer cell lines and in patient tumours treated with RAD001 (everolimus), so this record carries a human pharmacodynamic component, not only in-vitro data. |
| 2006 | R | TOR signaling in growth and metabolism WUL2006 Landmark review synthesizing TOR signalling in growth and metabolism across organisms. |
| 2006 | M | The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity SCH2006 In human cultured cells, the amount of mTOR-raptor complex correlated with overall mitochondrial activity. Disrupting the complex with rapamycin lowered mitochondrial membrane potential, oxygen consumption and ATP-synthetic capacity. mTOR and mTOR-raptor complexes were found in purified mitochondrial fractions, and rapamycin markedly changed the mitochondrial phosphoproteome. RNA interference against TSC2, S6K1, raptor or rictor led the authors to conclude that mTOR regulates mitochondrial activity independently of its previously known targets, and they proposed that mTOR activity shifts the balance between mitochondrial and non-mitochondrial ATP production. Boundary: Cultured human cell line with acute pharmacological and RNAi manipulation; the link to lifespan is a hypothesis drawn from lower organisms, not tested here. Drafted from the abstract only. |
| 2005 | M | hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase BYF2005 Opens a second, non-canonical route by which amino acids reach mTORC1. The class III PI 3-kinase hVps34 is switched off by amino acid or glucose starvation and by AMPK activation, and is required for S6K1 and 4E-BP1 phosphorylation, yet it sits outside the insulin/class I PI3K input (it does not affect Akt or TSC2 phosphorylation). Boundary: cell lines and knockdown/overexpression only; the step is nutrient-regulated but the sensor itself is not identified. |
| 2005 | M | Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase NOB2005 The companion paper to BYF2005, from a different laboratory: the amino acid input to mTORC1 is separate from the insulin input and runs through class 3 PI3K (hVps34), not through class 1 PI3K. Historically important because it states that the amino acid branch is the older one and that insulin signalling was grafted onto it. Boundary: cell lines, pharmacological and knockdown evidence; the later Rag/Ragulator account describes a different route to the same target, and the two accounts are not reconciled in the work this Atlas holds. |
| 2005 | M | Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis MA2005 The MAPK input to mTORC1. In mammalian cells, ERK phosphorylates TSC2 and inactivates the TSC complex, so growth signalling through Ras/ERK converges on the same brake that Akt releases. This is the third major upstream arm alongside PI3K/Akt and AMPK. Its practical significance is that it offers a route to mTORC1 activation that PI3K inhibitors do not close - though that inference is mechanistic; no human data here. |
| 2004 | M | Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome COR2004 Asked why two inherited tumour syndromes, tuberous sclerosis and Peutz-Jeghers syndrome, look so alike under the microscope. Re-expressing LKB1 in LKB1-null HeLa cells raised AMPK activation-loop phosphorylation and lowered phosphorylation of S6K and 4E-BP1, while knocking LKB1 down did the opposite. The effect on mTOR outputs needed both AMPK and TSC2, placing LKB1 upstream of the TSC2-mTOR axis through AMPK. Together with Shaw et al. 2004 this is one of the two papers that tied energy stress, via LKB1 and AMPK, to TSC2. Boundary: cultured cell lines with overexpression and knockdown; the tumour-syndrome link is an interpretation, not a test in patients. |
| 2004 | M | The LKB1 tumor suppressor negatively regulates mTOR signaling SHAW2004 Reported that LKB1 is needed to switch mTOR signalling off when cellular ATP falls, and that this requires AMPK and TSC2. Lkb1-null fibroblasts and the hamartomatous gut polyps of Lkb1 mutant mice showed raised signalling downstream of mTOR. The authors proposed mTOR inhibitors as a treatment idea for Peutz-Jeghers syndrome. Published alongside Corradetti et al. 2004, which reached the same LKB1-AMPK-TSC2 link independently. Boundary: worked from the abstract only (no PMC full text); cell and mouse data, the treatment suggestion was not tested here. |
| 2003 | M | Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb TEE2003 TSC1-TSC2 acts as a GTPase-activating protein (GAP) for Rheb; when TSC is inactive, Rheb accumulates in its active GTP-bound form and activates mTOR signalling. |
| 2003 | M | GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR KIM2003 Discovered mLST8 (GbetaL), the third core subunit that clamps onto mTOR's kinase domain and stabilizes the complex. It fine-tunes how tightly Raptor holds mTOR in response to nutrients - a small but essential cog that later turned out to be especially critical for the mTORC2 complex. |
| 2003 | M | TSC2 mediates cellular energy response to control cell growth and survival INO2003 Established the energy-sensing arm of the pathway. When energy runs low, AMPK phosphorylates TSC2, boosting its ability to shut mTOR down - protecting the cell from burning through resources and from starvation-induced death. One of the founding papers for how mTOR reads the cell's fuel gauge (complements the Akt-TSC2 growth-factor arm). |
| 2002 | M | TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling INO2002 Akt directly phosphorylates and inactivates TSC2, disrupting the TSC1-TSC2 complex and releasing its inhibition of mTOR - the link between growth-factor/insulin signaling and mTORC1 activation. |
| 2002 | M | mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery KIM2002 Discovery of Raptor as the defining partner of mTOR in mTORC1. This is the paper that gives mTORC1 its identity: Raptor is the scaffold that lets mTOR find and phosphorylate its targets (S6K1), and the complex is stabilized under starvation. Companion paper to Hara 2002. |
| 2002 | M | Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action HARA2002 Independent co-discovery of Raptor (same issue of Cell as Kim 2002). Showed Raptor is essential for mTOR to phosphorylate 4E-BP1 and S6K1, and that knocking it down in worms mimics loss of TOR - confirming Raptor as a core, conserved mediator of TOR action. |
| 2002 | M | Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling GAO2002 The authors asked how the Tsc1 and Tsc2 tumour suppressors relate to TOR, the nutrient-sensing kinase. They showed that Tsc1 and Tsc2 can physically associate with TOR and act upstream of TOR in fly genetic tests. In fly and mammalian cells lacking Tsc1 or Tsc2, S6K activity rose, and this increase depended on TOR. S6K normally switches off when cells are starved of amino acids, but cells without Tsc1-Tsc2 stayed resistant to that starvation. The authors proposed that the Tsc1-Tsc2 complex restrains the TOR response to amino acids. Boundary: Drosophila and cultured mammalian cells; S6K activity is used as the readout of TOR. Later work placed amino acid sensing mainly on the Rag GTPase arm rather than through TSC, so the amino acid part of the model is not the current consensus. |
| 2002 | M | Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling TEE2002 The authors coexpressed hamartin (TSC1) and tuberin (TSC2) in cultured cells and followed two main outputs of mTOR. Together, the two proteins reduced phosphorylation of 4E-BP1, so more 4E-BP1 stayed bound to the translation factor eIF4E; a TSC2 mutant found in TSC patients was defective at this. Hamartin plus tuberin also lowered S6K1 activity, but did not affect S6K1 mutants that resist rapamycin, which points to mTOR as the step being blocked. In nutrient-deprived cells, hamartin and tuberin prevented amino acids from switching S6K1 back on. The authors concluded that the TSC1-TSC2 complex acts as an inhibitor of mTOR signalling and suggested that TSC tumours may come from too much mTOR activity. Boundary: overexpression in cultured mammalian cells; the link to tumours in TSC patients is a proposal, not tested in patient tissue here. |
| 2001 | M | Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways ROM2001 Shows IGF-1 drives muscle fiber hypertrophy through Akt, via both the mTOR and GSK3 branches, in cultured myotubes, establishing mTOR as a central node for muscle growth signaling. |
| 1997 | M | Rapamycin suppresses 5'TOP mRNA translation through inhibition of p70s6k JEF1997 In mammalian cells, rapamycin selectively blocked the mitogen-induced increase in translation of 5'TOP mRNAs, which encode ribosomal proteins and elongation factors, and in parallel blocked activation of p70 S6 kinase. Using reporter mRNAs, the authors showed that an intact 5'TOP tract was required for the rapamycin effect. A dominant-interfering p70s6k reduced translation of the reporter with the intact 5'TOP but not the disrupted one, and a rapamycin-resistant p70s6k (Thr389 changed to an acidic residue) removed the inhibitory effect of rapamycin on 5'TOP translation. The authors concluded that rapamycin suppresses 5'TOP translation through p70s6k. Boundary: Cell lines with overexpressed kinase mutants and reporter mRNAs. Later genetic work (S6K knockouts, rpS6 knock-in) found 5'TOP control persisting without S6K1 or rpS6 phosphorylation, so the S6K step proposed here is not the current consensus. Drafted from the abstract only. |
| 2026 | PP | ER-Lysosome Cholesterol Exchange Regulates Lysosomal Motility Through mTOR-Dependent LAMTOR1 Phosphorylation MUT2026 Identifies a new layer of control over mTORC1's lysosomal machinery: cholesterol exchange between the ER and lysosome regulates lysosome movement via mTOR-dependent phosphorylation of LAMTOR1, a core component of the Ragulator complex that anchors the Rag GTPases already in this Atlas. |
| 2026 | PP | mTORC1 supports progression toward activation competence in quiescent adult neural stem cells THE2026 In the adult zebrafish brain, mTORC1 activity is enriched during a long quiescence phase in which neural stem cells become able to activate; perturbing mTORC1 changes how cells progress through this phase, setting the tempo of the move towards activation while preserving stemness. Preprint, not peer-reviewed. |
| 2025 | PP | The tumor suppressor CYLD acts as a deubiquitinase for mTOR to constrain its activity FER2025 An RNAi screen identified the tumor suppressor CYLD as a deubiquitinase that binds mTOR and removes non-degradative K63-linked ubiquitin chains from several of its residues, restraining both mTORC1 and mTORC2. Cells lacking CYLD show hyperactive mTORC1/2, higher protein synthesis, larger cell size and resistance to serum-starvation-induced cell death. In C. elegans, knocking down cyld-1 fully abolishes the extended lifespan of low-TORC1-activity mutants, and skin biopsies from CYLD cutaneous syndrome patients show mTORC1 hyperactivation. Preprint, not peer-reviewed. |
| 2024 | PP | Targeting mTOR restores tau-induced metabolic, mitochondrial, and cognitive deficits in a tauopathy mouse model TAN2024 In mice engineered to overexpress a phosphomimetic tau variant, one week of rapamycin partially mitigated tau-driven mitochondrial dysfunction and cognitive impairment in the Morris water maze - extends the mTOR-autophagy-neurodegeneration link (already seen with Huntington's) to a direct tau-phosphorylation mechanism relevant to Alzheimer's. |
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