TSC1/TSC2
Tuberin-hamartin tumor suppressor complex; acts as a GTPase-activating protein for Rheb; integrates growth-factor and energy signals to control mTORC1.
The pathway's master brake. A two-protein 'off switch' for mTORC1. It works like a brake pedal on the protein Rheb - when a cell lacks nutrients or growth signals, this complex clamps down on Rheb and keeps mTORC1 turned off.
Integrates Akt, AMPK, ERK/RSK, GSK3 and REDD1 inputs. Regulation is substantially about lysosomal recruitment, not only phosphorylation-driven activity change.
TL;DR. TSC1/TSC2 appears in 44 curated studies in Oliver's mTOR Atlas: 1 in people (1 human study); 17 in animal models; 26 at the molecular level (cells, biochemistry, structure). It has 9 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| 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 |
| TSC1/TSC2 inhibits Rheb mechanism: gap-activity · this link in full · on the map table | TSC2 forces Rheb to switch itself off – the one step where TSC acts as a tumour-suppressing brake. Holds under: In vitro, Drosophila and mammalian cell biochemistry (INOK2003, GAR2003). GAP activity is shown in cells and in vitro; not measured in human tissue by these sources. plausible in people, not shown directly · settled in the literature | M | INOK2003, GAR2003 |
| Akt/PKB inhibits TSC1/TSC2 mechanism: phosphorylation · this link in full · on the map table | Akt tags TSC2 to disable it. Growth signals work by releasing a brake, not by pressing a gas pedal. Holds under: In mouse liver, Akt phosphorylation of TSC2 is the main route by which insulin switches on mTORC1, but feeding activates hepatic mTORC1 without it; that response needs dietary protein instead (KAL2026). The biochemical mechanism itself was shown in cultured human cells (INO2002). plausible in people, not shown directly · settled in the literature | A | INO2002, KAL2026, LAP2026, MAN2002, POT2002 |
| AMPK activates TSC1/TSC2 mechanism: phosphorylation · this link in full · on the map table | When energy is low, AMPK tags TSC2 and makes the brake on Rheb stronger. Holds under: Mammalian cell biochemistry (INO2003, INO2006). Not tested in whole animals or in people by the cited studies. Relative weight of this arm is cell-type dependent. AMPK reaches mTORC1 two ways – activating TSC2 and directly phosphorylating Raptor – and TSC2-null cells still suppress mTORC1 under energy stress, so the TSC2 arm is not universally the dominant one. Which arm carries the signal depends on TSC status, LKB1 status and the severity and duration of the energy stress. plausible in people, not shown directly · settled in the literature | M | INO2003, INO2006, BUD2008 |
| ERK / RSK (MAPK) inhibits TSC1/TSC2 mechanism: phosphorylation · this link in full · on the map table | A separate growth pathway also disables the TSC brake – a third route into mTORC1 that drugs blocking only PI3K/Akt can't shut down. Holds under: Single-study edge in this corpus; Roux 2004 describes the parallel RSK arm and is not yet held. plausible in people, not shown directly · emerging, few independent studies | M | MA2005 |
| REDD1 (DDIT4) activates TSC1/TSC2 mechanism: signal-relay · this link in full · on the map table | REDD1 acts through the TSC brake, so low oxygen and low growth-factor signals end up hitting the very same switch. Holds under: One study in mammalian cells (BRU2004). A single study, not replicated in this corpus, and not tested in whole animals or in people. plausible in people, not shown directly · emerging, few independent studies | M | BRU2004, DEY2008 |
| Energy & cellular stress recruits TSC1/TSC2 mechanism: translocation · this link in full · on the map table | Different kinds of stress all do the same physical thing: they drag TSC2 over to the lysosome, right next to Rheb. Moving it there is the switch, not making more of it. Holds under: Mammalian cell studies (DEM2016, MEN2014). Relocation of TSC2 to the lysosome is shown in cultured cells under several stresses; not tested in tissue or in people. plausible in people, not shown directly · emerging, few independent studies | M | DEM2016, MEN2014 |
| TBC1D7 required-for TSC1/TSC2 mechanism: complex-assembly · this link in full · on the map table | TBC1D7 is a smaller, easy-to-miss third piece of the TSC brake; losing it weakens the brake without removing it. Holds under: One study in human cells (DIB2012). A single study; consequences beyond cell-level complex assembly are not tested in whole animals or in people. plausible in people, not shown directly · settled in the literature | M | DIB2012 |
| Rag GTPases recruits TSC1/TSC2 mechanism: recruitment · this link in full · on the map table | Without amino acids, the Rags bring the TSC brake to the lysosome. Holds under: Mammalian cell lines under acute amino-acid withdrawal; the contribution of this route in tissues is not established. Single study. plausible in people, not shown directly · emerging, few independent studies | M | DEM2014 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| H | Human study | 1 |
| A | Animal model | 17 |
| M | Molecular — cells, biochemistry, structure | 26 |
Studies
| Year | Evidence | Study |
|---|---|---|
| 2010 | H | Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis KRU2010 In patients whose TSC1/TSC2 mutations cause brain tumors, everolimus shrank tumor volume by 30%+ in three-quarters of patients. Open-label and uncontrolled (n=28); randomised confirmation came later (FRA2013). |
| 2026 | A | Deubiquitinase USP7 stabilizes the histone demethylase KDM5B and promotes the progression of renal fibrosis through the TSC1/mTOR axis LV2026S USP7 deubiquitinates and stabilizes the histone demethylase KDM5B, which represses TSC1 transcription and thereby activates mTOR, promoting kidney fibrosis in two mouse injury models; USP7 is upregulated in human CKD kidneys and correlates with fibrosis severity. Genetic or pharmacological USP7 inhibition restores TSC1 expression, suppresses mTOR activation, and attenuates fibrosis in these mice, making the USP7-KDM5B-TSC1-mTOR axis a candidate intervention point; the human data are correlative only. |
| 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 | 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 | Impaired mTOR/SREBP1-Mediated Lipogenesis as a Mechanism of Hepatic Glycogen Accumulation in a Carnivorous Fish Model, Largemouth Bass (Micropterus salmoides) TAO2026 mTOR/SREBP1 signaling governs hepatic glucose partitioning; the insulin-responsive mTOR/SREBP1 axis promotes lipogenesis versus glycogen accumulation. In this model -- a carnivorous fish -- impairment of the axis is associated with hepatic glycogen overload mimicking glucose intolerance. |
| 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. |
| 2018 | A | mTOR signaling regulates central and peripheral circadian clock function RAM2018 mTOR sets how fast and how strongly the circadian clock ticks. Inhibiting mTOR lengthened the clock period and flattened its amplitude; activating it shortened the period and raised the amplitude, in cells, in ex vivo brain (SCN) and liver clocks, and in mTOR heterozygous mice, whose locomotor rhythm ran longer. The study starts from the observation that mTOR activity itself oscillates over 24 hours in many tissues. |
| 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 | 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. |
| 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. |
| 2009 | A | mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells CHE2009 mTOR hyperactivation drives HSC aging; rapamycin restores hematopoietic stem-cell function. |
| 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 | 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 | Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis EHN2008 Rapamycin reverses learning and memory deficits in a Tsc2+/- tuberous sclerosis model. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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 | 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 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 | 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 | 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 | 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 | 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. |
| 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 | The TSC-mTOR signaling pathway regulates the innate inflammatory response WEI2008 The TSC-mTOR pathway controls the innate inflammatory response of monocytes/macrophages. |
| 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. |
| 2006 | M | TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth INO2006 TSC2 integrates Wnt and energy signals through coordinated AMPK and GSK3 phosphorylation. |
| 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 | Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies SHA2004 The companion paper to Harrington 2004, published two months later. In cultured mammalian cells, constitutive Rheb/mTOR/S6K activity depletes IRS1 and IRS2, producing cellular insulin resistance and impaired survival signalling. Together the two papers establish the S6K1 -> IRS negative feedback arm. |
| 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 | 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 | Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway MAN2002 The authors combined biochemistry with a search for Akt consensus motifs and picked out tuberin, the TSC2 tumour suppressor protein, as a likely Akt substrate. They showed that activating PI3K leads to phosphorylation of tuberin at sites matching the Akt motif, and that Akt can phosphorylate tuberin both in vitro and in cells. Two of these sites, S939 and T1462, were regulated by PI3K, and T1462 stayed phosphorylated in tumour cell lines lacking PTEN. A tuberin mutant without the main PI3K-dependent sites blocked activation of S6K1. Together with papers from other labs in the same months, this was one of the early papers to link growth-factor signalling through Akt to the TSC complex and mTORC1 output. Boundary: cultured mammalian cells and in vitro kinase assays, with overexpressed tuberin mutants; no whole-animal or human tissue data. |
| 2002 | M | Akt regulates growth by directly phosphorylating Tsc2 POT2002 Working in fruit flies, the authors showed that Akt directly phosphorylates the Drosophila Tsc2 protein in vitro at two conserved residues, Ser924 and Thr1518. Tsc2 with these sites mutated no longer responded to Akt signalling, and its complex with Tsc1 became more stable. Turning up Akt signalling in fly tissue increased cell size, broke up the Tsc1-Tsc2 complex and changed where the two proteins sat in the cell. Expressing a Tsc2 mutant that Akt cannot phosphorylate blocked the growth signals from Akt, which led the authors to propose Tsc2 as the key Akt target for growth in the insulin pathway. Boundary: Drosophila tissues and in vitro biochemistry with overexpressed mutant proteins; the claim that Tsc2 carries all Akt growth signals was tested in flies, not in mammals. |
| 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. |
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