Pathway link TSC-MTORC1
TSC1/TSC2 mTORC1
TSC1/TSC2 inhibits mTORC1.
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.)
The conditions it 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.
- Time it takes
- seconds
- Step
- indirect (through steps not drawn here)
- Measured in
- human, mammalian cells
- Where in the cell
- lysosome
- Reaches people?
- shown in people
- How settled
- settled in the literature
Studies behind it
| Year | Evidence | Study |
|---|---|---|
| 2003 | M | Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward RhebTEE2003 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 | Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signalingINOK2003 TSC2 is a GAP for Rheb; loss of TSC2 raises Rheb-GTP and constitutively activates mTOR. |
| 2010 | H | Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosisKRU2010 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 | Impaired Chaperone-Mediated Autophagy Accelerates Intervertebral Disc Degeneration by Inducing MIDN Accumulation to Target TSC2 for Proteasomal DegradationCHEN2026C 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 | 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. |
| 2014 | M | Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2DEM2014 Amino-acid starvation recruits TSC2 to the lysosome to inhibit Rheb and TORC1. |
| 2010 | M | mTORC1 controls fasting-induced ketogenesis and its modulation by ageingSEN2010 mTORC1 controls fasting-induced hepatic ketogenesis via PPARalpha, and this is blunted with age. |
| 2002 | M | Tsc tumour suppressor proteins antagonize amino-acid-TOR signallingGAO2002 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 signalingTEE2002 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. |
| 2002 | A | A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cellsKWI2002 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. |
| 2008 | M | Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttlingDEY2008 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. |
| 2015 | A | mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiationPOL2015 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 miceTSA2012 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. |
| 2013 | M | Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosisBAT2013 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. |
| 2008 | A | Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complexZEN2008 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. |
Points the other way
No study in the Atlas contradicts this link. That means none in this curated set, not none in the literature.
Who has checked this
- Checked by
- No researcher outside the project has checked this link yet.
- Curator sign-off
- Not signed off yet. This link was drafted with AI help and has not been reviewed link by link; treat it as a proposal until it is.
- Curated by
- Oliver Barton, with AI help for drafting; see how links are checked.
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