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.
Integrates Akt, AMPK, ERK/RSK, GSK3 and REDD1 inputs. Regulation is substantially about lysosomal recruitment, not only phosphorylation-driven activity change.
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| H | Human study | 1 |
| A | Animal model | 3 |
| M | Molecular — cells, biochemistry, structure | 5 |
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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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 directly activates mTORC1. |
| 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. The founding paper 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. |