Rheb
Small GTPase that directly activates mTORC1 when in its GTP-bound state; held inactive by TSC1/TSC2.
The switch that turns mTORC1 on once the Rags have brought it to the lysosome. A small molecular switch that directly turns mTORC1 on when it's in its 'active' state. The TSC1/TSC2 brake keeps it held inactive until nutrient and growth signals say otherwise.
Realigns the mTOR active site; the convergence point of the entire growth-factor arm and the reason localisation alone is not activation. Note a declared simplification in this map: Rheb is farnesylated and distributes across the endomembrane system, with a substantial ER and Golgi pool, and which pool supplies the activating Rheb is still debated. It is drawn on the lysosomal band because that is where it meets mTORC1.
TL;DR. Rheb appears in 15 curated studies in Oliver's mTOR Atlas: 2 in animal models; 13 at the molecular level (cells, biochemistry, structure). No study in people is recorded for it in the Atlas yet. It has 2 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| 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 |
| 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 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| A | Animal model | 2 |
| M | Molecular — cells, biochemistry, structure | 13 |
No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.
Studies
| Year | Evidence | Study |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 2005 | M | Rheb binds and regulates the mTOR kinase LON2005 Rheb binds the mTOR kinase domain and directly stimulates its activity. |
| 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. |
| 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 | Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2 GAR2003 Insulin activates Rheb-GTP, inhibited by TSC1/2, positioning Rheb as the direct upstream activator of TOR. |
| 2003 | M | Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling INOK2003 TSC2 is a GAP for Rheb; loss of TSC2 raises Rheb-GTP and constitutively activates mTOR. |
| 2003 | M | Rheb promotes cell growth as a component of the insulin/TOR signalling network SAU2003 Rheb promotes cell growth as a component of the insulin/TOR network in Drosophila. |
| 2003 | M | Rheb is an essential regulator of S6K in controlling cell growth in Drosophila STO2003 Rheb is an essential regulator of S6K controlling cell growth downstream of TSC in Drosophila. |
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