Pathway link RHEB-MTORC1
Rheb mTORC1
Rheb activates mTORC1.
Switched-on Rheb docks onto mTORC1 and physically reshapes it into its working form – the actual "on" switch.
The conditions it holds under
Cryo-EM structures, in vitro biochemistry, Drosophila and one mouse study (INOK2003, SAU2003, YAN2017, CUI2025, DEL2011) define how Rheb activates mTORC1 in reconstituted and cellular systems. Human tissue evidence is genetic and indirect: brain-restricted somatic RHEB variants in focal cortical dysplasia and hemimegalencephaly go with strong pS6 staining in the lesions (BAL2019, a cohort of 80 children in which RHEB is one of four activator genes; LEE2021, three patients). That shows the pathway running hot when Rheb is altered; it does not measure Rheb-GTP loading or mTORC1 activity 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.
- Time it takes
- seconds
- Step
- direct (one molecule acts on the other)
- Measured in
- mammalian cells, human brain tissue (somatic RHEB variants)
- Where in the cell
- lysosome
- Reaches people?
- plausible in people, not shown directly
- How settled
- settled in the literature
Studies behind it
| Year | Evidence | Study |
|---|---|---|
| 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. |
| 2003 | M | Rheb promotes cell growth as a component of the insulin/TOR signalling networkSAU2003 Rheb promotes cell growth as a component of the insulin/TOR network in Drosophila. |
| 2017 | M | Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40YAN2017 Structures reveal how RHEB allosterically activates and PRAS40 inhibits mTORC1. |
| 2025 | M | Structural basis for mTORC1 activation on the lysosomal membraneCUI2025 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. |
| 2011 | A | The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2DEL2011 mTORC1 and mTORC2 selectively program distinct CD4 helper T-cell lineages. |
| 2019 | H | Dissecting the genetic basis of focal cortical dysplasia: a large cohort study.BAL2019 In 80 children operated for drug-resistant epilepsy, deep sequencing of brain and matched blood found brain-restricted gain-of-function variants in mTOR-pathway activators (MTOR, AKT3, PIK3CA and RHEB) only in focal cortical dysplasia type 2 (FCD2) and hemimegalencephaly (HME): 29 of 62 cases (47%). Loss-of-function variants in repressors (DEPDC5, TSC1, TSC2) were found in FCD2 as well. All 25 FCD2 cases examined showed strong pS6 staining, a readout of mTOR activity, in dysmorphic neurons and balloon cells, including cases with no variant found. RHEB is one of four activator genes reported here; the RHEB-specific case count sits in the paper's tables and is not recorded in this entry. Observational, single centre, and the variants were not tested for function in this paper. |
| 2021 | H | Gradient of brain mosaic RHEB variants causes a continuum of cortical dysplasia.LEE2021 Three patients with cortical malformations carried brain-restricted somatic RHEB variants (p.Y35L in two, p.E40V in one) that were absent from blood. The size of the malformation followed the variant load: 2.6% in a small transmantle FCD, 8.9% in a lobar FCD, 17.6% in hemimegalencephaly. Dysmorphic neurons and balloon cells stained strongly for pS6, a readout of raised mTOR activity, while non-mTOR FCD type I and control tissue did not. In the two patients with enough tissue, laser capture microdissection found the variants enriched in these abnormal cells. Only three patients, two of them reported earlier; the effect of the variants on Rheb itself was not tested in this paper. |
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
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- 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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