Rheb (Ras homolog enriched in brain)
Rheb is a small GTPase that, in its GTP-bound (active) form, directly binds and activates mTORC1 at the lysosomal membrane. Its activity is controlled by the TSC1/TSC2 GAP complex ...
Classification
Category: Upstream regulator (small GTPase)
Aliases: Rheb GTPase
Relationship to mTOR complexes: Direct activator of mTORC1 — see mTORC1 vs mTORC2 for the full complex-level map.
Summary
Rheb is a small GTPase that, in its GTP-bound (active) form, directly binds and activates mTORC1 at the lysosomal membrane. Its activity is controlled by the TSC1/TSC2 GAP complex (which inactivates it) rather than by a known GEF in the canonical pathway description used in this dataset.
| Upstream of | MTORC1 |
| Downstream of | TSC1/TSC2 (Tuberous Sclerosis Complex 1/2) |
- TSC1/TSC2 GAP activity converts Rheb-GTP to inactive Rheb-GDP (inhibitory input)
- Absence of TSC1/2 inhibition (i.e. active AKT signaling suppressing TSC2) allows Rheb to remain GTP-bound and active
- Rheb-GTP directly binds and activates mTORC1 kinase activity at the lysosomal membrane
- Rheb is the final upstream switch immediately controlling mTORC1 activation; TSC1/2 acts on Rheb, not directly on mTORC1.
- Rheb activity is necessary but must be considered alongside amino-acid-driven Rag/Ragulator localization signaling (see /rag-gtpases) -- mTORC1 activation in the canonical model requires both Rheb-GTP AND proper lysosomal localization via Rag GTPases.
Source tier
Tier 2 · Biological synthesis (author-cluster reviews, not primary trial data) Reference synthesis attributed in the brief to the Saxton & Sabatini; Laplante & Sabatini; and Liu & Sabatini mTOR review literature (author-cluster attribution, tier 2, brief ยง4). Exact article-level PMID/DOI not supplied in the sourcing brief and is not fabricated here.