RHEB
Function
Small GTPase that acts as an allosteric activator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation and growth (PubMed:12172553, PubMed:12271141, PubMed:12842888, PubMed:12869586, PubMed:12906785, PubMed:15340059, PubMed:15854902, PubMed:16098514, PubMed:20381137, PubMed:22819219, PubMed:24529379, PubMed:29416044, PubMed:32470140, PubMed:33157014). In response to nutrients, growth factors or amino acids, specifically activates the protein kinase activity of MTOR, the catalytic component of the mTORC1 complex: acts by causing a conformational change that allows the alignment of residues in the active site of MTOR, thereby enhancing the phosphorylation of ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1) (PubMed:29236692, PubMed:33157014). RHEB is also required for localization of the TSC-TBC complex to lysosomal membranes (PubMed:24529379). In response to starvation, RHEB is inactivated by the TSC-TBC complex, preventing activation of mTORC1 (PubMed:24529379, PubMed:33157014). Has low intrinsic GTPase activity (PubMed:15340059).
Post-translational modifications
Farnesylation is important for efficiently activating mTORC1-mediated signaling.
Polyubiquitinated in response to amino acid, promoting its interaction with MTOR and mTORC1 activation (PubMed:33157014). Deubiquitination by ATXN3 promotes recruitment of the TSC-TBC complex and RHEB inactivation by TSC2 (PubMed:33157014). Monoubiquitinated at Lys-8 by RNF152, promoting its association with the TSC-TBC complex (PubMed:30514904). Deubiquitinated at Lys-8 by USP4, promoting mTORC1 activation (PubMed:30514904).
Phosphorylation by MAPKAPK5 impairs GTP-binding and inactivation.
Sequence Similarities
Belongs to the small GTPase superfamily. Rheb family.
Tissue Specificity
Ubiquitous (PubMed:8543055). Highest levels observed in skeletal and cardiac muscle (PubMed:8543055).
Cellular localization
- Endomembrane system
- Lipid-anchor
- Cytoplasmic side
- Lysosome membrane
- Lipid-anchor
- Cytoplasmic side
- Golgi apparatus membrane
- Lipid-anchor
- Cytoplasmic side
- Endoplasmic reticulum membrane
- Lipid-anchor
- Cytoplasmic side
- Cytoplasm
- Cytosol
- Farnesylation is required for recruitment to lysosomal membranes, where it activates the mTORC1 complex.
Alternative names
RHEB2, RHEB, GTP-binding protein Rheb, Ras homolog enriched in brain