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Details on Person UniProt:Q15382 RHEB

Class:Id	ReferenceGeneProduct:63056
_chainChangeLog	chain:1-181 added on Fri February 6 2015;propeptide:182-184 added on Fri February 6 2015
_displayName	UniProt:Q15382 RHEB
_timestamp	2026-02-20 22:48:20
chain	chain:1-181 propeptide:182-184
checksum	8F4C8080BDF928FD
comment	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, PubMed:25816988). 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).CATALYTIC ACTIVITY GTP + H2O = GDP + phosphate + H(+)ACTIVITY REGULATION Alternates between an inactive form bound to GDP and an active form bound to GTP (PubMed:12271141, PubMed:12842888, PubMed:12869586, PubMed:12906785, PubMed:15340059, PubMed:22819219, PubMed:24529379). Inactivated by the TSC-TBC complex via the GTPase activating protein (GAP) domain of TSC2 (PubMed:12271141, PubMed:12842888, PubMed:12869586, PubMed:12906785, PubMed:15340059, PubMed:22819219, PubMed:24529379). Autoinhibited by Tyr-35, which constrains the active site conformation, restricting the access of the catalytic Asp-65 to the nucleotide-binding pocket (PubMed:22819219). Specifically inhibited by NR1 (4-bromo-6-(3,4-dichlorophenylthio)-1-(4-(dimethylcarbamoyl)benzyl)-1H-indole-2-carboxylic acid) (PubMed:29416044).SUBUNIT Associates with the mTORC1 complex (MTOR, MLST8 and RPTOR) in a guanyl nucleotide-independent manner (PubMed:15854902, PubMed:16098514, PubMed:24529379). Interacts with TSC2 (PubMed:15854902, PubMed:22819219, PubMed:24529379, PubMed:25816988). Interacts with MCRS1; the interaction maintains RHEB at the lysosome in its active GTP-bound form and prevents its interaction with the mTORC1 complex inhibitor TSC2, ensuring activation of the mTORC1 complex by RHEB (PubMed:25816988). Interacts (when prenylated) with PDE6D; this promotes release from membranes (PubMed:22002721).INTERACTION Farnesylation is required for recruitment to lysosomal membranes, where it activates the mTORC1 complex.TISSUE SPECIFICITY Ubiquitous (PubMed:8543055). Highest levels observed in skeletal and cardiac muscle (PubMed:8543055).PTM Farnesylation is important for efficiently activating mTORC1-mediated signaling.PTM 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).PTM Phosphorylation by MAPKAPK5 impairs GTP-binding and inactivation.MISCELLANEOUS The conserved catalytic Gln-64 found in other Ras-like GTPases does not seem to be involved in GTP hydrolysis in RHEB.SIMILARITY Belongs to the small GTPase superfamily. Rheb family.
description	recommendedName: fullName evidence="26"GTP-binding protein Rheb ecNumber evidence="8 16"3.6.5.- alternativeName: Ras homolog enriched in brain
geneName	RHEB RHEB2
identifier	Q15382
isSequenceChanged	FALSE
keyword	3D-structure Cytoplasm Endoplasmic reticulum Golgi apparatus GTP-binding Hydrolase Isopeptide bond Lipoprotein Lysosome Magnesium Membrane Metal-binding Methylation Nucleotide-binding Phosphoprotein Prenylation Proteomics identification Reference proteome Ubl conjugation
modified	[InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9862192] Weiser, Joel, 2024-02-26 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9939033] Weiser, Joel, 2025-02-21 [InstanceEdit:9963647] Weiser, Joel, 2025-08-15 [InstanceEdit:9983091] Weiser, Joel, 2026-02-20
name	RHEB
referenceDatabase	[ReferenceDatabase:2] UniProt
referenceGene	[ReferenceDNASequence:8988624] ENSEMBL:ENSG00000106615 RHEB [Homo sapiens]
secondaryIdentifier	RHEB_HUMAN B3KWN6 D3DX13 Q53Y56 Q99444
sequenceLength	184
species	[Species:48887] Homo sapiens
(referenceEntity)	[EntityWithAccessionedSequence:165190] RHEB [lysosomal membrane] [Homo sapiens] [EntityWithAccessionedSequence:377338] RHEB [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:5083677] RHEB [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:5656350] RHEB [endosome membrane] [Homo sapiens]
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No pathways have been reviewed or authored by UniProt:Q15382 RHEB (63056)