Affinage

RHEB

GTP-binding protein Rheb · UniProt Q15382

Length
184 aa
Mass
20.5 kDa
Annotated
2026-06-10
100 papers in source corpus 45 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RHEB is a farnesylated Ras-family small GTPase that functions as the proximal, essential activator of mTOR complex 1 (mTORC1), positioned genetically downstream of the TSC1/TSC2 tumor suppressor complex and upstream of TOR/S6K to control cell and tissue growth (PMID:12869586, PMID:12842888, PMID:12766776, PMID:12766775, PMID:12893813). GTP-bound RHEB binds directly to the mTOR catalytic domain (and LST8) independently of TSC2, and structural work shows it engages a site distal from the active site to drive a global conformational change that allosterically realigns active-site residues and accelerates catalysis; nucleotide-deficient RHEB still binds mTOR but traps it inactive (PMID:15854902, PMID:29236692). RHEB is held in a constitutively high GTP-charged state, and its activity is set by the TSC2 GAP domain, which uses an 'asparagine thumb' (N1643) rather than a canonical arginine finger to stabilize the GTP γ-phosphate and accelerate hydrolysis (PMID:15340059, PMID:12214276, PMID:33436626). This switch is integrated with upstream cues: amino acids/arginine and RNF152/USP4 ubiquitination control TSC–RHEB association and lysosomal positioning, while energy stress engages a p38β–PRAK cascade that phosphorylates RHEB at Ser130 to impair nucleotide binding (PMID:21336308, PMID:30514904, PMID:26742086). RHEB requires C-terminal CAAX farnesylation (not geranylgeranylation) and Rce1/Icmt processing for ER/Golgi endomembrane localization, making it the critical farnesyltransferase-inhibitor target for mTOR pathway suppression (PMID:16046393, PMID:16006564). Beyond mTORC1, RHEB has multiple mTOR-independent activities, including inhibition of B-Raf/C-Raf kinase activity and heterodimerization (PMID:15150271, PMID:16803888), mitochondrial activation of pyruvate dehydrogenase via PDP (PMID:33725483), GTP-dependent destabilization of BACE1 (PMID:24368770), and PERK-mediated eIF2α phosphorylation (PMID:25660019). In vivo, RHEB is essential for embryonic cardiovascular development and growth (PMID:21321084), and a brain somatic gain-of-function mutation (p.Y35L) causes focal cortical dysplasia type II with seizures that are rescued by rapamycin (PMID:31337748).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1994 Medium

    Established RHEB as a distinct Ras-family GTPase with intrinsic GTP-binding/hydrolysis activity and a farnesylation signal, providing the molecular starting point for all later mechanistic work.

    Evidence Differential cloning with bacterial fusion-protein GTPase assays and sequence analysis in activity-induced neurons

    PMID:8206940

    Open questions at the time
    • No effector or pathway assigned at discovery
    • GTPase regulator (GAP/GEF) not identified
  2. 1997 Medium

    Distinguished RHEB from oncogenic Ras by showing it is farnesylated, non-transforming, and interacts differentially with Raf-1, hinting at a non-canonical Ras-like signaling role.

    Evidence In vitro/in vivo farnesylation assays, NIH 3T3 transformation assays, and Raf-1 co-IP with mutagenesis

    PMID:9001246 PMID:9099708

    Open questions at the time
    • Physiological RHEB effector still unknown
    • Biological consequence of Raf-1 binding undefined
  3. 2002 Medium

    Showed RHEB is maintained in an unusually high GTP-bound state insensitive to growth conditions and inhibits B-Raf, framing it as a constitutively-active GTPase with a Raf-directed activity.

    Evidence GTP/GDP loading assays across three cell lines, endogenous B-Raf co-IP, kinase and Elk-1 reporter assays

    PMID:12214276

    Open questions at the time
    • Did not connect RHEB to mTOR
    • Mechanism of constitutive GTP-loading unexplained
  4. 2003 High

    Placed RHEB in the TSC–mTOR axis by identifying TSC2 as a direct RHEB GAP and showing RHEB is rate-limiting for S6K/4EBP1 phosphorylation downstream of TSC1/TSC2 and upstream of mTOR.

    Evidence In vitro GAP assays, in vivo GTP-loading, genetic epistasis in mammalian cells and Drosophila, rapamycin/FTI sensitivity

    PMID:12214276 PMID:12766775 PMID:12766776 PMID:12842888 PMID:12869586 PMID:12893813

    Open questions at the time
    • Direct RHEB–mTOR contact not yet demonstrated
    • How RHEB-GTP activates the kinase unknown
  5. 2004 High

    Defined the unusual catalytic chemistry of TSC2 GAP action (asparagine thumb, not arginine finger) and dissociated RHEB membrane targeting from its ability to drive S6K signaling.

    Evidence Site-directed mutagenesis with in vitro GAP and cell-based S6K assays

    PMID:15340059

    Open questions at the time
    • Structural basis of the asparagine-thumb mechanism not yet resolved
    • Role of farnesylation in vivo left ambiguous
  6. 2005 High

    Demonstrated that RHEB binds the mTOR catalytic domain/LST8 directly and GTP-dependently to switch on kinase activity, identifying the long-sought RHEB–mTORC1 contact.

    Evidence Reciprocal co-IP, in vitro kinase assays with RHEB nucleotide and switch-I mutants, nucleotide-charging analysis

    PMID:15854902 PMID:15878852

    Open questions at the time
    • Structural mechanism of activation unresolved
    • Whether an intermediate effector was required remained debated
  7. 2005 High

    Resolved the prenylation requirement of RHEB, showing it is exclusively farnesylated and traffics to ER/Golgi endomembranes via Rce1/Icmt processing, making RHEB the key farnesyltransferase-inhibitor target for mTOR blockade.

    Evidence In vitro prenylation with purified enzymes, Rce1/Icmt knockout imaging, FTI/GGTI treatment and geranylgeranylatable mutant rescue

    PMID:16006564 PMID:16046393

    Open questions at the time
    • Functional role of endomembrane vs lysosomal pools not fully separated
    • How localization couples to mTOR activation unclear
  8. 2008 Medium

    Identified candidate RHEB effectors and broadened its mTOR-independent reach, proposing PLD1 as a GTP-dependent effector required for mTOR activation and linking RHEB to neuronal axon formation and dormant-tumor survival.

    Evidence In vitro PLD1 binding/activity assays, RNAi, neuronal overexpression/RNAi morphology, ATF6α/RHEB shRNA in a tumor dormancy model

    PMID:18550814 PMID:18650380 PMID:18842593

    Open questions at the time
    • Relative contribution of PLD1 versus direct mTOR binding unresolved
    • Tissue-context dependence of effectors unclear
  9. 2009 High

    Reconstituted RHEB as a direct, specific GTP-dependent activator of raptor-containing mTORC1 in vitro and refuted FKBP38 as the obligate intermediary effector, settling the directness of RHEB–mTORC1 coupling.

    Evidence In vitro mTORC1 kinase assays with recombinant RHEB and effector-domain mutants; three independent in vitro assays failing to detect RHEB–FKBP38

    PMID:17991864 PMID:19222999 PMID:19299511

    Open questions at the time
    • FKBP38 proposal (17991864) and its refutation reflect conflicting evidence
    • Mechanism of kinase acceleration still structurally undefined
  10. 2009 Medium

    Established a discrete mTOR-independent function in proteostasis, showing RHEB disrupts dynein–cargo interactions to block aggresome formation and sensitize cells to misfolded-protein death.

    Evidence TSC1/TSC2 knockout cells, RHEB perturbation, dynein–cargo co-IP, rapamycin controls

    PMID:19458266

    Open questions at the time
    • Direct RHEB–dynein interaction not established
    • Single lab, single-readout proteostasis phenotype
  11. 2011 High

    Added a direct RHEB-targeted regulatory layer for energy stress, showing PRAK phosphorylates RHEB at Ser130 to impair nucleotide binding and inhibit mTORC1 independently of AMPK–TSC2.

    Evidence In vitro PRAK kinase assay, Ser130 mutagenesis, nucleotide-binding assay, p38β/PRAK depletion epistasis

    PMID:21336308

    Open questions at the time
    • In vivo significance of Ser130 phosphorylation not established
    • Phosphatase reversing this mark unknown
  12. 2011 High

    Defined RHEB's organismal requirement, showing knockout is embryonic-lethal with impaired cardiovascular development and reduced TORC1 activity, and that Rheb heterozygosity rescues Tsc1-null embryos.

    Evidence Rheb knockout mice, embryonic fibroblast TORC1/cell-size assays, Tsc1/Rheb genetic epistasis

    PMID:21321084

    Open questions at the time
    • Tissue-specific essential functions not dissected here
    • mTORC1-dependent versus -independent contributions to lethality unresolved
  13. 2015 Medium

    Mapped how nutrient and effector cues control the RHEB pool, identifying MCRS1 as a maintainer of lysosomal RHEB and an mTOR-independent PERK–eIF2α translational-suppression branch of RHEB signaling.

    Evidence siRNA/Cre-lox MEFs with RHEB localization and TSC2 co-IP; RHEB perturbation with PERK inhibition and eIF2α/protein-synthesis assays

    PMID:25660019 PMID:25816988

    Open questions at the time
    • Mechanism by which MCRS1 retains RHEB at lysosomes unclear
    • Direct RHEB–PERK contact not demonstrated
  14. 2017 High

    Provided the near-atomic mechanism of mTORC1 activation, showing RHEB binds mTOR distally and drives an allosteric conformational change that realigns the active site, with cancer mutations mimicking RHEB's relief of autoinhibition.

    Evidence Cryo-EM of RHEB–mTORC1 (3.4 Å) and mTORC1 (3.0 Å) with crystal structures and in vitro kinase assays of cancer mutants

    PMID:29236692

    Open questions at the time
    • Dynamics of the conformational transition not time-resolved
    • How upstream signals modulate this interface structurally not shown
  15. 2018 Medium

    Demonstrated RHEB switch II as a druggable surface, with the small molecule NR1 binding switch II to selectively block mTORC1 (S6K1) without inhibiting AKT/ERK or causing prolonged mTORC2 inhibition.

    Evidence NR1 binding assay, S6K1/AKT/ERK phosphorylation in cells, in vivo mouse mTORC1 assays, rapamycin comparison

    PMID:29416044

    Open questions at the time
    • Co-structure of NR1–RHEB not reported here
    • Therapeutic window in disease models untested
  16. 2018 Medium

    Identified a ubiquitin-switch controlling RHEB–TSC association, with RNF152 ubiquitinating RHEB to favor TSC binding/inactivation and AKT-dependent USP4 deubiquitinating RHEB to release it for mTORC1 activation.

    Evidence Reciprocal co-IP, ubiquitination assays, RNF152/USP4 perturbation, AKT inhibition, mTORC1 assays

    PMID:30514904

    Open questions at the time
    • Ubiquitinated RHEB residues not mapped
    • Single-lab pathway awaiting independent confirmation
  17. 2016 High

    Defined an amino-acid input acting through RHEB, showing arginine displaces the TSC complex from lysosomes and from RHEB to relieve allosteric inhibition and enable maximal growth-factor-driven mTORC1 activation.

    Evidence Lysosomal fractionation and TSC2–RHEB co-IP under arginine-replete/-depleted conditions across multiple cell types

    PMID:26742086

    Open questions at the time
    • Arginine sensor upstream of TSC displacement not identified here
    • Quantitative coupling to RHEB GTP state not measured
  18. 2019 High

    Extended RHEB's biological reach in vivo, establishing it as a transcriptional ATF6 target driving cardiac hypertrophy and as an essential, amino-acid-coupled mTORC1 regulator for Treg cell suppressive identity.

    Evidence ChIP and cardiac-specific ATF6 KO with AAV9-RHEB rescue; Treg-specific Rheb1/Rheb2 double-KO mice with immune phenotyping

    PMID:30582446 PMID:31668641

    Open questions at the time
    • Whether RHEB transcriptional induction is general or tissue-restricted unclear
    • Division of labor between Rheb1 and Rheb2 not resolved
  19. 2019 High

    Linked RHEB hyperactivation directly to human neurological disease, showing the brain somatic RHEB p.Y35L gain-of-function mutation causes focal cortical dysplasia type II with seizures rescued by rapamycin.

    Evidence Exome sequencing, GTPγS-binding and S6 phosphorylation assays, in utero electroporation mouse model with EEG and rapamycin treatment

    PMID:31337748

    Open questions at the time
    • Spectrum of pathogenic RHEB mutations not defined
    • Cell-type origin of cytomegalic neurons not fully mapped
  20. 2021 High

    Resolved the TSC complex architecture and confirmed the catalytic GAP mechanism at the RHEB interface, showing a 2:2:1 TSC1:TSC2:TBC1D7 assembly in which the TSC2 asparagine thumb (N1643) stabilizes the GTP γ-phosphate.

    Evidence Cryo-EM of the human TSC complex with GAP-domain mutagenesis and biochemical assays

    PMID:33436626

    Open questions at the time
    • Conformational coupling between TSC binding and RHEB nucleotide state not captured
    • How upstream signals remodel this complex on lysosomes unresolved
  21. 2021 High

    Defined a mitochondrial, mTOR-independent metabolic function, showing activity- and lactate-driven RHEB import via Tom20 activates pyruvate dehydrogenase through PDP, and that Schwann-cell RHEB loss impairs PDH and causes peripheral axon degeneration.

    Evidence Schwann-cell-specific Rheb KO and gain-of-function mice, mitochondrial fractionation, RHEB–Tom20 and RHEB–PDP co-IP, PDH activity and acetyl-CoA/ATP/lactate measurements, rapamycin controls

    PMID:33725483 PMID:34619097

    Open questions at the time
    • How a farnesylated GTPase enters the matrix mechanistically unclear
    • Whether mitochondrial RHEB pool exists in non-neural tissues unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the diverse upstream inputs (ubiquitination, Ser130 phosphorylation, arginine/TSC displacement, MCRS1) are quantitatively integrated to set RHEB's GTP state at the lysosome, and how a single farnesylated GTPase partitions between endomembrane mTORC1 activation and its distinct mTOR-independent functions (B-Raf inhibition, mitochondrial PDH activation, BACE1 destabilization, PERK signaling).
  • No unified model of RHEB GTP-state regulation across inputs
  • Spatial/temporal partitioning between mTOR-dependent and -independent pools undefined
  • Structural basis for non-mTOR effector engagement (PDP, B-Raf, BACE1) unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 4 GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 3
Localization
GO:0005764 lysosome 2 GO:0005783 endoplasmic reticulum 2 GO:0005794 Golgi apparatus 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1643685 Disease 2
Partners
BACE1BRAFMTORPDPPLD1RAF1TOM20TSC2

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 TSC2 is a GTPase-activating protein (GAP) directly toward Rheb; TSC2 stimulates Rheb GTP hydrolysis, reducing active Rheb-GTP levels, and thereby inhibiting mTOR-dependent phosphorylation of S6K and 4EBP1. Rheb acts downstream of TSC1/TSC2 and upstream of mTOR. In vitro GAP activity assays, co-immunoprecipitation, dominant-negative and constitutively active mutant expression, genetic epistasis in mammalian cells Genes & development High 12766775 12766776 12842888 12869586
2003 Rheb is an essential regulator of S6 kinase (S6K) activity downstream of Tsc1/Tsc2 and upstream of TOR in Drosophila; loss-of-function Rheb mutations arrest larval growth and prevent G1-S progression, and overexpression promotes cell and tissue growth in a rapamycin-sensitive manner. Drosophila genetic screen, loss-of-function mutations, overexpression, rapamycin sensitivity assay Nature cell biology High 12766775 12766776 12893813
2004 TSC2 GAP activity toward Rheb requires a catalytic 'asparagine thumb' (Asn residues in TSC2) rather than the arginine finger found in Ras-GAPs; Arg15 of Rheb (equivalent to Gly12 in Ras) is important for Rheb to serve as a TSC2 GAP substrate. Farnesylation and membrane localization of Rheb are not essential for Rheb to stimulate S6K phosphorylation. Site-directed mutagenesis, in vitro GAP activity assay, cell-based S6K phosphorylation assay Molecular and cellular biology High 15340059
2005 Rheb binds directly to the mTOR catalytic domain and to LST8 within mTOR complex 1 (TOR complex 1), independently of its ability to bind TSC2. Rheb-GTP binding enables activation of the TOR kinase; mTOR polypeptides bound to Rheb(Gln64Leu) (near-90% GTP-charged) exhibit substantially higher kinase activity, while nucleotide-deficient Rheb mutants bind mTOR but trap it in an inactive state. Co-immunoprecipitation (in vivo and in vitro), in vitro kinase assay, switch-I domain mutagenesis, nucleotide-charging analysis Current biology : CB High 15854902
2005 Amino acid withdrawal reversibly inhibits binding of Rheb to endogenous and recombinant mTOR without altering Rheb GTP-charging. The inhibitory effect is exerted through an action on mTOR at a site largely distinct from the Rheb-binding region; deletion of the C-terminal lobe of the mTOR catalytic domain abolishes the inhibitory effect of amino acid withdrawal on Rheb binding. Co-immunoprecipitation, mTOR deletion mutants, GTP-charging assays, amino acid withdrawal/re-addition experiments The Journal of biological chemistry High 15878852
1994 Rheb is a novel Ras-family small GTPase that binds and hydrolyzes GTP and contains a C-terminal CAAX box predicted to signal farnesylation for membrane targeting. It is rapidly and transiently induced in hippocampal neurons by seizures and NMDA-dependent synaptic activity. Differential cloning, bacterial fusion protein GTP-binding and GTPase activity assay, Northern blot, sequence analysis The Journal of biological chemistry Medium 8206940
1997 Rheb is farnesylated in vitro and in vivo and is sensitive to farnesyltransferase inhibition. Unlike Ras, Rheb does not transform NIH 3T3 cells but instead antagonizes oncogenic Ras transformation and signaling, similar to KRev-1/Rap1A. In vitro and in vivo farnesylation assays, NIH 3T3 transformation assay, oncogenic Ras co-expression The Journal of biological chemistry Medium 9099708
1997 Rheb interacts with Raf-1 kinase; unlike H-Ras, the Rheb-Raf-1 interaction is potentiated by growth factors combined with cAMP-elevating agents. Protein kinase A-dependent phosphorylation of Ser43 in Raf-1 reciprocally potentiates Raf-1 binding to Rheb and decreases its interaction with H-Ras. A single amino acid in the G2 effector domain is critical for the differential binding properties of Rheb versus Ras. Co-immunoprecipitation, mutagenesis, cAMP stimulation, PKA phosphorylation assays Molecular and cellular biology Medium 9001246
2002 Rheb is maintained in a high GTP-bound (activated) state in mammalian cells, much more so than Ras or Rap1, and its activation state is unaffected by changes in growth conditions. Rheb binds B-Raf kinase and inhibits B-Raf kinase activity and B-Raf-dependent Elk-1 transcriptional activation. GTP/GDP loading assays in three mammalian cell lines, co-immunoprecipitation of endogenous Rheb with B-Raf, in vitro kinase assay, Elk-1 reporter assay Oncogene Medium 12214276
2003 TSC2 binds Rheb-GTP in vitro and reduces Rheb GTP levels in vivo; overexpression of Rheb but not Rap1 promotes S6 kinase activation in a rapamycin-dependent manner. Rheb-mediated S6 phosphorylation is blocked by a farnesyl transferase inhibitor. In vitro pulldown (Rheb-GTP binding), in vivo GTP-loading assay, S6K phosphorylation assay, FTI treatment The Journal of biological chemistry High 12842888
2004 Constitutive activation of the Rheb/mTOR/S6K cassette (by TSC1/TSC2 deletion or ectopic Rheb expression) is sufficient to induce insulin resistance by downregulating IRS1 and IRS2, rendering Akt refractory to activation by IRS-dependent growth factor pathways. Genetic deletion of TSC1/TSC2 in mouse embryonic fibroblasts, ectopic Rheb overexpression, Western blot for IRS1/IRS2 protein levels and Akt phosphorylation Current biology : CB High 15380067
2004 Rheb inhibits wild-type B-Raf kinase activity and this function is independent of mTOR/rapamycin (mTOR-independent). The interaction of endogenous Rheb with B-Raf is enhanced by serum and Ras overexpression. A farnesylation-defective Rheb mutant can still co-immunoprecipitate with and inhibit B-Raf, indicating that farnesylation is not required for B-Raf inhibition by Rheb. B-Raf inhibition and S6K activation are separable activities of Rheb. Co-immunoprecipitation, in vitro B-Raf kinase assay, rapamycin treatment, farnesylation-defective Rheb mutant The Journal of biological chemistry Medium 15150271
2005 Rheb localizes to endomembranes (endoplasmic reticulum, Golgi) rather than the plasma membrane, dependent on C-terminal CAAX farnesylation but not palmitoylation. Rce1 and Icmt post-prenylation processing steps are required for proper Rheb endomembrane localization; without the polybasic region or palmitoylation sites, Rheb diffusely localizes when Rce1 or Icmt are absent. Confocal microscopy with fluorescent protein fusions, Rce1 and Icmt knockout fibroblasts, farnesyltransferase and geranylgeranyltransferase inhibitors, CAAX cysteine mutagenesis The Journal of biological chemistry High 16046393
2005 Rheb farnesylation (via the C-terminal CAAX motif) is completely blocked by the FTI SCH66336 (lonafarnib) and Rheb is not alternatively geranylgeranylated. Rheb and Rheb2 C-terminal peptides are substrates for farnesyltransferase but not geranylgeranyltransferase-1 in vitro. FTI-mediated inhibition of mTOR/S6 signaling is reversed by a Rheb mutant engineered for geranylgeranylation, establishing Rheb as the critical FTI target for mTOR pathway inhibition. In vitro prenylation assay with purified enzymes, metabolic labeling in cell culture, S6 phosphorylation assay, Rheb CSVL geranylgeranylatable mutant rescue The Journal of biological chemistry High 16006564
2006 Rheb inhibits both B-Raf and C-Raf kinase activities and inhibits B-Raf/C-Raf heterodimerization; these effects are rapamycin-insensitive (mTOR-independent). Rheb activation is associated with decreased B-Raf (Ser-446) and C-Raf (Ser-338) phosphorylation and inhibits the association of B-Raf with H-Ras. In vitro kinase assay, co-immunoprecipitation of B-Raf/C-Raf heterodimers, rapamycin treatment The Journal of biological chemistry Medium 16803888
2006 Drosophila Rheb (dRheb) has an inhibitory effect on dTORC2 activity in Drosophila S2 cells; this appears to be mediated by a feedback mechanism involving dTORC1 and dS6K rather than direct Rheb-TORC2 interaction. Mammalian Rheb does not activate TORC2 in HEK293 cells. TSC1/TSC2 have opposite effects on TORC1 and TORC2. S2 cell RNAi, Akt and S6K phosphorylation as TORC2/TORC1 functional readouts, Drosophila genetics Proceedings of the National Academy of Sciences of the United States of America Medium 16627617
2007 Rheb activates mTOR by antagonizing FKBP38, an endogenous inhibitor of mTOR structurally related to FKBP12; Rheb interacts directly with FKBP38 in a GTP-dependent manner and prevents FKBP38 association with mTOR. Co-immunoprecipitation, in vitro binding assay, RNAi knockdown, mTOR kinase assay Science (New York, N.Y.) Medium 17991864
2009 The Rheb-FKBP38 interaction proposed in Science 2007 was not detected in three independent in vitro assay systems; cell biological experiments show FKBP38 plays only a very minor role, if any, in mTORC1 activation. FKBP38 is therefore not the long-sought Rheb effector linking Rheb to mTORC1 activation. Three independent in vitro binding assays, cell biological experiments FEBS letters Medium 19222999
2009 Rheb specifically activates mTORC1 but not mTORC2 in a GTP-dependent manner in vitro; the activation requires the effector domain of Rheb and a raptor-containing mTORC1 complex. Rheb increases binding of the substrate 4E-BP1 to mTORC1. Other GTPases (KRas, RalA/B, Cdc42) do not activate mTORC1. Rheb does not induce mTOR autophosphorylation. FKBP38-depleted mTORC1 preparations are still activated by Rheb. In vitro mTORC1 kinase assay using immunoprecipitated mTORC1 from nutrient-starved cells, recombinant Rheb addition, effector domain mutants, substrate binding assay The Journal of biological chemistry High 19299511
2008 Rheb directly binds and activates PLD1 (but not PLD2) in a GTP-dependent manner in vitro, establishing PLD1 as a bona fide effector of Rheb. PLD1 is required (by RNAi) for Rheb activation of the mTOR pathway; TSC2 overexpression suppresses PLD1 activation, and TSC2 deletion elevates basal PLD activity. In vitro binding and PLD activity assay with recombinant proteins, RNAi knockdown, PLD activity assay, PI3K/AMPK pharmacological inhibitors Proceedings of the National Academy of Sciences of the United States of America High 18550814
2009 Rheb inhibits aggresome formation and sensitizes cells to death upon misfolded protein accumulation by disrupting the interaction between dynein and misfolded protein cargos, thereby blocking dynein-dependent retrograde transport. This function is independent of mTOR complex 1. Genetic TSC1/TSC2 knockout cells, Rheb overexpression/knockdown, co-immunoprecipitation of dynein with misfolded protein cargos, rapamycin treatment to distinguish mTOR-dependent from mTOR-independent effects Proceedings of the National Academy of Sciences of the United States of America Medium 19458266
2009 Rheb localizes primarily to endoplasmic reticulum and Golgi apparatus (Rheb1 and Rheb2). Post-prenylation processing by Rce1 and Icmt is required for proper Rheb localization but dispensable for Rheb-induced activation of S6K; farnesylthiosalicylic acid (FTS) blocks S6K activation induced by constitutively active mTOR downstream of Rheb, suggesting FTS inhibits mTOR downstream of Rheb. Immunofluorescence microscopy, Rce1 and Icmt knockout cells, S6K phosphorylation assay, FTS treatment Oncogene Medium 19838215
2011 PRAK (p38-regulated/activated kinase) directly phosphorylates Rheb at Ser130, which impairs the nucleotide-binding ability of Rheb and inhibits Rheb-mediated mTORC1 activation. This operates downstream of a p38β-PRAK cascade activated by energy starvation, independently of AMPK-mediated TSC2 and Raptor phosphorylation. In vitro kinase assay (PRAK phosphorylating Rheb), site-directed mutagenesis of Ser130, nucleotide binding assay, mTORC1 activity assay, PRAK/p38β depletion experiments Nature cell biology High 21336308
2008 Rheb overexpression induces multiple axon formation in hippocampal neurons via mTOR; Rheb suppression by RNAi blocks axon specification. mTOR acts through 4E-BP1 translation control; downstream of Rheb-mTOR, Rap1B levels are maintained by counteracting Smurf2-mediated degradation. Neuronal overexpression/RNAi in dissociated hippocampal neurons, morphological readout (axon number), rapamycin inhibition, 4E-BP1 mutant expression, Smurf2 RNAi rescue The Journal of biological chemistry Medium 18842593
2008 ATF6α transcription factor induces Rheb expression, which activates mTOR signaling independently of Akt, promoting survival of quiescent/dormant tumor cells. Knockdown of ATF6α or Rheb reverts dormant tumor cell resistance to rapamycin. shRNA knockdown of ATF6α and Rheb, rapamycin treatment, in vivo dormancy model, mTOR activity assays Proceedings of the National Academy of Sciences of the United States of America Medium 18650380
2010 Tsc2–Rheb signaling controls EphA receptor-dependent axon guidance; EphA receptor activation by ephrin-A ligands decreases ERK1/2-mediated inhibition of Tsc2, thereby inactivating the mTOR pathway. Tsc2 deficiency with hyperactive Rheb constitutively activates mTOR and inhibits ephrin-induced growth cone collapse. Tsc2 haploinsufficient mice (retinogeniculate projection analysis), ERK1/2 activity assay in neurons, growth cone collapse assay, mTOR activity assays Nature neuroscience High 20062052
2017 Cryo-EM structure of RHEB-mTORC1 at 3.4 Å shows RHEB binds to mTOR distally from the kinase active site and causes a global conformational change that allosterically realigns active-site residues to accelerate catalysis. Cancer-associated hyperactivating mutations map to elements that maintain the inactive state and biochemically mimic RHEB relieving auto-inhibition. Cryo-EM structure determination (3.0 Å mTORC1; 3.4 Å RHEB-mTORC1), crystal structures of RAPTOR-TOS and mTOR FRB-substrate complexes, in vitro kinase assays, biochemical characterization of cancer mutations Nature High 29236692
2018 Ubiquitination of Rheb by the lysosome-anchored E3 ligase RNF152 promotes Rheb binding to the TSC complex and keeps Rheb inactive. EGF activates AKT-dependent phosphorylation of USP4, causing deubiquitination of Rheb and its release from the TSC complex, enabling mTORC1 activation. Co-immunoprecipitation, ubiquitination assays, RNF152 and USP4 knockdown/overexpression, AKT inhibition, mTORC1 activity assays Cell research Medium 30514904
2015 MCRS1 is required for amino acid-dependent mTORC1 activation by maintaining Rheb at lysosome surfaces; MCRS1 suppression promotes Rheb/TSC2 interaction, renders Rheb inactive, and relocalizes Rheb from lysosomes to recycling endocytic vesicles. siRNA knockdown, inducible Cre/lox MEFs, co-immunoprecipitation (Rheb-TSC2, Rheb-MCRS1), immunofluorescence localization of Rheb Developmental cell Medium 25816988
2015 Rheb inhibits protein synthesis by enhancing phosphorylation of eIF2α through activation of the ER kinase PERK, in a manner independent of mTORC1. Rheb overexpression and knockdown, eIF2α phosphorylation assays, PERK inhibition/knockdown, protein synthesis assays Cell reports Medium 25660019
2013 GTP-bound Rheb interacts with BACE1 (β-secretase) and promotes its degradation through proteasomal and lysosomal pathways, independently of mTOR signaling. Rheb overexpression depletes BACE1 protein and reduces Aβ generation, while Rheb knockdown promotes BACE1 accumulation. Co-immunoprecipitation (GTP-Rheb with BACE1), proteasome and lysosome inhibitor experiments, Rheb overexpression/RNAi, Aβ measurement The Journal of biological chemistry Medium 24368770
2016 Arginine suppresses lysosomal localization of the TSC complex and its interaction with Rheb, thereby relieving allosteric inhibition of Rheb by TSC and enabling maximal mTORC1 activation by growth factors. This mechanism does not involve regulation of mTORC1 lysosomal localization. Lysosomal fractionation, co-immunoprecipitation of TSC2 with Rheb under arginine-replete vs. -depleted conditions, mTORC1 activity assays in multiple cell types including hESC-derived lineages eLife High 26742086
2021 Structural analysis at near-atomic resolution reveals the TSC complex has an arch-shaped 2:2:1 (TSC1:TSC2:TBC1D7) stoichiometry. Structural and biochemical analysis of the TSC2 GAP domain–Rheb interface confirms that the TSC2 asparagine thumb (N1643) stabilizes the γ-phosphate of GTP to accelerate Rheb GTP hydrolysis. Cryo-EM structure of human TSC complex, biochemical GAP activity assays, mutagenesis of catalytic residues Nature communications High 33436626
2021 Rheb is dynamically trafficked to the mitochondrial matrix through its interaction with Tom20 in response to neuronal activity and lactate. Mitochondria-localized Rheb activates pyruvate dehydrogenase (PDH) by physically associating with PDH phosphatase (PDP), enhancing PDP activity and its association with the catalytic E1α-subunit of PDH to reduce PDH phosphorylation and increase acetyl-CoA and ATP production. This function is independent of mTORC1. SC-specific Rheb knockout mice and gain-of-function models, mitochondrial fractionation, co-immunoprecipitation (Rheb-Tom20, Rheb-PDP), PDH activity assay, acetyl-CoA and ATP measurement, rapamycin comparison Developmental cell High 33725483
2021 SC-specific Rheb knockout suppresses pyruvate dehydrogenase (PDH) activity independently of mTORC1 and shifts pyruvate metabolism toward lactate production in Schwann cells, causing age-dependent peripheral axon degeneration. Schwann cell-specific Rheb knockout mice, PDH activity assay, lactate measurement, peripheral nerve function tests Developmental cell High 34619097
2019 ATF6 transcription factor directly transcriptionally induces RHEB expression (confirmed by chromatin immunoprecipitation) in cardiac myocytes, which activates mTORC1 to promote compensatory cardiac hypertrophy. ATF6 cardiac-specific knockout blunts hypertrophy and is rescued by ectopic RHEB. Chromatin immunoprecipitation (ATF6 on RHEB promoter), cardiac-specific ATF6 knockout mice (TAC and exercise models), AAV9-RHEB rescue, mTORC1 activity assays Circulation research High 30582446
2018 A small molecule (NR1) binds Rheb in the switch II domain and selectively blocks mTORC1 signaling (inhibits S6K1 phosphorylation) without inhibiting AKT or ERK. Unlike rapamycin, NR1 does not cause prolonged mTORC2 inhibition. Rheb switch II domain point mutations that impair mTORC1 activation are mimicked by NR1 binding. Small molecule binding assay (NR1 binding to Rheb switch II), S6K1/AKT/ERK phosphorylation assays in cells, in vivo mouse kidney and muscle mTORC1 assay, comparison with rapamycin Nature communications Medium 29416044
2017 Rheb inhibits beiging of white adipose tissue through an mTORC1-independent mechanism involving stabilization of PDE4D5, which degrades cAMP and reduces PKA activity and UCP1 expression. Adipose-specific Rheb knockout increases cAMP, PKA activity, and UCP1; partial, but not complete, rescue by rapamycin confirms the mTORC1-independent component. Adipose-specific Rheb knockout mice, cAMP measurement, PKA activity assay, PDE4D5 protein stability assay, rapamycin treatment comparison, primary adipocyte overexpression Diabetes Medium 28242620
2011 Rheb knockout mice die around midgestation, most likely due to impaired cardiovascular development; Rheb-null embryonic fibroblasts show decreased TORC1 activity, reduced cell size, and impaired proliferation. Rheb heterozygosity extends the lifespan of Tsc1-null embryos, establishing genetic interaction between Tsc1 and Rheb in vivo. Rheb knockout mouse generation, embryonic phenotype analysis, embryonic fibroblast TORC1 activity and cell size assays, Tsc1/Rheb double-mutant epistasis Molecular and cellular biology High 21321084
2019 In Treg cells, Rheb1 and Rheb2 (Rheb GTPases) are central regulators of amino acid-dependent mTORC1 activation; mice with Rheb1/Rheb2-deficient Treg cells develop fatal autoimmune disease with reduced effector Treg accumulation. Rheb1/Rheb2 enforce the eTreg cell suppressive gene signature, whereas Rag GTPases regulate mitochondrial and lysosomal fitness. Conditional Treg-specific Rheb1/Rheb2 double-knockout mice, mTORC1 activity assays, immune phenotyping, gene expression profiling Immunity High 31668641
2010 NMR structure of Rheb-GDP shows the canonical Ras GTPase fold with GDP-dependent dynamics in the switch I and II regions. NMR revealed Ras effector-like binding of activated Rheb to the c-Raf Ras-binding domain (RBD) but with ~1000-fold lower affinity than Ras/RBD, suggesting lack of functional interaction with c-Raf. NMR structure determination of Rheb-GDP, NMR binding assay (Rheb to c-Raf RBD), affinity measurement The Journal of biological chemistry Medium 20685651
2011 Rheb and raptor negatively regulate skeletal myogenic differentiation through suppression of IRS1; knockdown of Rheb enhances myogenic differentiation with increased Akt activation and elevated IRS1 protein levels and reduced IRS1 Ser307 phosphorylation. IRS1 knockdown eliminates the enhancement elicited by Rheb knockdown, placing IRS1 downstream of the Rheb-mTOR/raptor inhibitory pathway in myogenesis. C2C12 myoblast siRNA knockdown and overexpression, myogenic differentiation assays, IRS1/Akt phosphorylation Western blots, epistasis by IRS1 co-knockdown The Journal of biological chemistry Medium 21852229
2019 Brain somatic doublet mutation RHEB p.Y35L increases Rheb GTPλS-binding activity, elevates mTOR/S6 phosphorylation in cells, and when expressed via in utero electroporation in mice causes cytomegalic neurons, dysregulated neuron migration, abnormal EEG, and seizures recapitulating focal cortical dysplasia type II; rapamycin rescues the EEG and seizure phenotype. Whole exome sequencing, GTPλS binding assay, in utero electroporation in mice, S6 phosphorylation assay, EEG recording, rapamycin treatment Experimental & molecular medicine High 31337748

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes & development 1513 12869586
2005 Rheb binds and regulates the mTOR kinase. Current biology : CB 796 15854902
2004 Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Current biology : CB 673 15380067
2003 Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nature cell biology 532 12766776
2017 Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature 443 29236692
2003 Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nature cell biology 434 12766775
2003 Rheb fills a GAP between TSC and TOR. Trends in biochemical sciences 393 14607085
2007 Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science (New York, N.Y.) 321 17991864
2003 Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. The Journal of biological chemistry 311 12842888
2008 ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo. Proceedings of the National Academy of Sciences of the United States of America 297 18650380
2005 Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency. The Journal of biological chemistry 281 15878852
2006 Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase. Oncogene 254 17041622
1994 rheb, a growth factor- and synaptic activity-regulated gene, encodes a novel Ras-related protein. The Journal of biological chemistry 240 8206940
2004 Follicle-stimulating hormone activation of hypoxia-inducible factor-1 by the phosphatidylinositol 3-kinase/AKT/Ras homolog enriched in brain (Rheb)/mammalian target of rapamycin (mTOR) pathway is necessary for induction of select protein markers of follicular differentiation. The Journal of biological chemistry 221 14982927
2008 Signalling through RHEB-1 mediates intermittent fasting-induced longevity in C. elegans. Nature 215 19079239
2004 Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity. Molecular and cellular biology 208 15340059
2010 Tsc2-Rheb signaling regulates EphA-mediated axon guidance. Nature neuroscience 198 20062052
2004 The Rheb family of GTP-binding proteins. Cellular signalling 160 15240005
2009 Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein. The Journal of biological chemistry 158 19299511
2016 Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity. eLife 152 26742086
2006 TSC1/TSC2 and Rheb have different effects on TORC1 and TORC2 activity. Proceedings of the National Academy of Sciences of the United States of America 149 16627617
2005 The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity. The Journal of biological chemistry 147 16006564
1997 The Ras-related protein Rheb is farnesylated and antagonizes Ras signaling and transformation. The Journal of biological chemistry 146 9099708
2009 The Rheb-mTOR pathway is upregulated in reactive astrocytes of the injured spinal cord. The Journal of neuroscience : the official journal of the Society for Neuroscience 143 19176818
2008 Phospholipase D1 is an effector of Rheb in the mTOR pathway. Proceedings of the National Academy of Sciences of the United States of America 143 18550814
2003 Drosophila Rheb GTPase is required for cell cycle progression and cell growth. Journal of cell science 130 12893813
2019 Amino Acids License Kinase mTORC1 Activity and Treg Cell Function via Small G Proteins Rag and Rheb. Immunity 121 31668641
2002 Rheb is in a high activation state and inhibits B-Raf kinase in mammalian cells. Oncogene 118 12214276
2011 Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy-depletion-induced suppression of mTORC1. Nature cell biology 114 21336308
2018 Ubiquitination of Rheb governs growth factor-induced mTORC1 activation. Cell research 107 30514904
2006 Fission yeast Tor2 links nitrogen signals to cell proliferation and acts downstream of the Rheb GTPase. Genes to cells : devoted to molecular & cellular mechanisms 103 17121544
2019 ATF6 Regulates Cardiac Hypertrophy by Transcriptional Induction of the mTORC1 Activator, Rheb. Circulation research 102 30582446
2000 The Saccharomyces cerevisiae Rheb G-protein is involved in regulating canavanine resistance and arginine uptake. The Journal of biological chemistry 100 10753927
2014 Ral and Rheb GTPase activating proteins integrate mTOR and GTPase signaling in aging, autophagy, and tumor cell invasion. Molecular cell 99 24389102
2008 Tumorigenic activity and therapeutic inhibition of Rheb GTPase. Genes & development 97 18708578
2021 Structural insights into TSC complex assembly and GAP activity on Rheb. Nature communications 94 33436626
2003 Identification of dominant negative mutants of Rheb GTPase and their use to implicate the involvement of human Rheb in the activation of p70S6K. The Journal of biological chemistry 94 12869548
2021 Rheb-regulated mitochondrial pyruvate metabolism of Schwann cells linked to axon stability. Developmental cell 91 34619097
2005 Analysis of mTOR signaling by the small G-proteins, Rheb and RhebL1. FEBS letters 85 16098514
2005 Differential membrane localization of ERas and Rheb, two Ras-related proteins involved in the phosphatidylinositol 3-kinase/mTOR pathway. The Journal of biological chemistry 83 16046393
2009 Rheb controls misfolded protein metabolism by inhibiting aggresome formation and autophagy. Proceedings of the National Academy of Sciences of the United States of America 82 19458266
2009 Differential requirement of CAAX-mediated posttranslational processing for Rheb localization and signaling. Oncogene 82 19838215
2004 Regulation of B-Raf kinase activity by tuberin and Rheb is mammalian target of rapamycin (mTOR)-independent. The Journal of biological chemistry 81 15150271
2019 Long noncoding RNA BFAL1 mediates enterotoxigenic Bacteroides fragilis-related carcinogenesis in colorectal cancer via the RHEB/mTOR pathway. Cell death & disease 79 31515468
2013 Rheb/mTORC1 signaling promotes kidney fibroblast activation and fibrosis. Journal of the American Society of Nephrology : JASN 77 23661807
2011 Neurofibromatosis-1 regulates mTOR-mediated astrocyte growth and glioma formation in a TSC/Rheb-independent manner. Proceedings of the National Academy of Sciences of the United States of America 76 21896734
2014 PDK4 protein promotes tumorigenesis through activation of cAMP-response element-binding protein (CREB)-Ras homolog enriched in brain (RHEB)-mTORC1 signaling cascade. The Journal of biological chemistry 75 25164809
2014 Defective mitophagy driven by dysregulation of rheb and KIF5B contributes to mitochondrial reactive oxygen species (ROS)-induced nod-like receptor 3 (NLRP3) dependent proinflammatory response and aggravates lipotoxicity. Redox biology 74 25462067
2011 Non-canonical functions of the tuberous sclerosis complex-Rheb signalling axis. EMBO molecular medicine 73 21412983
2018 A small molecule inhibitor of Rheb selectively targets mTORC1 signaling. Nature communications 72 29416044
2010 Mammalian target of rapamycin activator RHEB is frequently overexpressed in human carcinomas and is critical and sufficient for skin epithelial carcinogenesis. Cancer research 72 20388784
1997 Rheb interacts with Raf-1 kinase and may function to integrate growth factor- and protein kinase A-dependent signals. Molecular and cellular biology 71 9001246
2013 Rheb and Rags come together at the lysosome to activate mTORC1. Biochemical Society transactions 68 23863162
2006 Rheb inhibits C-raf activity and B-raf/C-raf heterodimerization. The Journal of biological chemistry 66 16803888
2015 MCRS1 binds and couples Rheb to amino acid-dependent mTORC1 activation. Developmental cell 63 25816988
2011 Rheb is essential for murine development. Molecular and cellular biology 62 21321084
2015 Point mutations of the mTOR-RHEB pathway in renal cell carcinoma. Oncotarget 61 26255626
2014 Recent progress in the study of the Rheb family GTPases. Cellular signalling 60 24863881
2008 Rheb and mTOR regulate neuronal polarity through Rap1B. The Journal of biological chemistry 59 18842593
2009 Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor. Biochemical Society transactions 57 19143636
2008 Constitutively active Rheb induces oncogenic transformation. Oncogene 55 18521078
2013 mTOR direct interactions with Rheb-GTPase and raptor: sub-cellular localization using fluorescence lifetime imaging. BMC cell biology 54 23311891
2009 The evolutionarily conserved TSC/Rheb pathway activates Notch in tuberous sclerosis complex and Drosophila external sensory organ development. The Journal of clinical investigation 53 20038815
2019 A brain somatic RHEB doublet mutation causes focal cortical dysplasia type II. Experimental & molecular medicine 50 31337748
2010 Ras homolog enriched in brain (Rheb) enhances apoptotic signaling. The Journal of biological chemistry 48 20685651
2010 Hydrogen peroxide induces Beclin 1-independent autophagic cell death by suppressing the mTOR pathway via promoting the ubiquitination and degradation of Rheb in GSH-depleted RAW 264.7 cells. Free radical research 47 21067284
2021 Rheb mediates neuronal-activity-induced mitochondrial energetics through mTORC1-independent PDH activation. Developmental cell 44 33725483
2015 Rheb Inhibits Protein Synthesis by Activating the PERK-eIF2α Signaling Cascade. Cell reports 44 25660019
2021 RHEB/mTOR hyperactivity causes cortical malformations and epileptic seizures through increased axonal connectivity. PLoS biology 43 34038402
2013 Rheb GTPase regulates β-secretase levels and amyloid β generation. The Journal of biological chemistry 43 24368770
2010 Impaired ATF6α processing, decreased Rheb and neuronal cell cycle re-entry in Huntington's disease. Neurobiology of disease 39 20732420
2009 Reassessment of the role of FKBP38 in the Rheb/mTORC1 pathway. FEBS letters 39 19222999
2010 Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis. Oncogene 38 20818424
2016 14-3-3 proteins regulate Tctp-Rheb interaction for organ growth in Drosophila. Nature communications 37 27151460
2013 Rheb and mammalian target of rapamycin in mitochondrial homoeostasis. Open biology 37 24352740
2004 The mTOR/S6K signalling pathway: the role of the TSC1/2 tumour suppressor complex and the proto-oncogene Rheb. Novartis Foundation symposium 37 15562827
2007 Rheb-TOR signaling promotes protein synthesis, but not glucose or amino acid import, in Drosophila. BMC biology 36 17371599
2012 Rag GTPases and AMPK/TSC2/Rheb mediate the differential regulation of mTORC1 signaling in response to alcohol and leucine. American journal of physiology. Cell physiology 35 22442136
2022 Quercetin mediates TSC2-RHEB-mTOR pathway to regulate chondrocytes autophagy in knee osteoarthritis. Gene 34 35093450
2021 Tetrandrine Modulates Rheb-mTOR Signaling-Mediated Selective Autophagy and Protects Pulmonary Fibrosis. Frontiers in pharmacology 34 34880752
2010 Rheb G-Proteins and the Activation of mTORC1. The Enzymes 34 25429186
2015 p53 Deletion or Hotspot Mutations Enhance mTORC1 Activity by Altering Lysosomal Dynamics of TSC2 and Rheb. Molecular cancer research : MCR 33 26385560
2013 TSC1/2 regulates intestinal stem cell maintenance and lineage differentiation through Rheb-TORC1-S6K but independently of nutritional status or Notch regulation. Journal of cell science 33 23843608
2022 miR-199a-3p/5p regulate tumorgenesis via targeting Rheb in non-small cell lung cancer. International journal of biological sciences 32 35844793
2015 Rheb signaling and tumorigenesis: mTORC1 and new horizons. International journal of cancer 32 26234902
2011 Raptor and Rheb negatively regulate skeletal myogenesis through suppression of insulin receptor substrate 1 (IRS1). The Journal of biological chemistry 32 21852229
2010 Lovastatin induces VSMC differentiation through inhibition of Rheb and mTOR. American journal of physiology. Cell physiology 32 20375271
2020 Coordination of Rheb lysosomal membrane interactions with mTORC1 activation. F1000Research 31 32518628
2008 Characterization of the Rheb-mTOR signaling pathway in mammalian cells: constitutive active mutants of Rheb and mTOR. Methods in enzymology 31 18413257
2007 The TSC/Rheb/TOR signaling pathway in fission yeast and mammalian cells: temperature sensitive and constitutive active mutants of TOR. Cell cycle (Georgetown, Tex.) 31 17637564
2005 Akt-dependent cell size regulation by the adhesion molecule on glia occurs independently of phosphatidylinositol 3-kinase and Rheb signaling. Molecular and cellular biology 31 15798201
2019 Silencing of RHEB inhibits cell proliferation and promotes apoptosis in colorectal cancer cells via inhibition of the mTOR signaling pathway. Journal of cellular physiology 30 31332784
2017 Rheb Inhibits Beiging of White Adipose Tissue via PDE4D5-Dependent Downregulation of the cAMP-PKA Signaling Pathway. Diabetes 30 28242620
2024 The mTOR pathway genes MTOR, Rheb, Depdc5, Pten, and Tsc1 have convergent and divergent impacts on cortical neuron development and function. eLife 29 38411613
2019 Cryo-EM insight into the structure of MTOR complex 1 and its interactions with Rheb and substrates. F1000Research 29 30647914
2010 Regulation of androgen receptor transactivity and mTOR-S6 kinase pathway by Rheb in prostate cancer cell proliferation. The Prostate 29 20127734
2019 ReishiMax inhibits mTORC1/2 by activating AMPK and inhibiting IGFR/PI3K/Rheb in tumor cells. Signal transduction and targeted therapy 27 31637001
2015 Rheb promotes cancer cell survival through p27Kip1-dependent activation of autophagy. Molecular carcinogenesis 27 25594310
2013 Farnesyltransferase inhibitor tipifarnib inhibits Rheb prenylation and stabilizes Bax in acute myelogenous leukemia cells. Haematologica 27 23996484
2016 VPS34 regulates TSC1/TSC2 heterodimer to mediate RheB and mTORC1/S6K1 activation and cellular transformation. Oncotarget 25 27409169

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