Rheb (Ras homolog enriched in brain; CG1081) is the Drosophila member of the Rheb family of Ras-superfamily small GTPases. It is C-terminally farnesylated (CaaX box) and associates with endomembranes, including the Golgi apparatus, where its recruitment depends on GOLPH3/sauron. GTP-loaded Rheb is the direct upstream activator of the TOR kinase complex TORC1; its activity is restrained by the Tsc1/Tsc2 GTPase-activating protein complex, which relays insulin/PI3K-Akt, PDGF/VEGF-receptor and nutrient inputs, and Tctp has been reported to promote its GTP loading. Through TORC1 and its effectors (S6K, 4E-BP, Atg1) Rheb drives protein synthesis, ribosome biogenesis and cell growth, and represses autophagy. Loss of Rheb arrests larval growth and reduces cell size and G1-S progression, whereas overexpression enlarges cells and tissues, enlarges neuromuscular junctions and causes TOR-dependent photoreceptor axon misrouting. TORC2 output is reduced by Rheb, most likely through TORC1-S6K feedback.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000082 G1/S transition of mitotic cell cycle | IMP PMID:12893813 Drosophila Rheb GTPase is required for cell cycle progressio... | KEEP AS NON CORE | Summary: Inhibition of dRheb arrests cultured cells in G1. Reason: The G1 arrest is most parsimoniously a consequence of reduced cell growth via TOR (as the authors propose), so this is an indirect effect on the cell cycle. Supporting Evidence: PMID:12893813 Inhibition of dRheb activity in cultured cells results in their arrest in G1 and a reduction in size |
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt SubCell mapping (Golgi apparatus membrane), itself transferred from human RHEB. Reason: Drosophila Rheb localises to Golgi stacks of primary spermatocytes, dependent on dGOLPH3 (sau), so the ISS/IEA transfer from human RHEB is now backed by direct fly data. As a farnesylated CaaX protein Rheb is on the cytoplasmic face of the membrane. Supporting Evidence: PMID:36435842 we observed that Rheb localized to Golgi stacks of primary spermatocytes, as assessed by co-staining with the Golgi marker Lava lamp file:DROME/Rheb/Rheb-uniprot.txt Golgi apparatus membrane |
| GO:0000139 Golgi membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from human RHEB Golgi localization. Reason: Drosophila Rheb localises to Golgi stacks of primary spermatocytes, dependent on dGOLPH3 (sau), so the ISS/IEA transfer from human RHEB is now backed by direct fly data. As a farnesylated CaaX protein Rheb is on the cytoplasmic face of the membrane. Supporting Evidence: PMID:36435842 we observed that Rheb localized to Golgi stacks of primary spermatocytes, as assessed by co-staining with the Golgi marker Lava lamp PMID:36435842 dGOLPH3 depletion decreased the amount of Rheb protein localized to the Golgi apparatus |
| GO:0002052 positive regulation of neuroblast proliferation | IGI PMID:30245208 Hsp83/Hsp90 Physically Associates with Insulin Receptor to P... | KEEP AS NON CORE | Summary: Hsp83 promotes NSC reactivation upstream of InR/PI3K/Akt; Rheb overexpression used in genetic interaction (abstract-only cache). Reason: Rheb-TOR activity promotes neural stem cell exit from quiescence; context-specific downstream role of TORC1 activation. Supporting Evidence: PMID:30245208 In the Drosophila brain, insulin receptor (InR)/phosphatidylinositol 3-kinase (PI3K)/Akt pathway triggers NSC reactivation PMID:31167138 Stimulation of target of rapamycin (TOR) signaling by Rheb overexpression activates the InR/PI3K/Akt cascade, promoting premature NSC exit from quiescence |
| GO:0002052 positive regulation of neuroblast proliferation | IMP PMID:31167138 STRIPAK Members Orchestrate Hippo and Insulin Receptor Signa... | KEEP AS NON CORE | Summary: Rheb expression in NSCs rescues reactivation in mob4 mutants. Reason: Rheb-TOR activity promotes neural stem cell exit from quiescence; context-specific downstream role of TORC1 activation. Supporting Evidence: PMID:31167138 Stimulation of target of rapamycin (TOR) signaling by Rheb overexpression activates the InR/PI3K/Akt cascade, promoting premature NSC exit from quiescence |
| GO:0003924 GTPase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the Ras/Rheb PANTHER family node; GTPase activity is ancestral to the family and Rheb retains the G-box motifs. Reason: Rheb is a Ras-superfamily small GTPase whose GTP-bound form activates TORC1 and whose GTP hydrolysis is stimulated by the Tsc1/Tsc2 GAP; intrinsic GTPase activity is the switch mechanism. Rows on this term from IBA, IEA, ISS and IDA are consistent. Supporting Evidence: file:DROME/Rheb/Rheb-uniprot.txt Belongs to the small GTPase superfamily. Rheb family. file:DROME/Rheb/Rheb-uniprot.txt Binds GTP and exhibits intrinsic GTPase activity |
| GO:0003924 GTPase activity | IDA PMID:12893813 Drosophila Rheb GTPase is required for cell cycle progressio... | ACCEPT | Summary: IDA from Patel et al. 2003 (abstract-only cache); the paper characterised dRheb as a Ras-superfamily G-protein required for growth. Reason: Rheb is a Ras-superfamily small GTPase whose GTP-bound form activates TORC1 and whose GTP hydrolysis is stimulated by the Tsc1/Tsc2 GAP; intrinsic GTPase activity is the switch mechanism. Rows on this term from IBA, IEA, ISS and IDA are consistent. The cached abstract does not describe the biochemical assay; deferring to the FlyBase curator who read the full text. Supporting Evidence: PMID:12893813 a novel, highly conserved member of the Ras superfamily of G-proteins file:DROME/Rheb/Rheb-uniprot.txt Binds GTP and exhibits intrinsic GTPase activity |
| GO:0003924 GTPase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro small GTPase signature (IPR001806) mapping to GTPase activity. Reason: Rheb is a Ras-superfamily small GTPase whose GTP-bound form activates TORC1 and whose GTP hydrolysis is stimulated by the Tsc1/Tsc2 GAP; intrinsic GTPase activity is the switch mechanism. Rows on this term from IBA, IEA, ISS and IDA are consistent. Supporting Evidence: file:DROME/Rheb/Rheb-uniprot.txt Belongs to the small GTPase superfamily. Rheb family. file:DROME/Rheb/Rheb-uniprot.txt Binds GTP and exhibits intrinsic GTPase activity |
| GO:0003924 GTPase activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from human RHEB (Q15382), whose GTPase activity is well characterised. Reason: Rheb is a Ras-superfamily small GTPase whose GTP-bound form activates TORC1 and whose GTP hydrolysis is stimulated by the Tsc1/Tsc2 GAP; intrinsic GTPase activity is the switch mechanism. Rows on this term from IBA, IEA, ISS and IDA are consistent. Supporting Evidence: file:DROME/Rheb/Rheb-uniprot.txt Binds GTP and exhibits intrinsic GTPase activity Reactome:R-DME-110491 DRheb (a small GTPase called Ras homologue enriched in brain) is a target for DTSC2 GAP activity |
| GO:0005515 protein binding | IPI PMID:17301792 Drosophila TCTP is essential for growth and proliferation th... | REMOVE | Summary: Rheb binds Tctp (Q9VGS2); TCTP was reported to act as a Rheb GEF. Reason: Bare protein binding is uninformative and is removed under the protein-binding policy. The interaction itself is credible and is recorded in the reason/notes; the functional consequence (Rheb as the GTPase whose activity or localization the partner regulates) is captured by the TORC1-activation and Golgi terms. Supporting Evidence: PMID:17301792 dTCTP directly associates with dRheb and displays guanine nucleotide exchange activity with it in vivo and in vitro |
| GO:0005515 protein binding | IPI PMID:31666534 The neuronal ceroid lipofuscinosis protein Cln7 functions in... | REMOVE | Summary: Rheb co-immunoprecipitates with Cln7 (Q9VS51) in S2 cells. Reason: Bare protein binding is uninformative and is removed under the protein-binding policy. The interaction itself is credible and is recorded in the reason/notes; the functional consequence (Rheb as the GTPase whose activity or localization the partner regulates) is captured by the TORC1-activation and Golgi terms. Supporting Evidence: PMID:31666534 We expressed epitope-tagged forms of Rheb and Cln7 in Drosophila S2 cells and were able to co-immunoprecipiate the two proteins |
| GO:0005515 protein binding | IPI PMID:36435842 GOLPH3 protein controls organ growth by interacting with TOR... | REMOVE | Summary: GST-Tctp pulls down Rheb; dGOLPH3 promotes the Tctp-Rheb association. Reason: Bare protein binding is uninformative and is removed under the protein-binding policy. The interaction itself is credible and is recorded in the reason/notes; the functional consequence (Rheb as the GTPase whose activity or localization the partner regulates) is captured by the TORC1-activation and Golgi terms. Supporting Evidence: PMID:36435842 GST-Tctp also precipitated Rheb protein |
| GO:0005515 protein binding | IPI PMID:36435842 GOLPH3 protein controls organ growth by interacting with TOR... | REMOVE | Summary: Rheb co-precipitates with dGOLPH3 (sau, Q9VQ93), which recruits Rheb to the Golgi. Reason: Bare protein binding is uninformative and is removed under the protein-binding policy. The interaction itself is credible and is recorded in the reason/notes; the functional consequence (Rheb as the GTPase whose activity or localization the partner regulates) is captured by the TORC1-activation and Golgi terms. Supporting Evidence: PMID:36435842 Remarkably, Rheb co-precipitates with GFP-dGOLPH3 but not with GFP-dGOLPH3K167A-R170L |
| GO:0005525 GTP binding | IEA GO_REF:0000002 | ACCEPT | Summary: GTP binding from InterPro small GTPase signatures; UniProt annotates conserved G1-G5 GTP-binding residues by similarity to human RHEB. Reason: GTP binding is intrinsic to the Rheb switch; GTP-bound Rheb is the active TORC1-stimulating form. Supporting Evidence: file:DROME/Rheb/Rheb-uniprot.txt Binds GTP and exhibits intrinsic GTPase activity file:DROME/Rheb/Rheb-uniprot.txt Belongs to the small GTPase superfamily. Rheb family. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt SubCell mapping (ER membrane) transferred from human RHEB. Reason: ER membrane localization is transferred from human RHEB, which is reported on ER and Golgi endomembranes via its farnesyl anchor. No Drosophila-specific evidence; the transfer is plausible for a CaaX GTPase but where TORC1 activation happens (Golgi/lysosome) is the functionally relevant site, so this is kept as non-core. Supporting Evidence: file:DROME/Rheb/Rheb-uniprot.txt Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from human RHEB ER localization. Reason: ER membrane localization is transferred from human RHEB, which is reported on ER and Golgi endomembranes via its farnesyl anchor. No Drosophila-specific evidence; the transfer is plausible for a CaaX GTPase but where TORC1 activation happens (Golgi/lysosome) is the functionally relevant site, so this is kept as non-core. Supporting Evidence: file:DROME/Rheb/Rheb-uniprot.txt Endoplasmic reticulum membrane |
| GO:0005829 cytosol | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt SubCell mapping (cytosol), transferred from human RHEB. Reason: A cytosolic pool of a prenylated small GTPase (e.g. bound to chaperones or before membrane insertion) is plausible, but the active pool is membrane-bound; peripheral to function. Supporting Evidence: file:DROME/Rheb/Rheb-uniprot.txt Cytoplasm, cytosol |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA (is_active_in plasma membrane) from the Ras/Rheb family node PTN000631348, seeded mostly by Ras/Ral/Rap GTPases. Reason: Plasma membrane is a Ras-family property (H-/K-/N-Ras, Ral, Rap) propagated from the broad Ras/Rheb node. Rheb lacks the second palmitoylation/polybasic signal that targets Ras to the plasma membrane; fly and human Rheb are reported on Golgi/ER and (in mammals) lysosomal membranes, and no Drosophila evidence places Rheb at the plasma membrane. Reactome places DRheb at the plasma membrane only as a modelling convention for its inferred GEF/GAP reactions. Over-annotation, not removed because a minor PM pool cannot be excluded. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN000631348 SUPPORTS SOURCE BUT NOT TARGET Broad Ras/Ral/Rap/Rheb node; the plasma membrane seeds are Ras, Ral and Rap GTPases with plasma-membrane targeting signals that Rheb lacks. Rheb-clade evidence places it on Golgi/ER (and lysosomal) endomembranes. Supporting Evidence: PMID:36435842 we observed that Rheb localized to Golgi stacks of primary spermatocytes, as assessed by co-staining with the Golgi marker Lava lamp file:DROME/Rheb/Rheb-uniprot.txt Golgi apparatus membrane file:DROME/Rheb/Rheb-deep-research-manual.md No Drosophila evidence for plasma membrane localization was found in cached literature. |
| GO:0005886 plasma membrane | TAS Reactome:R-DME-110491 | MARK AS OVER ANNOTATED | Summary: Reactome reaction (Reactome:R-DME-110491) placing DRheb at the plasma membrane; the Drosophila reactions are inferred by analogy, not observed. Reason: Plasma membrane is a Ras-family property (H-/K-/N-Ras, Ral, Rap) propagated from the broad Ras/Rheb node. Rheb lacks the second palmitoylation/polybasic signal that targets Ras to the plasma membrane; fly and human Rheb are reported on Golgi/ER and (in mammals) lysosomal membranes, and no Drosophila evidence places Rheb at the plasma membrane. Reactome places DRheb at the plasma membrane only as a modelling convention for its inferred GEF/GAP reactions. Over-annotation, not removed because a minor PM pool cannot be excluded. Supporting Evidence: PMID:36435842 we observed that Rheb localized to Golgi stacks of primary spermatocytes, as assessed by co-staining with the Golgi marker Lava lamp Reactome:R-DME-110491 DRheb (a small GTPase called Ras homologue enriched in brain) is a target for DTSC2 GAP activity |
| GO:0005886 plasma membrane | TAS Reactome:R-DME-165127 | MARK AS OVER ANNOTATED | Summary: Reactome reaction (Reactome:R-DME-165127) placing DRheb at the plasma membrane; the Drosophila reactions are inferred by analogy, not observed. Reason: Plasma membrane is a Ras-family property (H-/K-/N-Ras, Ral, Rap) propagated from the broad Ras/Rheb node. Rheb lacks the second palmitoylation/polybasic signal that targets Ras to the plasma membrane; fly and human Rheb are reported on Golgi/ER and (in mammals) lysosomal membranes, and no Drosophila evidence places Rheb at the plasma membrane. Reactome places DRheb at the plasma membrane only as a modelling convention for its inferred GEF/GAP reactions. Over-annotation, not removed because a minor PM pool cannot be excluded. Supporting Evidence: PMID:36435842 we observed that Rheb localized to Golgi stacks of primary spermatocytes, as assessed by co-staining with the Golgi marker Lava lamp Reactome:R-DME-110491 DRheb (a small GTPase called Ras homologue enriched in brain) is a target for DTSC2 GAP activity |
| GO:0005886 plasma membrane | TAS Reactome:R-DME-165129 | MARK AS OVER ANNOTATED | Summary: Reactome reaction (Reactome:R-DME-165129) placing DRheb at the plasma membrane; the Drosophila reactions are inferred by analogy, not observed. Reason: Plasma membrane is a Ras-family property (H-/K-/N-Ras, Ral, Rap) propagated from the broad Ras/Rheb node. Rheb lacks the second palmitoylation/polybasic signal that targets Ras to the plasma membrane; fly and human Rheb are reported on Golgi/ER and (in mammals) lysosomal membranes, and no Drosophila evidence places Rheb at the plasma membrane. Reactome places DRheb at the plasma membrane only as a modelling convention for its inferred GEF/GAP reactions. Over-annotation, not removed because a minor PM pool cannot be excluded. Supporting Evidence: PMID:36435842 we observed that Rheb localized to Golgi stacks of primary spermatocytes, as assessed by co-staining with the Golgi marker Lava lamp Reactome:R-DME-110491 DRheb (a small GTPase called Ras homologue enriched in brain) is a target for DTSC2 GAP activity |
| GO:0005886 plasma membrane | TAS Reactome:R-DME-165131 | MARK AS OVER ANNOTATED | Summary: Reactome reaction (Reactome:R-DME-165131) placing DRheb at the plasma membrane; the Drosophila reactions are inferred by analogy, not observed. Reason: Plasma membrane is a Ras-family property (H-/K-/N-Ras, Ral, Rap) propagated from the broad Ras/Rheb node. Rheb lacks the second palmitoylation/polybasic signal that targets Ras to the plasma membrane; fly and human Rheb are reported on Golgi/ER and (in mammals) lysosomal membranes, and no Drosophila evidence places Rheb at the plasma membrane. Reactome places DRheb at the plasma membrane only as a modelling convention for its inferred GEF/GAP reactions. Over-annotation, not removed because a minor PM pool cannot be excluded. Supporting Evidence: PMID:36435842 we observed that Rheb localized to Golgi stacks of primary spermatocytes, as assessed by co-staining with the Golgi marker Lava lamp Reactome:R-DME-110491 DRheb (a small GTPase called Ras homologue enriched in brain) is a target for DTSC2 GAP activity |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | MODIFY | Summary: InterPro mapping to signal transduction. Reason: Correct but general; the gene already carries the more specific small GTPase-mediated signal transduction (IBA) and positive regulation of TORC1 signaling. Proposed replacements: small GTPase-mediated signal transduction Supporting Evidence: PMID:12766776 Genetic and biochemical tests indicate that Rheb functions in the insulin signalling pathway downstream of Tsc1-Tsc2 and upstream of TOR |
| GO:0007264 small GTPase-mediated signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the Ras/Rheb family node. Reason: Rheb is the small GTPase that transduces Tsc1/Tsc2 (and upstream insulin/PVR) signals to TORC1; small GTPase-mediated signal transduction is an accurate description of its role. Supporting Evidence: PMID:12766776 Genetic and biochemical tests indicate that Rheb functions in the insulin signalling pathway downstream of Tsc1-Tsc2 and upstream of TOR Reactome:R-DME-110491 DRheb (a small GTPase called Ras homologue enriched in brain) is a target for DTSC2 GAP activity |
| GO:0007430 terminal branching, open tracheal system | IMP PMID:25977367 Compensatory branching morphogenesis of stalk cells in the D... | KEEP AS NON CORE | Summary: mTOR pathway mutants phenocopy vATPase (okg/cnj) terminal cell defects (abstract-only cache). Reason: Tissue-specific developmental consequence of TOR pathway loss in tracheal terminal cells; indirect. Supporting Evidence: PMID:25977367 Consistent with recent reports that the mTOR and vATPase pathways intersect, we found that mTOR pathway mutants phenocopied okg and cnj |
| GO:0008286 insulin receptor signaling pathway | IMP PMID:11782951 Regulation of cell size in growth, development and human dis... | KEEP AS NON CORE | Summary: IMP attributed to a 2002 Bioessays review on PI3K/PKB/S6K; the abstract does not mention Rheb. Reason: Rheb is a component of the insulin/TOR network downstream of Akt-Tsc1/Tsc2 and upstream of TOR. It is a legitimate participant in insulin receptor signaling, but its defining role is the TORC1 branch, so this is kept as non-core. The cited reference is a review whose abstract does not mention Rheb, an unusual source for an IMP; the claim is kept on the strength of PMID:12766776 and the reference is flagged for FlyBase to check. Supporting Evidence: PMID:12766776 Genetic and biochemical tests indicate that Rheb functions in the insulin signalling pathway downstream of Tsc1-Tsc2 and upstream of TOR |
| GO:0008286 insulin receptor signaling pathway | IMP PMID:12766776 Rheb promotes cell growth as a component of the insulin/TOR ... | KEEP AS NON CORE | Summary: Genetic and biochemical tests place Rheb in the insulin pathway downstream of Tsc1-Tsc2 and upstream of TOR. Reason: Rheb is a component of the insulin/TOR network downstream of Akt-Tsc1/Tsc2 and upstream of TOR. It is a legitimate participant in insulin receptor signaling, but its defining role is the TORC1 branch, so this is kept as non-core. Supporting Evidence: PMID:12766776 Genetic and biochemical tests indicate that Rheb functions in the insulin signalling pathway downstream of Tsc1-Tsc2 and upstream of TOR |
| GO:0008286 insulin receptor signaling pathway | IMP PMID:16627617 TSC1/TSC2 and Rheb have different effects on TORC1 and TORC2... | KEEP AS NON CORE | Summary: S2-cell analysis of Rheb effects on TORC1/TORC2 downstream of insulin signaling. Reason: Rheb is a component of the insulin/TOR network downstream of Akt-Tsc1/Tsc2 and upstream of TOR. It is a legitimate participant in insulin receptor signaling, but its defining role is the TORC1 branch, so this is kept as non-core. Supporting Evidence: PMID:16627617 The Ras homology enriched in brain (Rheb) small GTPase is known to be a key upstream activator of TORC1 |
| GO:0010507 negative regulation of autophagy | IMP PMID:24265594 Role of autophagy in glycogen breakdown and its relevance to... | MODIFY | Summary: Rheb overexpression in muscle blocks GFP-Atg8 autophagosome formation. Reason: TORC1 represses autophagy initiation via Atg1; Rheb overexpression blocks starvation-induced autophagy. Valid indirect regulatory effect through TORC1, non-core. The assay (GFP-Atg8 autophagosomes) measures macroautophagy, so the more specific negative regulation of macroautophagy, already carried by this gene, is preferred. Proposed replacements: negative regulation of macroautophagy Supporting Evidence: PMID:24265594 the localization of GFPβAtg8 to autophagosomes in starved/CQ-treated muscles was completely blocked by Rheb overexpression compared to controls |
| GO:0012505 endomembrane system | IEA GO_REF:0000044 | MODIFY | Summary: UniProt SubCell mapping (endomembrane system). Reason: Correct but general: the evidence (direct fly Golgi data and human RHEB transfer) supports the specific endomembranes Golgi membrane and ER membrane, both already carried by this gene. Proposed replacements: Golgi membrane endoplasmic reticulum membrane Supporting Evidence: PMID:36435842 we observed that Rheb localized to Golgi stacks of primary spermatocytes, as assessed by co-staining with the Golgi marker Lava lamp file:DROME/Rheb/Rheb-uniprot.txt Endoplasmic reticulum membrane |
| GO:0012505 endomembrane system | ISS GO_REF:0000024 | MODIFY | Summary: ISS from human RHEB (endomembrane system). Reason: Correct but general: the evidence (direct fly Golgi data and human RHEB transfer) supports the specific endomembranes Golgi membrane and ER membrane, both already carried by this gene. Proposed replacements: Golgi membrane endoplasmic reticulum membrane Supporting Evidence: PMID:36435842 we observed that Rheb localized to Golgi stacks of primary spermatocytes, as assessed by co-staining with the Golgi marker Lava lamp file:DROME/Rheb/Rheb-uniprot.txt Endoplasmic reticulum membrane |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: InterPro Ras-type small GTPase signature mapped to membrane. Reason: Correct but general; Rheb is a farnesylated GTPase on endomembranes, specifically Golgi membrane (direct fly data) and ER membrane (by similarity), both already annotated. Proposed replacements: Golgi membrane endoplasmic reticulum membrane Supporting Evidence: PMID:36435842 we observed that Rheb localized to Golgi stacks of primary spermatocytes, as assessed by co-staining with the Golgi marker Lava lamp file:DROME/Rheb/Rheb-uniprot.txt Endoplasmic reticulum membrane |
| GO:0016239 positive regulation of macroautophagy | IMP PMID:22952930 Advantages and limitations of different p62-based assays for... | REMOVE | Summary: p62 aggregation assay; Rheb overexpression increased p62 dot number (not statistically significant). Reason: The sign is reversed: increased p62 dots indicate reduced autophagic degradation, i.e. Rheb (via TORC1) inhibits macroautophagy, as PMID:18474623 and PMID:24265594 show. The full text reports the Rheb effect in this paper as not statistically significant, so the row cannot be repointed to the corrected sign either. Negative regulation of macroautophagy (GO:0016242) is already annotated from PMID:18474623, so removing this row loses nothing. Supporting Evidence: PMID:22952930 Enhancing TOR signaling by overexpression of its activator Rheb or knockdown of the Rheb inhibitor Tsc2 also increased p62 dot number, although in case of Rheb the phenotypes were so variable that the change was not statistically significant PMID:18474623 In clones of cells mutant for Tsc2 or overexpressing Rheb, both of which result in constitutive TOR activation, formation of GFP-2xFYVE cytoplasmic punctae in response to starvation was greatly diminished PMID:24265594 the localization of GFPβAtg8 to autophagosomes in starved/CQ-treated muscles was completely blocked by Rheb overexpression compared to controls |
| GO:0016242 negative regulation of macroautophagy | IMP PMID:18474623 The class III PI(3)K Vps34 promotes autophagy and endocytosi... | KEEP AS NON CORE | Summary: Rheb overexpression diminishes starvation-induced GFP-2xFYVE punctae in fat body clones. Reason: TORC1 represses autophagy initiation via Atg1; Rheb overexpression blocks starvation-induced autophagy. Valid indirect regulatory effect through TORC1, non-core. Supporting Evidence: PMID:18474623 In clones of cells mutant for Tsc2 or overexpressing Rheb, both of which result in constitutive TOR activation, formation of GFP-2xFYVE cytoplasmic punctae in response to starvation was greatly diminished |
| GO:0030307 positive regulation of cell growth | IMP PMID:12893813 Drosophila Rheb GTPase is required for cell cycle progressio... | ACCEPT | Summary: dRheb is required for growth of individual cells; inhibition reduces cell size. Reason: Rheb is a dose-dependent driver of cellular growth: loss reduces and overexpression increases cell size, in a TOR-dependent way. This is the major biological outcome of its TORC1-activating function. Supporting Evidence: PMID:12893813 we show that dRheb is required in the whole organism for viability (growth) and for the growth of individual cells PMID:12893813 Inhibition of dRheb activity in cultured cells results in their arrest in G1 and a reduction in size |
| GO:0033500 carbohydrate homeostasis | IMP PMID:21464442 Drosophila insulin pathway mutants affect visual physiology ... | KEEP AS NON CORE | Summary: Hypomorphic Rheb allele combinations alter whole-body carbohydrate content (up in one, down in another). Reason: A systemic metabolic consequence of reduced insulin/TOR signaling, with inconsistent direction between alleles; indirect and non-core. Supporting Evidence: PMID:21464442 The three heteroallelic combinations of Dp110, InR3T5/E19, and Rheb7A1/7A1 exhibited significant increases, whereas Rheb44.1/7A1 had a discrete decrease |
| GO:0035264 multicellular organism growth | IMP PMID:21464442 Drosophila insulin pathway mutants affect visual physiology ... | KEEP AS NON CORE | Summary: Hypomorphic Rheb alleles reduce body size/weight. Reason: Organismal growth is a systemic consequence of reduced TOR signaling; Rheb loss arrests larval growth. Accurate but downstream of the core cell-autonomous function. Supporting Evidence: PMID:12766776 Mutation of Rheb suspends larval growth and prevents progression from first to second instar |
| GO:0042594 response to starvation | IEP PMID:12766776 Rheb promotes cell growth as a component of the insulin/TOR ... | MARK AS OVER ANNOTATED | Summary: rheb mRNA is rapidly induced by protein starvation. Reason: An expression change (IEP) shows the gene responds to starvation, not that the product does any of the work of a starvation response. Rheb's nutrient-related role is captured by TORC1 regulation. Supporting Evidence: PMID:12766776 Levels of rheb mRNA are rapidly induced in response to protein starvation |
| GO:0042632 cholesterol homeostasis | IMP PMID:27326933 A Drosophila Genome-Wide Screen Identifies Regulators of Ste... | KEEP AS NON CORE | Summary: Genome-wide RNAi screen in the prothoracic gland; TOR signaling regulates cholesterol trafficking for steroidogenesis (abstract-only cache). Reason: Plausible indirect effect of TOR signaling on autophagosomal cholesterol mobilisation; screen-level evidence, full text not available. Kept as non-core in deference to the curator. Supporting Evidence: PMID:27326933 These cholesterol-trafficking mechanisms are regulated by TOR and feedback signaling that couples steroidogenesis with growth and ensures proper maturation timing |
| GO:0043539 protein serine/threonine kinase activator activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the Rheb subfamily node (PTN000631830), seeded by human RHEB, S. pombe Rhb1 and Drosophila Rheb. Reason: This is the most informative molecular function for Rheb: GTP-loaded Rheb directly stimulates the kinase activity of TORC1. Drosophila Rheb is inside the Rheb clade and has its own experimental support for activating TORC1 (UniProt FUNCTION, PMID:22493059), so the node placement holds. Supporting Evidence: file:DROME/Rheb/Rheb-uniprot.txt Activates the protein kinase activity of TORC1, and thereby plays a role in the regulation of apoptosis (PubMed:22493059) PMID:22493059 expression of TOR and RAPTOR, together with their upstream activator Rheb, was sufficient to provide TORC1 activity |
| GO:0045176 apical protein localization | IMP PMID:25977367 Compensatory branching morphogenesis of stalk cells in the D... | MARK AS OVER ANNOTATED | Summary: TOR pathway mutant terminal cells show reduced apical domains / mislocalized apical proteins (abstract-only cache). Reason: Rheb does none of the work of localizing apical proteins; the phenotype is a downstream morphological consequence of reduced TOR-driven growth of the apical domain. The abstract attributes apical protein mislocalization to vATPase-deficient cells and states only that TOR mutants phenocopy. Supporting Evidence: PMID:25977367 Consistent with recent reports that the mTOR and vATPase pathways intersect, we found that mTOR pathway mutants phenocopied okg and cnj |
| GO:0045727 positive regulation of translation | IMP PMID:17371599 Rheb-TOR signaling promotes protein synthesis, but not gluco... | KEEP AS NON CORE | Summary: Rheb and TOR are required for normal protein synthesis; Rheb overexpression increases it in vivo. Reason: Translation is regulated by TORC1 targets (S6K, 4E-BP); Rheb acts upstream through TORC1. Real but indirect. Supporting Evidence: PMID:17371599 Fed larvae overexpressing Rheb showed an increase in protein synthesis of 140β180% relative to controls |
| GO:0045793 positive regulation of cell size | IMP PMID:12766776 Rheb promotes cell growth as a component of the insulin/TOR ... | ACCEPT | Summary: Increased Rheb promotes cell growth in multiple tissues. Reason: Rheb is a dose-dependent driver of cellular growth: loss reduces and overexpression increases cell size, in a TOR-dependent way. This is the major biological outcome of its TORC1-activating function. Supporting Evidence: PMID:12766776 Genetic and biochemical tests indicate that Rheb functions in the insulin signalling pathway downstream of Tsc1-Tsc2 and upstream of TOR |
| GO:0045793 positive regulation of cell size | IMP PMID:17371599 Rheb-TOR signaling promotes protein synthesis, but not gluco... | ACCEPT | Summary: dsRheb S2 cells are smaller than controls. Reason: Rheb is a dose-dependent driver of cellular growth: loss reduces and overexpression increases cell size, in a TOR-dependent way. This is the major biological outcome of its TORC1-activating function. Supporting Evidence: PMID:17371599 we noted that S2 cells subjected to 72 hours of dsRheb- or dsTOR-treatment were smaller than control cells |
| GO:0045793 positive regulation of cell size | IMP PMID:19216764 PDGF/VEGF signaling controls cell size in Drosophila. | ACCEPT | Summary: Genome-wide RNAi screen: Rheb silencing decreases S2 cell size. Reason: Rheb is a dose-dependent driver of cellular growth: loss reduces and overexpression increases cell size, in a TOR-dependent way. This is the major biological outcome of its TORC1-activating function. Supporting Evidence: PMID:19216764 Silencing positive regulators of the pathway (Rheb, Tor, Raptor and S6k) led to a significant decrease in cell size |
| GO:0045793 positive regulation of cell size | IMP PMID:21951762 Drosophila insulin and target of rapamycin (TOR) pathways re... | ACCEPT | Summary: Rheb (UAS-RhebAV4) expression increases ommatidial cell size. Reason: Rheb is a dose-dependent driver of cellular growth: loss reduces and overexpression increases cell size, in a TOR-dependent way. This is the major biological outcome of its TORC1-activating function. Supporting Evidence: PMID:21951762 we activated the TOR pathway by expressing rheb using the UAS-RhebAV4 line |
| GO:0045887 positive regulation of synaptic assembly at neuromuscular junction | IMP PMID:22319582 Diet and energy-sensing inputs affect TorC1-mediated axon mi... | KEEP AS NON CORE | Summary: Neuronal Rheb overexpression enlarges NMJ synapses, via TORC2. Reason: Overexpression-only gain-of-function evidence, but the direction (more Rheb, larger synapses) is consistent with the term and Tor-dependent; non-core. Supporting Evidence: PMID:22319582 Neuron-specific overexpression of Rheb resulted in neuromuscular synapses approximately 50% larger than corresponding synapses in animals lacking a Gal4 driver PMID:22319582 Synaptic phenotypes responded differently compared to axon guidance and behavioral phenotypes, and we show that this is due to a dependence on different downstream Tor complexes |
| GO:0048010 vascular endothelial growth factor receptor signaling pathway | IGI PMID:23878397 Platelet-derived growth factor/vascular endothelial growth f... | KEEP AS NON CORE | Summary: PVR (PDGF/VEGF receptor) sustains TORC1 activity through Tsc1/Tsc2; Rheb knockdown was used to place PVR upstream of Rheb. Reason: Rheb is downstream of PVR in the PVR-Tsc-Rheb-TORC1 axis in S2/Kc cells; a genuine but non-core pathway context for its TORC1-activating function. Supporting Evidence: PMID:23878397 TORC1 activation by PVR involves Tsc1/Tsc2 and, in a cell-type-dependent manner, Lobe (ortholog of PRAS40) |
| GO:0055088 lipid homeostasis | IMP PMID:21464442 Drosophila insulin pathway mutants affect visual physiology ... | MARK AS OVER ANNOTATED | Summary: Lipid content measured in Rheb hypomorphs. Reason: The paper reports no significant lipid change for three of four Rheb allele combinations, and Rheb7A1 homozygotes have normal lipid levels; the support for a Rheb role in lipid homeostasis from this paper is weak. Supporting Evidence: PMID:21464442 No significant differences were found for Dp1105W3/5W3 or for three of four mutant combinations for Rheb |
| GO:0090070 positive regulation of ribosome biogenesis | IMP PMID:17371599 Rheb-TOR signaling promotes protein synthesis, but not gluco... | KEEP AS NON CORE | Summary: Rheb and TOR regulate ribosome biogenesis in S2 cells. Reason: Ribosome biogenesis is a TORC1 output; Rheb acts upstream. Real but indirect. Supporting Evidence: PMID:17371599 Thus, Rheb and TOR regulate ribosome biogenesis in Drosophila S2 cells, and do so independently of PI3K and Akt |
| GO:1902669 positive regulation of axon guidance | IMP PMID:22319582 Diet and energy-sensing inputs affect TorC1-mediated axon mi... | MARK AS OVER ANNOTATED | Summary: Neuronal Rheb overexpression causes photoreceptor axon misrouting. Reason: The only data are overexpression-induced misrouting (axons overshooting their targets), a TORC1-dependent disruption of guidance; this does not show that Rheb positively regulates axon guidance, and no loss-of-function guidance phenotype is reported. Supporting Evidence: PMID:22319582 Rheb overexpression in neurons caused some axon bundles to continue growing beyond their proper R7/R8 termination targets to eventually stop elsewhere within the medulla PMID:22319582 Heterozygosity for a Tor null mutation almost completely rescued Rheb-induced axon guidance abnormalities |
| GO:1903940 negative regulation of TORC2 signaling | IDA PMID:22493059 LST8 regulates cell growth via target-of-rapamycin complex 2... | KEEP AS NON CORE | Summary: UniProt IDA for negative regulation of TORC2 signaling (abstract-only cache). Reason: In S2 cells Rheb inhibits TORC2 output (Akt phosphorylation), most likely indirectly through TORC1-S6K feedback. This is a real but indirect regulatory effect, not the core activity. Note that UniProt's FUNCTION text for PMID:22493059 says Rheb 'may also have a role in activating TORC2 signaling', which conflicts with the negative IDA row from that paper (abstract-only; not verifiable here). Supporting Evidence: PMID:16627617 This negative effect of dRheb on dTORC2 is possibly due to a feedback mechanism involving dTORC1 and dS6K |
| GO:1903940 negative regulation of TORC2 signaling | IMP PMID:16627617 TSC1/TSC2 and Rheb have different effects on TORC1 and TORC2... | KEEP AS NON CORE | Summary: dRheb knockdown/overexpression shows an inhibitory effect on dTORC2 in S2 cells. Reason: In S2 cells Rheb inhibits TORC2 output (Akt phosphorylation), most likely indirectly through TORC1-S6K feedback. This is a real but indirect regulatory effect, not the core activity. Note that UniProt's FUNCTION text for PMID:22493059 says Rheb 'may also have a role in activating TORC2 signaling', which conflicts with the negative IDA row from that paper (abstract-only; not verifiable here). Supporting Evidence: PMID:16627617 This negative effect of dRheb on dTORC2 is possibly due to a feedback mechanism involving dTORC1 and dS6K |
| GO:1904263 positive regulation of TORC1 signaling | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the Rheb subfamily node (PTN000631830); the gene's own experimental data are among the seeds. Reason: Core function: GTP-bound Rheb is the direct upstream activator of TORC1 in Drosophila, acting downstream of Tsc1/Tsc2; loss reduces and overexpression increases TORC1 output (S6K phosphorylation, growth) in a TOR-dependent manner. Supporting Evidence: PMID:12766776 Genetic and biochemical tests indicate that Rheb functions in the insulin signalling pathway downstream of Tsc1-Tsc2 and upstream of TOR PMID:22493059 expression of TOR and RAPTOR, together with their upstream activator Rheb, was sufficient to provide TORC1 activity |
| GO:1904263 positive regulation of TORC1 signaling | IDA PMID:22493059 LST8 regulates cell growth via target-of-rapamycin complex 2... | ACCEPT | Summary: In lst8 mutants, expressing TOR and RAPTOR with Rheb was sufficient to provide TORC1 activity. Reason: Core function: GTP-bound Rheb is the direct upstream activator of TORC1 in Drosophila, acting downstream of Tsc1/Tsc2; loss reduces and overexpression increases TORC1 output (S6K phosphorylation, growth) in a TOR-dependent manner. Supporting Evidence: PMID:22493059 expression of TOR and RAPTOR, together with their upstream activator Rheb, was sufficient to provide TORC1 activity file:DROME/Rheb/Rheb-uniprot.txt Activates the protein kinase activity of TORC1, and thereby plays a role in the regulation of apoptosis (PubMed:22493059) |
| GO:1904263 positive regulation of TORC1 signaling | IMP PMID:16627617 TSC1/TSC2 and Rheb have different effects on TORC1 and TORC2... | ACCEPT | Summary: Rheb activates TORC1 (S6K phosphorylation) in S2 cells. Reason: Core function: GTP-bound Rheb is the direct upstream activator of TORC1 in Drosophila, acting downstream of Tsc1/Tsc2; loss reduces and overexpression increases TORC1 output (S6K phosphorylation, growth) in a TOR-dependent manner. Supporting Evidence: PMID:16627617 The Ras homology enriched in brain (Rheb) small GTPase is known to be a key upstream activator of TORC1 |
| GO:1904263 positive regulation of TORC1 signaling | IMP PMID:21951762 Drosophila insulin and target of rapamycin (TOR) pathways re... | ACCEPT | Summary: Rheb expression increases S6K phosphorylation and Myc accumulation in S2 cells and discs. Reason: Core function: GTP-bound Rheb is the direct upstream activator of TORC1 in Drosophila, acting downstream of Tsc1/Tsc2; loss reduces and overexpression increases TORC1 output (S6K phosphorylation, growth) in a TOR-dependent manner. Supporting Evidence: PMID:21951762 co-expression of S6K with Rheb was able to substantially induce Myc protein accumulation, an event that correlated with phosphorylation of S6K on Thr 398 and GSK3Ξ² on Ser 9 |
| GO:1904263 positive regulation of TORC1 signaling | IMP PMID:22319582 Diet and energy-sensing inputs affect TorC1-mediated axon mi... | ACCEPT | Summary: Rheb overexpression phenotypes in neurons all require Tor and are rescued by Tor heterozygosity. Reason: Core function: GTP-bound Rheb is the direct upstream activator of TORC1 in Drosophila, acting downstream of Tsc1/Tsc2; loss reduces and overexpression increases TORC1 output (S6K phosphorylation, growth) in a TOR-dependent manner. Supporting Evidence: PMID:22319582 Heterozygosity for a Tor null mutation almost completely rescued Rheb-induced axon guidance abnormalities PMID:22319582 Synaptic phenotypes responded differently compared to axon guidance and behavioral phenotypes, and we show that this is due to a dependence on different downstream Tor complexes |
| GO:1904263 positive regulation of TORC1 signaling | IMP PMID:28829944 Spatial Activation of TORC1 Is Regulated by Hedgehog and E2F... | ACCEPT | Summary: TORC1 activation in the eye second mitotic wave (abstract-only cache). Reason: Core function: GTP-bound Rheb is the direct upstream activator of TORC1 in Drosophila, acting downstream of Tsc1/Tsc2; loss reduces and overexpression increases TORC1 output (S6K phosphorylation, growth) in a TOR-dependent manner. The cached abstract does not mention Rheb explicitly; deferring to the curator who read the full text. Supporting Evidence: PMID:28829944 TORC1 is necessary for the proper G1/S transition of the cells, and the activation of TORC1 rescues the cell-cycle defect of Hh signaling-deficient cells in the SMW |
| GO:1904503 negative regulation of lipophagy | IMP PMID:29503179 Inflammation-Modulated Metabolic Reprogramming Is Required f... | KEEP AS NON CORE | Summary: TOR controls lipogenesis vs ATG1-dependent lipophagy in infected enterocytes (abstract-only cache). Reason: Consistent with Rheb-TORC1 repression of Atg1-dependent autophagy; indirect and context-specific. The cached abstract does not name Rheb; deferring to the curator who read the full text. Supporting Evidence: PMID:29503179 Infection induces signaling cascades involving TRAF3 and kinases AMPK and WTS, which regulate TOR kinase to control the balance of lipogenesis versus lipolysis |
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Download this section (compressed HTML)Q: Does Drosophila Rheb inhibit TORC2 only indirectly through TORC1-S6K feedback, or also directly? UniProt's text for PMID:22493059 ('may also have a role in activating TORC2 signaling') and the negative regulation of TORC2 IDA row from the same paper disagree.
Q: Is Tctp a bona fide Rheb GEF in vivo, given that the GEF activity of mammalian TCTP toward RHEB has been disputed?
Q: Where does Drosophila Rheb activate TORC1 in somatic cells: Golgi (GOLPH3-dependent), lysosomal membranes as in mammals, or both?
Q: Should PMID:11782951 (a 2002 review not mentioning Rheb in its abstract) be the reference for an IMP insulin receptor signaling annotation, or is it mis-keyed?
Experiment: Image endogenously tagged Rheb (CRISPR knock-in) in fat body and imaginal disc cells with Golgi and lysosome markers under fed and starved conditions, and test TORC1 output after GOLPH3/sau depletion.
Experiment: Measure TORC2 (Akt S505) phosphorylation in Rheb loss-of-function cells with and without S6K co-depletion to separate direct from feedback effects of Rheb on TORC2.
Ras homolog enriched in brain (Rheb) encodes a Ras homolog that is the target of the product of gig. It activates the protein kinase encoded by mTor, leading to enlarged cell size.
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