{"gene":"RRAGB","run_date":"2026-06-10T07:46:27","timeline":{"discoveries":[{"year":2018,"finding":"TRIM37 interacts with MTOR and RRAGB proteins, enhances the MTOR-RRAGB interaction, and promotes lysosomal localization of MTOR, thereby activating amino acid-stimulated MTORC1 signaling. Loss of TRIM37 reduces TFEB phosphorylation, causing its nuclear translocation and transcriptional activation of autophagy/lysosome genes.","method":"Co-immunoprecipitation, lysosomal localization assays, phosphorylation analysis, nuclear translocation assays, knockdown/knockout functional experiments","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and localization assays with functional readouts (TFEB phosphorylation, nuclear translocation, autophagy induction), single lab, multiple orthogonal methods","pmids":["29940807"],"is_preprint":false},{"year":2022,"finding":"NUFIP2 contributes to MTOR inactivation at the lysosome together with LGALS8 (galectin-8) via the Ragulator-RRAGA-RRAGB complex following lysosomal damage.","method":"Proteomic recruitment assays to damaged lysosomes, co-immunoprecipitation, functional MTOR inactivation assays, lysosome immunopurification (LysoIP)","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lysosome immunopurification with proteomic validation and functional MTOR assays, single lab, multiple orthogonal methods","pmids":["36394332"],"is_preprint":false},{"year":2022,"finding":"circEXOC6B (a circular RNA) binds directly to RRAGB and inhibits RRAGB heterodimer formation, thereby suppressing mTORC1 pathway activation and reducing HIF1A levels. Additionally, HIF1A upregulates RRAGB transcription by binding to its promoter, forming a HIF1A-RRAGB-mTORC1 positive feedback loop.","method":"RNA pull-down, mass spectrometry, RNA-binding protein immunoprecipitation, co-immunoprecipitation, chromatin immunoprecipitation, dual-luciferase assay, western blot","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RNA pulldown, RIP, ChIP, luciferase, Co-IP) in single lab; note this paper is primarily about a circRNA, but the RRAGB mechanism (heterodimer inhibition, HIF1A-driven transcription) is directly experimentally established","pmids":["35739524"],"is_preprint":false},{"year":2023,"finding":"RRAGB overexpression in glioblastoma cells decreases expression of PI3K, phosphorylated AKT, mTOR, and S6K, and suppresses proliferation, migration, invasion, and induces G0/G1 cell cycle arrest. Restoring AKT activation offsets RRAGB's anti-proliferative and anti-migratory effects, indicating RRAGB acts upstream of AKT to suppress PI3K/AKT/mTOR signaling.","method":"Overexpression in GBM cell lines, western blot for PI3K/p-AKT/mTOR/S6K, proliferation/migration/invasion assays, AKT activation rescue experiment, xenograft and orthotopic mouse tumor models","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean gain-of-function with defined pathway readout and epistasis rescue (AKT activation), single lab, single study with in vitro and in vivo validation","pmids":["37517217"],"is_preprint":false},{"year":2024,"finding":"RRAGB is a direct target of miR-21-3p in endothelial progenitor cells; overexpression of RRAGB inhibits autophagic activity via the mTOR pathway and impairs EPC function (proliferation, migration, tube formation).","method":"Luciferase reporter assay (miR-21-3p/RRAGB targeting), overexpression of RRAGB, immunofluorescence and western blotting for mTOR pathway and autophagy markers, functional EPC assays","journal":"Regenerative therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — luciferase reporter and overexpression with functional readout, single lab, single study, limited mechanistic depth on RRAGB's direct mechanism","pmids":["39100534"],"is_preprint":false},{"year":2025,"finding":"circMRP4 acts as a sponge for miR-499-5p, leading to upregulation of RRAGB, which activates mTORC1/P70S6K signaling and mediates podocyte apoptosis and inflammation in diabetic kidney disease.","method":"Dual-luciferase reporter, RNA immunoprecipitation, RNA pull-down, knockdown/overexpression functional assays, western blot for mTORC1/P70S6K pathway","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — primarily a circRNA study; RRAGB role established via indirect pathway (miRNA sponge → RRAGB upregulation → mTORC1), single lab, single study","pmids":["39842531"],"is_preprint":false}],"current_model":"RRAGB (RagB) is a Ras-related GTPase that, as part of the Ragulator-RRAGA-RRAGB complex at the lysosome, promotes amino acid-stimulated mTORC1 activation by facilitating mTOR lysosomal localization; it is positively regulated by TRIM37 (which enhances the MTOR-RRAGB interaction), negatively regulated by circEXOC6B (which blocks RRAGB heterodimer formation), and transcriptionally induced by HIF1A, while also suppressing PI3K/AKT signaling in glioblastoma cells, and its loss impairs mTORC1-dependent TFEB phosphorylation leading to autophagy induction."},"narrative":{"mechanistic_narrative":"RRAGB (RagB) is a Ras-related GTPase that functions as part of a lysosomal Ragulator-RRAGA-RRAGB complex to control amino acid-dependent mTORC1 activation [PMID:36394332]. Productive signaling requires RRAGB heterodimer formation, and TRIM37 promotes RRAGB activity by binding both MTOR and RRAGB, enhancing the MTOR-RRAGB interaction and driving lysosomal localization of MTOR; loss of this input reduces TFEB phosphorylation, allowing TFEB nuclear translocation and induction of autophagy/lysosome genes [PMID:29940807]. Following lysosomal damage, RRAGB participates in the opposite direction, contributing to MTOR inactivation at the lysosome together with NUFIP2 and galectin-8 (LGALS8) [PMID:36394332]. RRAGB is transcriptionally induced by HIF1A binding its promoter, establishing a HIF1A-RRAGB-mTORC1 positive feedback loop, and its heterodimer formation is blocked by the circular RNA circEXOC6B, which suppresses mTORC1 signaling and lowers HIF1A [PMID:35739524]. In glioblastoma cells, RRAGB overexpression suppresses PI3K, phospho-AKT, mTOR and S6K and restrains proliferation, migration, invasion and cell cycle progression, acting upstream of AKT, since restoring AKT activation reverses these effects [PMID:37517217].","teleology":[{"year":2018,"claim":"Established how RRAGB-dependent mTORC1 activation is positively regulated, identifying TRIM37 as a factor that stabilizes the MTOR-RRAGB interaction and couples it to lysosomal recruitment and downstream TFEB control.","evidence":"Reciprocal Co-IP, lysosomal localization assays, TFEB phosphorylation and nuclear translocation readouts with knockdown/knockout","pmids":["29940807"],"confidence":"Medium","gaps":["Does not resolve whether TRIM37 acts on RRAGB nucleotide state or GTPase cycle","Direct biochemical demonstration of the MTOR-RRAGB binding interface absent","RRAGB heterodimer partner (RagC/D) role not addressed here"]},{"year":2022,"claim":"Showed that the Ragulator-RRAGA-RRAGB complex is also a node for shutting mTORC1 OFF, recruiting NUFIP2 and galectin-8 to inactivate MTOR after lysosomal membrane damage.","evidence":"Recruitment proteomics to damaged lysosomes, Co-IP, LysoIP, functional MTOR inactivation assays","pmids":["36394332"],"confidence":"Medium","gaps":["RRAGB's specific contribution versus RRAGA not dissected","Mechanism by which damage signals reach the Rag complex unclear","No nucleotide-state analysis of RRAGB during inactivation"]},{"year":2022,"claim":"Defined regulation of RRAGB at both the activity and transcriptional levels, with circEXOC6B blocking heterodimer assembly and HIF1A transcriptionally amplifying RRAGB in a feedback loop.","evidence":"RNA pull-down, mass spectrometry, RIP, Co-IP, ChIP, dual-luciferase assay, western blot","pmids":["35739524"],"confidence":"Medium","gaps":["Identity of the obligate heterodimer partner not biochemically defined","Whether circEXOC6B competes at the GTPase or dimer interface unknown","Feedback loop characterized primarily in a single cancer context"]},{"year":2023,"claim":"Tested RRAGB's net signaling output in glioblastoma, where gain-of-function suppressed PI3K/AKT/mTOR signaling and tumor phenotypes, placing RRAGB upstream of AKT via an epistasis rescue.","evidence":"Overexpression in GBM cell lines, pathway western blots, proliferation/migration/invasion assays, AKT rescue, xenograft and orthotopic models","pmids":["37517217"],"confidence":"Medium","gaps":["Apparent contradiction with RRAGB as an mTORC1 activator not mechanistically reconciled","Direct molecular link from RRAGB to PI3K/AKT not identified","Single-lab, single-tumor-type finding"]},{"year":2024,"claim":"Extended RRAGB regulation to a miRNA axis in endothelial progenitor cells, where miR-21-3p targets RRAGB and RRAGB overexpression inhibits autophagy through mTOR.","evidence":"Luciferase reporter, overexpression, immunofluorescence/western for mTOR and autophagy markers, EPC functional assays","pmids":["39100534"],"confidence":"Low","gaps":["Limited mechanistic depth on RRAGB's direct action","Single lab, single study","Direct miR-21-3p/RRAGB binding effect on protein level not fully traced to phenotype"]},{"year":2025,"claim":"Linked RRAGB to disease pathophysiology in diabetic kidney disease via a circMRP4/miR-499-5p axis that upregulates RRAGB to activate mTORC1/P70S6K and drive podocyte apoptosis.","evidence":"Dual-luciferase, RIP, RNA pull-down, knockdown/overexpression, western blot for mTORC1/P70S6K","pmids":["39842531"],"confidence":"Low","gaps":["RRAGB role inferred through an indirect miRNA-sponge chain","Direct RRAGB mechanism not interrogated","Single lab, single study"]},{"year":null,"claim":"How RRAGB's nucleotide cycle and obligate heterodimer partner are biochemically controlled, and how it can both activate lysosomal mTORC1 and suppress PI3K/AKT in a context-dependent manner, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or reconstituted GTPase-cycle analysis in the corpus","Identity and regulation of the heterodimer partner undefined","Mechanistic reconciliation of activating versus suppressive roles absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0]}],"complexes":["Ragulator-RRAGA-RRAGB complex"],"partners":["RRAGA","MTOR","TRIM37","NUFIP2","LGALS8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5VZM2","full_name":"Ras-related GTP-binding protein B","aliases":[],"length_aa":374,"mass_kda":43.2,"function":"Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade (PubMed:18497260, PubMed:20381137, PubMed:23723238, PubMed:24095279). Forms heterodimeric Rag complexes with RagC/RRAGC or RagD/RRAGD and cycles between an inactive GDP-bound and an active GTP-bound form: RagB/RRAGB is in its active form when GTP-bound RagB/RRAGB forms a complex with GDP-bound RagC/RRAGC (or RagD/RRAGD) and in an inactive form when GDP-bound RagB/RRAGB heterodimerizes with GTP-bound RagC/RRAGC (or RagD/RRAGD) (PubMed:18497260, PubMed:20381137, PubMed:23723238, PubMed:24095279). In its GTP-bound active form, promotes the recruitment of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB (PubMed:18497260, PubMed:20381137, PubMed:23723238). Involved in the RCC1/Ran-GTPase pathway (PubMed:9394008)","subcellular_location":"Cytoplasm; Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q5VZM2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RRAGB","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RRAGB","total_profiled":1310},"omim":[{"mim_id":"618834","title":"LATE ENDOSOMAL/LYSOSOMAL ADAPTOR, MAPK AND MTOR ACTIVATOR 4; LAMTOR4","url":"https://www.omim.org/entry/618834"},{"mim_id":"616599","title":"BLOC1-RELATED COMPLEX, SUBUNIT 6; BORCS6","url":"https://www.omim.org/entry/616599"},{"mim_id":"616203","title":"SOLUTE CARRIER FAMILY 38, MEMBER 9; SLC38A9","url":"https://www.omim.org/entry/616203"},{"mim_id":"608521","title":"LATE ENDOSOMAL/LYSOSOMAL ADAPTOR, MAPK AND MTOR ACTIVATOR 5; LAMTOR5","url":"https://www.omim.org/entry/608521"},{"mim_id":"300725","title":"RAS-RELATED GTP-BINDING PROTEIN B; RRAGB","url":"https://www.omim.org/entry/300725"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RRAGB"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q5VZM2","domains":[{"cath_id":"3.40.50.300","chopping":"38-69_104-239","consensus_level":"high","plddt":94.0865,"start":38,"end":239},{"cath_id":"3.30.450.190","chopping":"244-361","consensus_level":"high","plddt":93.5654,"start":244,"end":361}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VZM2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VZM2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VZM2-F1-predicted_aligned_error_v6.png","plddt_mean":81.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RRAGB","jax_strain_url":"https://www.jax.org/strain/search?query=RRAGB"},"sequence":{"accession":"Q5VZM2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5VZM2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5VZM2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VZM2"}},"corpus_meta":[{"pmid":"25651471","id":"PMC_25651471","title":"Dichotomy of Genetic Abnormalities in PEComas With Therapeutic Implications.","date":"2015","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25651471","citation_count":192,"is_preprint":false},{"pmid":"29940807","id":"PMC_29940807","title":"TRIM37 deficiency induces autophagy through deregulating the MTORC1-TFEB axis.","date":"2018","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/29940807","citation_count":39,"is_preprint":false},{"pmid":"35739524","id":"PMC_35739524","title":"circEXOC6B interacting with RRAGB, an mTORC1 activator, inhibits the progression of colorectal cancer by antagonizing the HIF1A-RRAGB-mTORC1 positive feedback loop.","date":"2022","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35739524","citation_count":34,"is_preprint":false},{"pmid":"15202009","id":"PMC_15202009","title":"Identification and characterization of human FOXN6, mouse Foxn6, and rat Foxn6 genes in silico.","date":"2004","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/15202009","citation_count":30,"is_preprint":false},{"pmid":"31886214","id":"PMC_31886214","title":"A Six-Gene Signature Predicts Survival of Adenocarcinoma Type of Non-Small-Cell Lung Cancer Patients: A Comprehensive Study Based on Integrated Analysis and Weighted Gene Coexpression Network.","date":"2019","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/31886214","citation_count":28,"is_preprint":false},{"pmid":"36394332","id":"PMC_36394332","title":"Membrane Atg8ylation, stress granule formation, and MTOR regulation during lysosomal damage.","date":"2022","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/36394332","citation_count":23,"is_preprint":false},{"pmid":"30900683","id":"PMC_30900683","title":"Glomerular Proteomic Profiles in the NZB/W F1 Hybrid Mouse Model of Lupus Nephritis.","date":"2019","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/30900683","citation_count":6,"is_preprint":false},{"pmid":"39100534","id":"PMC_39100534","title":"Berberine ameliorates endothelial progenitor cell function and wound healing in vitro and in vivo via the miR-21-3p/RRAGB axis for venous leg ulcers.","date":"2024","source":"Regenerative therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39100534","citation_count":4,"is_preprint":false},{"pmid":"39822017","id":"PMC_39822017","title":"A Clinicopathologic and Molecular Reappraisal of Myxoinflammatory Fibroblastic Sarcoma-A Controversial and Pathologically Challenging Low-Grade Sarcoma.","date":"2025","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39822017","citation_count":4,"is_preprint":false},{"pmid":"40584666","id":"PMC_40584666","title":"Transcriptome Remodeling and Adaptive Preservation of Muscle Protein Content in Hibernating Black Bears.","date":"2025","source":"Ecology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/40584666","citation_count":4,"is_preprint":false},{"pmid":"40243924","id":"PMC_40243924","title":"The Effect of Valine on the Synthesis of α-Casein in MAC-T Cells and the Expression and Phosphorylation of Genes Related to the mTOR Signaling Pathway.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40243924","citation_count":3,"is_preprint":false},{"pmid":"39842531","id":"PMC_39842531","title":"CircMRP4 orchestrates podocytes injury via the miR-499-5p/RRAGB/mTORC1 axis in diabetic kidney disease.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/39842531","citation_count":2,"is_preprint":false},{"pmid":"40166218","id":"PMC_40166218","title":"Transcriptome remodeling and adaptive preservation of muscle protein content in hibernating black bears.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40166218","citation_count":2,"is_preprint":false},{"pmid":"37517217","id":"PMC_37517217","title":"RRAGB-mediated suppression of PI3K/AKT exerts anti-cancer role in glioblastoma.","date":"2023","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/37517217","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10940,"output_tokens":1751,"usd":0.029542,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8525,"output_tokens":2618,"usd":0.054038,"stage2_stop_reason":"end_turn"},"total_usd":0.08358,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM37 interacts with MTOR and RRAGB proteins, enhances the MTOR-RRAGB interaction, and promotes lysosomal localization of MTOR, thereby activating amino acid-stimulated MTORC1 signaling. Loss of TRIM37 reduces TFEB phosphorylation, causing its nuclear translocation and transcriptional activation of autophagy/lysosome genes.\",\n      \"method\": \"Co-immunoprecipitation, lysosomal localization assays, phosphorylation analysis, nuclear translocation assays, knockdown/knockout functional experiments\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and localization assays with functional readouts (TFEB phosphorylation, nuclear translocation, autophagy induction), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"29940807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NUFIP2 contributes to MTOR inactivation at the lysosome together with LGALS8 (galectin-8) via the Ragulator-RRAGA-RRAGB complex following lysosomal damage.\",\n      \"method\": \"Proteomic recruitment assays to damaged lysosomes, co-immunoprecipitation, functional MTOR inactivation assays, lysosome immunopurification (LysoIP)\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lysosome immunopurification with proteomic validation and functional MTOR assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36394332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"circEXOC6B (a circular RNA) binds directly to RRAGB and inhibits RRAGB heterodimer formation, thereby suppressing mTORC1 pathway activation and reducing HIF1A levels. Additionally, HIF1A upregulates RRAGB transcription by binding to its promoter, forming a HIF1A-RRAGB-mTORC1 positive feedback loop.\",\n      \"method\": \"RNA pull-down, mass spectrometry, RNA-binding protein immunoprecipitation, co-immunoprecipitation, chromatin immunoprecipitation, dual-luciferase assay, western blot\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RNA pulldown, RIP, ChIP, luciferase, Co-IP) in single lab; note this paper is primarily about a circRNA, but the RRAGB mechanism (heterodimer inhibition, HIF1A-driven transcription) is directly experimentally established\",\n      \"pmids\": [\"35739524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RRAGB overexpression in glioblastoma cells decreases expression of PI3K, phosphorylated AKT, mTOR, and S6K, and suppresses proliferation, migration, invasion, and induces G0/G1 cell cycle arrest. Restoring AKT activation offsets RRAGB's anti-proliferative and anti-migratory effects, indicating RRAGB acts upstream of AKT to suppress PI3K/AKT/mTOR signaling.\",\n      \"method\": \"Overexpression in GBM cell lines, western blot for PI3K/p-AKT/mTOR/S6K, proliferation/migration/invasion assays, AKT activation rescue experiment, xenograft and orthotopic mouse tumor models\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean gain-of-function with defined pathway readout and epistasis rescue (AKT activation), single lab, single study with in vitro and in vivo validation\",\n      \"pmids\": [\"37517217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RRAGB is a direct target of miR-21-3p in endothelial progenitor cells; overexpression of RRAGB inhibits autophagic activity via the mTOR pathway and impairs EPC function (proliferation, migration, tube formation).\",\n      \"method\": \"Luciferase reporter assay (miR-21-3p/RRAGB targeting), overexpression of RRAGB, immunofluorescence and western blotting for mTOR pathway and autophagy markers, functional EPC assays\",\n      \"journal\": \"Regenerative therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — luciferase reporter and overexpression with functional readout, single lab, single study, limited mechanistic depth on RRAGB's direct mechanism\",\n      \"pmids\": [\"39100534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"circMRP4 acts as a sponge for miR-499-5p, leading to upregulation of RRAGB, which activates mTORC1/P70S6K signaling and mediates podocyte apoptosis and inflammation in diabetic kidney disease.\",\n      \"method\": \"Dual-luciferase reporter, RNA immunoprecipitation, RNA pull-down, knockdown/overexpression functional assays, western blot for mTORC1/P70S6K pathway\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — primarily a circRNA study; RRAGB role established via indirect pathway (miRNA sponge → RRAGB upregulation → mTORC1), single lab, single study\",\n      \"pmids\": [\"39842531\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RRAGB (RagB) is a Ras-related GTPase that, as part of the Ragulator-RRAGA-RRAGB complex at the lysosome, promotes amino acid-stimulated mTORC1 activation by facilitating mTOR lysosomal localization; it is positively regulated by TRIM37 (which enhances the MTOR-RRAGB interaction), negatively regulated by circEXOC6B (which blocks RRAGB heterodimer formation), and transcriptionally induced by HIF1A, while also suppressing PI3K/AKT signaling in glioblastoma cells, and its loss impairs mTORC1-dependent TFEB phosphorylation leading to autophagy induction.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RRAGB (RagB) is a Ras-related GTPase that functions as part of a lysosomal Ragulator-RRAGA-RRAGB complex to control amino acid-dependent mTORC1 activation [#1]. Productive signaling requires RRAGB heterodimer formation, and TRIM37 promotes RRAGB activity by binding both MTOR and RRAGB, enhancing the MTOR-RRAGB interaction and driving lysosomal localization of MTOR; loss of this input reduces TFEB phosphorylation, allowing TFEB nuclear translocation and induction of autophagy/lysosome genes [#0]. Following lysosomal damage, RRAGB participates in the opposite direction, contributing to MTOR inactivation at the lysosome together with NUFIP2 and galectin-8 (LGALS8) [#1]. RRAGB is transcriptionally induced by HIF1A binding its promoter, establishing a HIF1A-RRAGB-mTORC1 positive feedback loop, and its heterodimer formation is blocked by the circular RNA circEXOC6B, which suppresses mTORC1 signaling and lowers HIF1A [#2]. In glioblastoma cells, RRAGB overexpression suppresses PI3K, phospho-AKT, mTOR and S6K and restrains proliferation, migration, invasion and cell cycle progression, acting upstream of AKT, since restoring AKT activation reverses these effects [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established how RRAGB-dependent mTORC1 activation is positively regulated, identifying TRIM37 as a factor that stabilizes the MTOR-RRAGB interaction and couples it to lysosomal recruitment and downstream TFEB control.\",\n      \"evidence\": \"Reciprocal Co-IP, lysosomal localization assays, TFEB phosphorylation and nuclear translocation readouts with knockdown/knockout\",\n      \"pmids\": [\"29940807\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not resolve whether TRIM37 acts on RRAGB nucleotide state or GTPase cycle\", \"Direct biochemical demonstration of the MTOR-RRAGB binding interface absent\", \"RRAGB heterodimer partner (RagC/D) role not addressed here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed that the Ragulator-RRAGA-RRAGB complex is also a node for shutting mTORC1 OFF, recruiting NUFIP2 and galectin-8 to inactivate MTOR after lysosomal membrane damage.\",\n      \"evidence\": \"Recruitment proteomics to damaged lysosomes, Co-IP, LysoIP, functional MTOR inactivation assays\",\n      \"pmids\": [\"36394332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RRAGB's specific contribution versus RRAGA not dissected\", \"Mechanism by which damage signals reach the Rag complex unclear\", \"No nucleotide-state analysis of RRAGB during inactivation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined regulation of RRAGB at both the activity and transcriptional levels, with circEXOC6B blocking heterodimer assembly and HIF1A transcriptionally amplifying RRAGB in a feedback loop.\",\n      \"evidence\": \"RNA pull-down, mass spectrometry, RIP, Co-IP, ChIP, dual-luciferase assay, western blot\",\n      \"pmids\": [\"35739524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the obligate heterodimer partner not biochemically defined\", \"Whether circEXOC6B competes at the GTPase or dimer interface unknown\", \"Feedback loop characterized primarily in a single cancer context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Tested RRAGB's net signaling output in glioblastoma, where gain-of-function suppressed PI3K/AKT/mTOR signaling and tumor phenotypes, placing RRAGB upstream of AKT via an epistasis rescue.\",\n      \"evidence\": \"Overexpression in GBM cell lines, pathway western blots, proliferation/migration/invasion assays, AKT rescue, xenograft and orthotopic models\",\n      \"pmids\": [\"37517217\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent contradiction with RRAGB as an mTORC1 activator not mechanistically reconciled\", \"Direct molecular link from RRAGB to PI3K/AKT not identified\", \"Single-lab, single-tumor-type finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended RRAGB regulation to a miRNA axis in endothelial progenitor cells, where miR-21-3p targets RRAGB and RRAGB overexpression inhibits autophagy through mTOR.\",\n      \"evidence\": \"Luciferase reporter, overexpression, immunofluorescence/western for mTOR and autophagy markers, EPC functional assays\",\n      \"pmids\": [\"39100534\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Limited mechanistic depth on RRAGB's direct action\", \"Single lab, single study\", \"Direct miR-21-3p/RRAGB binding effect on protein level not fully traced to phenotype\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked RRAGB to disease pathophysiology in diabetic kidney disease via a circMRP4/miR-499-5p axis that upregulates RRAGB to activate mTORC1/P70S6K and drive podocyte apoptosis.\",\n      \"evidence\": \"Dual-luciferase, RIP, RNA pull-down, knockdown/overexpression, western blot for mTORC1/P70S6K\",\n      \"pmids\": [\"39842531\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"RRAGB role inferred through an indirect miRNA-sponge chain\", \"Direct RRAGB mechanism not interrogated\", \"Single lab, single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RRAGB's nucleotide cycle and obligate heterodimer partner are biochemically controlled, and how it can both activate lysosomal mTORC1 and suppress PI3K/AKT in a context-dependent manner, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural or reconstituted GTPase-cycle analysis in the corpus\", \"Identity and regulation of the heterodimer partner undefined\", \"Mechanistic reconciliation of activating versus suppressive roles absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"Ragulator-RRAGA-RRAGB complex\"],\n    \"partners\": [\"RRAGA\", \"MTOR\", \"TRIM37\", \"NUFIP2\", \"LGALS8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}