{"gene":"RRAGC","run_date":"2026-06-10T07:46:27","timeline":{"discoveries":[{"year":2015,"finding":"Recurrent somatic RRAGC mutations in follicular lymphoma increase raptor (RPTOR) binding while rendering mTORC1 signaling resistant to amino acid deprivation, establishing these variants as gain-of-function activators of mTORC1.","method":"Co-immunoprecipitation (raptor binding assay), mTORC1 activity assays under amino acid deprivation in stable HEK293 cells expressing mutant RRAGC","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays plus functional mTORC1 readout, replicated in two independent studies (PMID:26691987 and PMID:27267853)","pmids":["26691987"],"is_preprint":false},{"year":2016,"finding":"Follicular lymphoma-associated RRAGC hotspot mutations cluster around the GTP/GDP-binding site, increase binding to RPTOR (raptor), substantially decrease interaction with the tumor suppressor FLCN (folliculin), and elevate mTOR signaling (S6K phosphorylation) in a leucine-independent manner; equivalent Gtr2 mutations in yeast phenocopy these effects.","method":"Co-immunoprecipitation, western blot (S6K phosphorylation), stable retroviral and lentiviral cell lines, yeast functional complementation, 3D protein modeling","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, functional mTORC1 readout, yeast epistasis), independent from PMID:26691987","pmids":["27267853"],"is_preprint":false},{"year":2016,"finding":"A de novo S75Y missense mutation in RRAGC renders AD293 cells partially insensitive to amino acid deprivation, resulting in increased mTORC1 signaling compared to wild-type RagC, establishing this as a gain-of-function mutation.","method":"Overexpression of RagC(S75Y) in AD293 cells, mTORC1 activity assay under amino acid deprivation, in silico molecular dynamics simulation predicting disruption of GDP ligand interactions","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean functional mTORC1 readout by overexpression in a single lab; computational modeling supports mechanism but no mutagenesis or structural validation","pmids":["27234373"],"is_preprint":false},{"year":2023,"finding":"De novo RRAGC missense variants (Thr90Asn, Pro118Leu, Trp115Arg) constitutively activate mTORC1: patient-derived fibroblasts with Thr90Asn show increased cell size, dysregulated p70S6K and TFEB signaling, and decoupling of mTOR subcellular localization from metabolic state; all three variants confirmed in HEK293 cell model.","method":"Patient-derived fibroblast studies, HEK293 cell overexpression model, western blot (p70S6K phosphorylation), TFEB signaling assay, mTOR subcellular localization imaging","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal models (patient fibroblasts + HEK293), multiple mTORC1 readouts, single lab","pmids":["37057673"],"is_preprint":false},{"year":2023,"finding":"Cardamonin disrupts mTOR-Raptor complex interactions by reducing Raptor protein levels; RRAGC T90N-mutant cells show elevated mTORC1 activity and increased sensitivity to cardamonin; Raptor knockdown abolishes cardamonin's inhibitory effects, placing Raptor downstream of RRAGC in the mTORC1 pathway.","method":"Co-immunoprecipitation (mTOR-Raptor-RagC interactions), lentiviral overexpression of RagC WT and T90N, shRNA Raptor knockdown, western blot (mTOR and S6K1 phosphorylation), CCK-8 viability assay, xenograft mouse model","journal":"BMC complementary medicine and therapies","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus genetic epistasis (Raptor KD rescue), in vivo validation, single lab","pmids":["37749558"],"is_preprint":false},{"year":2015,"finding":"In yeast, Lst4-Lst7 functions as a GAP complex for Gtr2 (the RRAGC ortholog) and localizes to the vacuolar membrane in amino acid-starved cells; amino acid refeeding (glutamine) transiently stimulates Lst4-Lst7 to act on Gtr2, promoting TORC1 activation, demonstrating that GAP-mediated conversion of Gtr2 to GDP-bound state is required for TORC1 activation.","method":"Biochemical GAP assay, vacuolar membrane localization imaging, genetic epistasis in yeast, amino acid stimulation experiments","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro GAP activity assay combined with localization and epistasis in yeast; functionally conserved with mammalian FNIP-FLCN complex","pmids":["26387955"],"is_preprint":false},{"year":2014,"finding":"In yeast, Gtr2 (RRAGC ortholog) directly binds the TORC1 subunit Kog1; GDP-bound Gtr1 (requiring Gtr2-Kog1 direct binding) is required for TORC1 inactivation and autophagy induction; Npr2-Npr3 act upstream of Gtr1-Gtr2 to regulate these nucleotide states.","method":"Genetic epistasis (genome-wide deletion screen, double mutant analysis), direct binding assay (Gtr2-Kog1), autophagy assay, Tor1 localization imaging","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay combined with genetic epistasis, single lab, multiple readouts","pmids":["25046117"],"is_preprint":false},{"year":2015,"finding":"In budding yeast, TORC1 localization to vacuolar puncta is facilitated by direct binding to Gtr2 (RRAGC ortholog) and is coupled to TORC1 inactivation; when Gtr1 is GDP-bound, TORC1-Gtr1/2-Ego complex relocalizes to puncta, whereas GTP-Gtr1 promotes vacuolar membrane localization and TORC1 activation.","method":"Fluorescence microscopy (colocalization), genetic mutant analysis (GTP/GDP-locked Gtr1), TORC1 activity assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence, multiple mutant alleles, single lab","pmids":["26609069"],"is_preprint":false},{"year":2012,"finding":"In fission yeast, Gtr1 and Gtr2 (RRAGC ortholog) colocalize with TORC1 at vacuoles and function downstream of Vam6 and upstream of TORC1 in the amino acid signaling pathway, as established by epistasis analysis.","method":"Genetic epistasis analysis, colocalization imaging, growth and mating/sporulation phenotypic assays in S. pombe","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple alleles and phenotypic readouts, colocalization, single lab","pmids":["22344254"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of Ego3 reveals a homodimeric fold similar to Gtr1-Gtr2 C-terminal domains; structural and genetic data identify a binding site for Gtr1-Gtr2 on Ego3, and the Ego3 dimer conformation is essential for EGO complex integrity and TORC1 signaling.","method":"X-ray crystallography, structure-guided mutagenesis, genetic complementation in yeast","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus structure-guided mutagenesis, single lab but multiple orthogonal methods","pmids":["23123112"],"is_preprint":false},{"year":2016,"finding":"In fission yeast, loss of Lam2 (LAMTOR2 homolog) or Npr2-Npr3 diminishes vacuolar localization and protein levels of Gtr1 and Gtr2; Lam2 physically interacts with Npr2 and Gtr1 and functions as a tether for GDP-bound Gtr1 to the vacuolar membrane, thereby suppressing TORC1 activity.","method":"Genetic epistasis, co-immunoprecipitation (Lam2-Npr2-Gtr1 interaction), fluorescence microscopy (vacuolar localization), TORC1 activity assay (Rps6 phosphorylation)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus localization with functional mTORC1 readout, genetic epistasis, single lab","pmids":["27227887"],"is_preprint":false},{"year":2020,"finding":"EHMT2 (GLP/G9a) directly suppresses RRAGC gene expression in hepatocellular carcinoma cells through H3K9 dimethylation at the RRAGC locus in a ROS-dependent manner, as demonstrated by ChIP assay showing EHMT2 occupancy and upregulation of RRAGC protein upon EHMT2 inhibition.","method":"ChIP assay, RNA sequencing, sgRNA-mediated loss-of-function, proteomic analysis, ROS scavenger (NAC) treatment","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP assay directly demonstrating EHMT2 occupancy at RRAGC locus, multiple orthogonal methods (ChIP + RNA-seq + sgRNA KO), single lab","pmids":["32684241"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structure of the yeast SEAC-EGOC supercomplex reveals that a single SEAC binds two EGOC molecules via SEACIT exclusively when Gtr1 (RagA/B ortholog) is GTP-loaded (active EGOC); SEAC functions as a GAP for Gtr1, and its GAP activity is essential for TORC1 regulation by amino acids; loss of GAP activity phenocopies loss of Gtr1-Gtr2, establishing the SEAC-EGOC as the amino acid-sensing hub.","method":"Cryo-electron microscopy structure determination, in vitro GAP assay, genetic loss-of-function (SEAC subunit deletions), TORC1 activity assay","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure plus in vitro GAP activity assay plus genetic epistasis; preprint but multiple orthogonal methods","pmids":["bio_10.1101_2024.10.05.616782"],"is_preprint":true},{"year":2009,"finding":"In budding yeast, overexpression of Gtr2 (but not its heterodimeric partner Gtr1) specifically suppresses both the toxicity and secretory defect caused by small molecules that perturb late exocytic transport, indicating Gtr2 can regulate a late exocytic pathway at the Golgi independently of Gtr1.","method":"Chemical-genetic screen, overexpression suppression assay, secretory cargo accumulation assay","journal":"Eukaryotic cell","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression suppression assay, single lab, indirect readout; no direct biochemical mechanism established","pmids":["19897736"],"is_preprint":false}],"current_model":"RRAGC encodes RagC, a Ras-family GTPase that forms an obligate heterodimer with RagA/B (Gtr1 in yeast) and localizes to the lysosomal/vacuolar membrane where, in its GDP-bound state, it enables the active Rag heterodimer to recruit and activate mTORC1 in response to amino acids; this nucleotide state is controlled by the FLCN-FNIP/Lst4-Lst7 GAP complex (which converts RagC to GDP-bound) and is read out through increased raptor binding; oncogenic RRAGC mutations cluster around the nucleotide-binding site, lock RagC in a raptor-binding-competent conformation, disrupt FLCN interaction, and render mTORC1 constitutively active regardless of amino acid availability, while transcription of RRAGC itself is epigenetically repressed by EHMT2-mediated H3K9 dimethylation in a ROS-dependent manner."},"narrative":{"mechanistic_narrative":"RRAGC encodes RagC, a Ras-family GTPase that operates as a nucleotide-state-dependent switch controlling amino acid-driven activation of mTORC1 at the lysosomal/vacuolar membrane [PMID:26691987, PMID:25046117]. Studies of the yeast ortholog Gtr2 establish that it functions as an obligate partner within the Rag/EGO heterodimer, directly binding the TORC1 subunit Kog1 and coupling TORC1 localization and activity to the Gtr1/Gtr2 nucleotide state [PMID:25046117, PMID:26609069], a configuration dependent on the EGO complex scaffold Ego3 [PMID:23123112]. Conversion of RagC/Gtr2 to its GDP-bound state is driven by GAP complexes — the Lst4-Lst7 complex (functionally conserved with mammalian FLCN-FNIP) acts on Gtr2 at the vacuolar membrane upon amino acid refeeding to promote TORC1 activation [PMID:26387955], and the SEAC-EGOC supercomplex serves as the amino acid-sensing hub whose GAP activity is essential for TORC1 regulation [PMID:bio_10.1101_2024.10.05.616782]. In disease, recurrent somatic and de novo RRAGC missense mutations cluster around the GTP/GDP-binding site, increase binding to raptor (RPTOR), decrease interaction with the tumor suppressor FLCN, and render mTORC1 signaling constitutively active and resistant to amino acid deprivation [PMID:26691987, PMID:27267853, PMID:27234373, PMID:37057673], driving follicular lymphoma and a developmental disorder marked by increased cell size and dysregulated p70S6K and TFEB signaling [PMID:37057673]. RRAGC raptor-dependent signaling is pharmacologically targetable, as RagC T90N-mutant cells are sensitized to raptor-depleting agents [PMID:37749558]. Transcription of RRAGC is epigenetically repressed by EHMT2-mediated H3K9 dimethylation at the RRAGC locus in a ROS-dependent manner [PMID:32684241].","teleology":[{"year":2012,"claim":"Placing RagC within an amino acid signaling cascade required defining where the Rag GTPases act relative to TORC1, answered by epistasis showing the Gtr1/Gtr2 heterodimer colocalizes with TORC1 at the vacuole downstream of Vam6 and upstream of TORC1.","evidence":"Genetic epistasis and colocalization imaging in fission yeast, with crystallography of the EGO scaffold Ego3","pmids":["22344254","23123112"],"confidence":"Medium","gaps":["Direct nucleotide-state dependence of RagC not yet resolved","Mammalian RagC behavior inferred from yeast orthologs"]},{"year":2014,"claim":"How RagC engages the TORC1 machinery was clarified by showing Gtr2 directly binds the TORC1 subunit Kog1 and that GDP-bound Gtr1 (dependent on this binding) drives TORC1 inactivation and autophagy.","evidence":"Direct binding assay, genome-wide deletion epistasis, autophagy and Tor1 localization readouts in budding yeast","pmids":["25046117"],"confidence":"Medium","gaps":["Single lab","Mammalian raptor-binding interface not directly mapped here"]},{"year":2015,"claim":"The mechanism setting RagC nucleotide state was established by identifying Lst4-Lst7 as a GAP for Gtr2 that converts it to GDP-bound, demonstrating GAP-driven RagC inactivation is required for amino acid-stimulated TORC1 activation.","evidence":"In vitro GAP assay, vacuolar localization imaging, glutamine refeeding and epistasis in yeast; functional parallels to TORC1 localization-coupled switching","pmids":["26387955","26609069"],"confidence":"High","gaps":["Mammalian FLCN-FNIP GAP activity inferred by conservation rather than measured here","Kinetics of nucleotide cycling in vivo not quantified"]},{"year":2015,"claim":"The clinical relevance of RagC was established by finding recurrent somatic RRAGC mutations in follicular lymphoma that increase raptor binding and render mTORC1 resistant to amino acid deprivation, defining them as gain-of-function activators.","evidence":"Reciprocal Co-IP raptor-binding assays and mTORC1 activity readouts under amino acid deprivation in HEK293 cells","pmids":["26691987"],"confidence":"High","gaps":["Structural basis of conformational locking not solved","In vivo tumorigenesis not directly demonstrated"]},{"year":2016,"claim":"The structural logic of oncogenic RRAGC mutations was defined by showing hotspot variants cluster at the nucleotide-binding site, simultaneously increase raptor binding and disrupt FLCN interaction, with yeast Gtr2 mutants phenocopying the effect.","evidence":"Co-IP, S6K phosphorylation western blots, yeast functional complementation, 3D modeling; independent de novo S75Y variant validated by overexpression and molecular dynamics","pmids":["27267853","27234373"],"confidence":"High","gaps":["No experimental structure of mutant RagC-FLCN complex","Allosteric path linking nucleotide site to raptor interface not resolved"]},{"year":2016,"claim":"Membrane tethering of the Rag GTPases was addressed by showing Lam2 (LAMTOR2 homolog) physically interacts with Npr2 and Gtr1 and tethers GDP-bound Gtr1 to the vacuole to suppress TORC1.","evidence":"Co-IP, vacuolar localization imaging, Rps6 phosphorylation readout, and epistasis in fission yeast","pmids":["27227887"],"confidence":"Medium","gaps":["Mammalian Ragulator-dependent tethering of RagC not directly tested here","Single lab"]},{"year":2020,"claim":"Regulation of RRAGC at the transcriptional level was established by showing EHMT2 directly represses RRAGC via H3K9 dimethylation at the locus in a ROS-dependent manner.","evidence":"ChIP for EHMT2 occupancy, RNA-seq, sgRNA loss-of-function, and ROS-scavenger treatment in hepatocellular carcinoma cells","pmids":["32684241"],"confidence":"Medium","gaps":["Functional consequence of RRAGC derepression on mTORC1 not quantified here","Single lab"]},{"year":2023,"claim":"Germline RRAGC variation as a developmental disease mechanism was established by showing de novo missense variants constitutively activate mTORC1 with increased cell size and decoupling of mTOR localization from metabolic state; raptor was confirmed as the actionable downstream node.","evidence":"Patient-derived fibroblasts and HEK293 models, p70S6K/TFEB readouts, localization imaging; raptor-depleting cardamonin sensitivity with shRNA epistasis and xenograft validation","pmids":["37057673","37749558"],"confidence":"Medium","gaps":["Single lab for each study","Long-term organismal consequences not modeled"]},{"year":2024,"claim":"The architecture of the amino acid-sensing hub was resolved by a cryo-EM structure of the SEAC-EGOC supercomplex, showing SEAC binds active GTP-loaded EGOC and that its GAP activity is essential for amino acid-dependent TORC1 regulation.","evidence":"Cryo-EM structure determination, in vitro GAP assay, and SEAC subunit deletion epistasis in yeast (preprint)","pmids":["bio_10.1101_2024.10.05.616782"],"confidence":"High","gaps":["Mammalian equivalent supercomplex not structurally resolved","Preprint, not peer-reviewed"]},{"year":null,"claim":"How oncogenic and developmental RRAGC mutations structurally lock the heterodimer into a raptor-competent, FLCN-resistant conformation, and whether RagC has Gtr1-independent roles, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No experimental structure of mutant mammalian RagC heterodimer with raptor or FLCN","Gtr2-specific Golgi/exocytic function (idx 13) lacks direct biochemical mechanism","Whether transcriptional repression of RRAGC alters tumor mTORC1 output is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[5,12]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,6,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,7,10]},{"term_id":"GO:0005773","term_label":"vacuole","supporting_discovery_ids":[5,7,8,10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,3]}],"complexes":["Rag GTPase heterodimer (RagA/B-RagC)","EGO complex (EGOC)","TORC1/mTORC1"],"partners":["RPTOR","FLCN","RRAGA","KOG1","LST4","LST7","EHMT2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HB90","full_name":"Ras-related GTP-binding protein C","aliases":["GTPase-interacting protein 2","TIB929"],"length_aa":399,"mass_kda":44.2,"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:20381137, PubMed:24095279, PubMed:27234373, PubMed:31601708, PubMed:31601764, PubMed:32612235, PubMed:34071043, PubMed:36697823, PubMed:37057673). Forms heterodimeric Rag complexes with RagA/RRAGA or RagB/RRAGB and cycles between an inactive GTP-bound and an active GDP-bound form: RagC/RRAGC is in its active form when GDP-bound RagC/RRAGC forms a complex with GTP-bound RagA/RRAGA (or RagB/RRAGB) and in an inactive form when GTP-bound RagC/RRAGC heterodimerizes with GDP-bound RagA/RRAGA (or RagB/RRAGB) (PubMed:24095279, PubMed:31601708, PubMed:31601764, PubMed:32868926). In its GDP-bound active form, promotes the recruitment of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB (PubMed:20381137, PubMed:24095279, PubMed:27234373, PubMed:32612235, PubMed:36697823). This is a crucial step in the activation of the MTOR signaling cascade by amino acids (PubMed:20381137, PubMed:24095279, PubMed:27234373). Also plays a central role in the non-canonical mTORC1 complex, which acts independently of RHEB and specifically mediates phosphorylation of MiT/TFE factors TFEB and TFE3: GDP-bound RagC/RRAGC mediates recruitment of MiT/TFE factors TFEB and TFE3 (PubMed:32612235, PubMed:36697823)","subcellular_location":"Cytoplasm; Nucleus; Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q9HB90/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RRAGC","classification":"Not Classified","n_dependent_lines":378,"n_total_lines":1208,"dependency_fraction":0.3129139072847682},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RRAGC","total_profiled":1310},"omim":[{"mim_id":"620609","title":"LONG-OLSEN-DISTELMAIER SYNDROME; LNGODS","url":"https://www.omim.org/entry/620609"},{"mim_id":"618834","title":"LATE ENDOSOMAL/LYSOSOMAL ADAPTOR, MAPK AND MTOR ACTIVATOR 4; LAMTOR4","url":"https://www.omim.org/entry/618834"},{"mim_id":"616203","title":"SOLUTE CARRIER FAMILY 38, MEMBER 9; SLC38A9","url":"https://www.omim.org/entry/616203"},{"mim_id":"611534","title":"NUCLEOLAR PROTEIN 8; NOL8","url":"https://www.omim.org/entry/611534"},{"mim_id":"608521","title":"LATE ENDOSOMAL/LYSOSOMAL ADAPTOR, MAPK AND MTOR ACTIVATOR 5; LAMTOR5","url":"https://www.omim.org/entry/608521"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RRAGC"},"hgnc":{"alias_symbol":["GTR2","FLJ13311"],"prev_symbol":[]},"alphafold":{"accession":"Q9HB90","domains":[{"cath_id":"3.40.50.300","chopping":"62-120_130-235","consensus_level":"high","plddt":77.0407,"start":62,"end":235},{"cath_id":"3.30.450.190","chopping":"239-371","consensus_level":"high","plddt":83.7617,"start":239,"end":371}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HB90","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HB90-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HB90-F1-predicted_aligned_error_v6.png","plddt_mean":68.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RRAGC","jax_strain_url":"https://www.jax.org/strain/search?query=RRAGC"},"sequence":{"accession":"Q9HB90","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HB90.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HB90/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HB90"}},"corpus_meta":[{"pmid":"26691987","id":"PMC_26691987","title":"Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma.","date":"2015","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26691987","citation_count":162,"is_preprint":false},{"pmid":"26387955","id":"PMC_26387955","title":"Amino Acids Stimulate TORC1 through Lst4-Lst7, a GTPase-Activating Protein Complex for the Rag Family GTPase Gtr2.","date":"2015","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26387955","citation_count":109,"is_preprint":false},{"pmid":"26609069","id":"PMC_26609069","title":"Dynamic relocation of the TORC1-Gtr1/2-Ego1/2/3 complex is regulated by Gtr1 and Gtr2.","date":"2015","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/26609069","citation_count":62,"is_preprint":false},{"pmid":"25046117","id":"PMC_25046117","title":"Reciprocal conversion of Gtr1 and Gtr2 nucleotide-binding states by Npr2-Npr3 inactivates TORC1 and induces autophagy.","date":"2014","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/25046117","citation_count":61,"is_preprint":false},{"pmid":"22344254","id":"PMC_22344254","title":"The Vam6 and Gtr1-Gtr2 pathway activates TORC1 in response to amino acids in fission yeast.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/22344254","citation_count":54,"is_preprint":false},{"pmid":"23123112","id":"PMC_23123112","title":"Ego3 functions as a homodimer to mediate the interaction between Gtr1-Gtr2 and Ego1 in the ego complex to activate TORC1.","date":"2012","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/23123112","citation_count":52,"is_preprint":false},{"pmid":"27267853","id":"PMC_27267853","title":"Recurrent Mutations in the MTOR Regulator RRAGC in Follicular Lymphoma.","date":"2016","source":"Clinical cancer research : an official journal of the American Association for Cancer 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one","url":"https://pubmed.ncbi.nlm.nih.gov/27227887","citation_count":9,"is_preprint":false},{"pmid":"37057673","id":"PMC_37057673","title":"De novo missense variants in RRAGC lead to a fatal mTORopathy of early childhood.","date":"2023","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37057673","citation_count":6,"is_preprint":false},{"pmid":"19897736","id":"PMC_19897736","title":"A chemical genetic screen for modulators of exocytic transport identifies inhibitors of a transport mechanism linked to GTR2 function.","date":"2009","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/19897736","citation_count":6,"is_preprint":false},{"pmid":"37749558","id":"PMC_37749558","title":"Raptor mediates the selective inhibitory effect of cardamonin on RRAGC-mutant B cell lymphoma.","date":"2023","source":"BMC complementary medicine and therapies","url":"https://pubmed.ncbi.nlm.nih.gov/37749558","citation_count":2,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.05.616782","title":"Structure and function of the yeast amino acid-sensing SEAC-EGOC supercomplex","date":"2024-10-05","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.05.616782","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.21.624702","title":"<i>SFPQ-TFE3</i>  gene fusion reciprocally regulates mTORC1 activity and induces lineage plasticity in a novel mouse model of renal tumorigenesis","date":"2024-11-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.21.624702","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11386,"output_tokens":3741,"usd":0.045137,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11335,"output_tokens":3675,"usd":0.074275,"stage2_stop_reason":"end_turn"},"total_usd":0.119412,"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\": 2015,\n      \"finding\": \"Recurrent somatic RRAGC mutations in follicular lymphoma increase raptor (RPTOR) binding while rendering mTORC1 signaling resistant to amino acid deprivation, establishing these variants as gain-of-function activators of mTORC1.\",\n      \"method\": \"Co-immunoprecipitation (raptor binding assay), mTORC1 activity assays under amino acid deprivation in stable HEK293 cells expressing mutant RRAGC\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays plus functional mTORC1 readout, replicated in two independent studies (PMID:26691987 and PMID:27267853)\",\n      \"pmids\": [\"26691987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Follicular lymphoma-associated RRAGC hotspot mutations cluster around the GTP/GDP-binding site, increase binding to RPTOR (raptor), substantially decrease interaction with the tumor suppressor FLCN (folliculin), and elevate mTOR signaling (S6K phosphorylation) in a leucine-independent manner; equivalent Gtr2 mutations in yeast phenocopy these effects.\",\n      \"method\": \"Co-immunoprecipitation, western blot (S6K phosphorylation), stable retroviral and lentiviral cell lines, yeast functional complementation, 3D protein modeling\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, functional mTORC1 readout, yeast epistasis), independent from PMID:26691987\",\n      \"pmids\": [\"27267853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A de novo S75Y missense mutation in RRAGC renders AD293 cells partially insensitive to amino acid deprivation, resulting in increased mTORC1 signaling compared to wild-type RagC, establishing this as a gain-of-function mutation.\",\n      \"method\": \"Overexpression of RagC(S75Y) in AD293 cells, mTORC1 activity assay under amino acid deprivation, in silico molecular dynamics simulation predicting disruption of GDP ligand interactions\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean functional mTORC1 readout by overexpression in a single lab; computational modeling supports mechanism but no mutagenesis or structural validation\",\n      \"pmids\": [\"27234373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"De novo RRAGC missense variants (Thr90Asn, Pro118Leu, Trp115Arg) constitutively activate mTORC1: patient-derived fibroblasts with Thr90Asn show increased cell size, dysregulated p70S6K and TFEB signaling, and decoupling of mTOR subcellular localization from metabolic state; all three variants confirmed in HEK293 cell model.\",\n      \"method\": \"Patient-derived fibroblast studies, HEK293 cell overexpression model, western blot (p70S6K phosphorylation), TFEB signaling assay, mTOR subcellular localization imaging\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal models (patient fibroblasts + HEK293), multiple mTORC1 readouts, single lab\",\n      \"pmids\": [\"37057673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cardamonin disrupts mTOR-Raptor complex interactions by reducing Raptor protein levels; RRAGC T90N-mutant cells show elevated mTORC1 activity and increased sensitivity to cardamonin; Raptor knockdown abolishes cardamonin's inhibitory effects, placing Raptor downstream of RRAGC in the mTORC1 pathway.\",\n      \"method\": \"Co-immunoprecipitation (mTOR-Raptor-RagC interactions), lentiviral overexpression of RagC WT and T90N, shRNA Raptor knockdown, western blot (mTOR and S6K1 phosphorylation), CCK-8 viability assay, xenograft mouse model\",\n      \"journal\": \"BMC complementary medicine and therapies\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus genetic epistasis (Raptor KD rescue), in vivo validation, single lab\",\n      \"pmids\": [\"37749558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In yeast, Lst4-Lst7 functions as a GAP complex for Gtr2 (the RRAGC ortholog) and localizes to the vacuolar membrane in amino acid-starved cells; amino acid refeeding (glutamine) transiently stimulates Lst4-Lst7 to act on Gtr2, promoting TORC1 activation, demonstrating that GAP-mediated conversion of Gtr2 to GDP-bound state is required for TORC1 activation.\",\n      \"method\": \"Biochemical GAP assay, vacuolar membrane localization imaging, genetic epistasis in yeast, amino acid stimulation experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro GAP activity assay combined with localization and epistasis in yeast; functionally conserved with mammalian FNIP-FLCN complex\",\n      \"pmids\": [\"26387955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In yeast, Gtr2 (RRAGC ortholog) directly binds the TORC1 subunit Kog1; GDP-bound Gtr1 (requiring Gtr2-Kog1 direct binding) is required for TORC1 inactivation and autophagy induction; Npr2-Npr3 act upstream of Gtr1-Gtr2 to regulate these nucleotide states.\",\n      \"method\": \"Genetic epistasis (genome-wide deletion screen, double mutant analysis), direct binding assay (Gtr2-Kog1), autophagy assay, Tor1 localization imaging\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay combined with genetic epistasis, single lab, multiple readouts\",\n      \"pmids\": [\"25046117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In budding yeast, TORC1 localization to vacuolar puncta is facilitated by direct binding to Gtr2 (RRAGC ortholog) and is coupled to TORC1 inactivation; when Gtr1 is GDP-bound, TORC1-Gtr1/2-Ego complex relocalizes to puncta, whereas GTP-Gtr1 promotes vacuolar membrane localization and TORC1 activation.\",\n      \"method\": \"Fluorescence microscopy (colocalization), genetic mutant analysis (GTP/GDP-locked Gtr1), TORC1 activity assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence, multiple mutant alleles, single lab\",\n      \"pmids\": [\"26609069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In fission yeast, Gtr1 and Gtr2 (RRAGC ortholog) colocalize with TORC1 at vacuoles and function downstream of Vam6 and upstream of TORC1 in the amino acid signaling pathway, as established by epistasis analysis.\",\n      \"method\": \"Genetic epistasis analysis, colocalization imaging, growth and mating/sporulation phenotypic assays in S. pombe\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple alleles and phenotypic readouts, colocalization, single lab\",\n      \"pmids\": [\"22344254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of Ego3 reveals a homodimeric fold similar to Gtr1-Gtr2 C-terminal domains; structural and genetic data identify a binding site for Gtr1-Gtr2 on Ego3, and the Ego3 dimer conformation is essential for EGO complex integrity and TORC1 signaling.\",\n      \"method\": \"X-ray crystallography, structure-guided mutagenesis, genetic complementation in yeast\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus structure-guided mutagenesis, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23123112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In fission yeast, loss of Lam2 (LAMTOR2 homolog) or Npr2-Npr3 diminishes vacuolar localization and protein levels of Gtr1 and Gtr2; Lam2 physically interacts with Npr2 and Gtr1 and functions as a tether for GDP-bound Gtr1 to the vacuolar membrane, thereby suppressing TORC1 activity.\",\n      \"method\": \"Genetic epistasis, co-immunoprecipitation (Lam2-Npr2-Gtr1 interaction), fluorescence microscopy (vacuolar localization), TORC1 activity assay (Rps6 phosphorylation)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus localization with functional mTORC1 readout, genetic epistasis, single lab\",\n      \"pmids\": [\"27227887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EHMT2 (GLP/G9a) directly suppresses RRAGC gene expression in hepatocellular carcinoma cells through H3K9 dimethylation at the RRAGC locus in a ROS-dependent manner, as demonstrated by ChIP assay showing EHMT2 occupancy and upregulation of RRAGC protein upon EHMT2 inhibition.\",\n      \"method\": \"ChIP assay, RNA sequencing, sgRNA-mediated loss-of-function, proteomic analysis, ROS scavenger (NAC) treatment\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP assay directly demonstrating EHMT2 occupancy at RRAGC locus, multiple orthogonal methods (ChIP + RNA-seq + sgRNA KO), single lab\",\n      \"pmids\": [\"32684241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structure of the yeast SEAC-EGOC supercomplex reveals that a single SEAC binds two EGOC molecules via SEACIT exclusively when Gtr1 (RagA/B ortholog) is GTP-loaded (active EGOC); SEAC functions as a GAP for Gtr1, and its GAP activity is essential for TORC1 regulation by amino acids; loss of GAP activity phenocopies loss of Gtr1-Gtr2, establishing the SEAC-EGOC as the amino acid-sensing hub.\",\n      \"method\": \"Cryo-electron microscopy structure determination, in vitro GAP assay, genetic loss-of-function (SEAC subunit deletions), TORC1 activity assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure plus in vitro GAP activity assay plus genetic epistasis; preprint but multiple orthogonal methods\",\n      \"pmids\": [\"bio_10.1101_2024.10.05.616782\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In budding yeast, overexpression of Gtr2 (but not its heterodimeric partner Gtr1) specifically suppresses both the toxicity and secretory defect caused by small molecules that perturb late exocytic transport, indicating Gtr2 can regulate a late exocytic pathway at the Golgi independently of Gtr1.\",\n      \"method\": \"Chemical-genetic screen, overexpression suppression assay, secretory cargo accumulation assay\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression suppression assay, single lab, indirect readout; no direct biochemical mechanism established\",\n      \"pmids\": [\"19897736\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RRAGC encodes RagC, a Ras-family GTPase that forms an obligate heterodimer with RagA/B (Gtr1 in yeast) and localizes to the lysosomal/vacuolar membrane where, in its GDP-bound state, it enables the active Rag heterodimer to recruit and activate mTORC1 in response to amino acids; this nucleotide state is controlled by the FLCN-FNIP/Lst4-Lst7 GAP complex (which converts RagC to GDP-bound) and is read out through increased raptor binding; oncogenic RRAGC mutations cluster around the nucleotide-binding site, lock RagC in a raptor-binding-competent conformation, disrupt FLCN interaction, and render mTORC1 constitutively active regardless of amino acid availability, while transcription of RRAGC itself is epigenetically repressed by EHMT2-mediated H3K9 dimethylation in a ROS-dependent manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RRAGC encodes RagC, a Ras-family GTPase that operates as a nucleotide-state-dependent switch controlling amino acid-driven activation of mTORC1 at the lysosomal/vacuolar membrane [#0, #6]. Studies of the yeast ortholog Gtr2 establish that it functions as an obligate partner within the Rag/EGO heterodimer, directly binding the TORC1 subunit Kog1 and coupling TORC1 localization and activity to the Gtr1/Gtr2 nucleotide state [#6, #7], a configuration dependent on the EGO complex scaffold Ego3 [#9]. Conversion of RagC/Gtr2 to its GDP-bound state is driven by GAP complexes — the Lst4-Lst7 complex (functionally conserved with mammalian FLCN-FNIP) acts on Gtr2 at the vacuolar membrane upon amino acid refeeding to promote TORC1 activation [#5], and the SEAC-EGOC supercomplex serves as the amino acid-sensing hub whose GAP activity is essential for TORC1 regulation [#12]. In disease, recurrent somatic and de novo RRAGC missense mutations cluster around the GTP/GDP-binding site, increase binding to raptor (RPTOR), decrease interaction with the tumor suppressor FLCN, and render mTORC1 signaling constitutively active and resistant to amino acid deprivation [#0, #1, #2, #3], driving follicular lymphoma and a developmental disorder marked by increased cell size and dysregulated p70S6K and TFEB signaling [#3]. RRAGC raptor-dependent signaling is pharmacologically targetable, as RagC T90N-mutant cells are sensitized to raptor-depleting agents [#4]. Transcription of RRAGC is epigenetically repressed by EHMT2-mediated H3K9 dimethylation at the RRAGC locus in a ROS-dependent manner [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Placing RagC within an amino acid signaling cascade required defining where the Rag GTPases act relative to TORC1, answered by epistasis showing the Gtr1/Gtr2 heterodimer colocalizes with TORC1 at the vacuole downstream of Vam6 and upstream of TORC1.\",\n      \"evidence\": \"Genetic epistasis and colocalization imaging in fission yeast, with crystallography of the EGO scaffold Ego3\",\n      \"pmids\": [\"22344254\", \"23123112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct nucleotide-state dependence of RagC not yet resolved\", \"Mammalian RagC behavior inferred from yeast orthologs\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"How RagC engages the TORC1 machinery was clarified by showing Gtr2 directly binds the TORC1 subunit Kog1 and that GDP-bound Gtr1 (dependent on this binding) drives TORC1 inactivation and autophagy.\",\n      \"evidence\": \"Direct binding assay, genome-wide deletion epistasis, autophagy and Tor1 localization readouts in budding yeast\",\n      \"pmids\": [\"25046117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mammalian raptor-binding interface not directly mapped here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The mechanism setting RagC nucleotide state was established by identifying Lst4-Lst7 as a GAP for Gtr2 that converts it to GDP-bound, demonstrating GAP-driven RagC inactivation is required for amino acid-stimulated TORC1 activation.\",\n      \"evidence\": \"In vitro GAP assay, vacuolar localization imaging, glutamine refeeding and epistasis in yeast; functional parallels to TORC1 localization-coupled switching\",\n      \"pmids\": [\"26387955\", \"26609069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian FLCN-FNIP GAP activity inferred by conservation rather than measured here\", \"Kinetics of nucleotide cycling in vivo not quantified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The clinical relevance of RagC was established by finding recurrent somatic RRAGC mutations in follicular lymphoma that increase raptor binding and render mTORC1 resistant to amino acid deprivation, defining them as gain-of-function activators.\",\n      \"evidence\": \"Reciprocal Co-IP raptor-binding assays and mTORC1 activity readouts under amino acid deprivation in HEK293 cells\",\n      \"pmids\": [\"26691987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of conformational locking not solved\", \"In vivo tumorigenesis not directly demonstrated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The structural logic of oncogenic RRAGC mutations was defined by showing hotspot variants cluster at the nucleotide-binding site, simultaneously increase raptor binding and disrupt FLCN interaction, with yeast Gtr2 mutants phenocopying the effect.\",\n      \"evidence\": \"Co-IP, S6K phosphorylation western blots, yeast functional complementation, 3D modeling; independent de novo S75Y variant validated by overexpression and molecular dynamics\",\n      \"pmids\": [\"27267853\", \"27234373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental structure of mutant RagC-FLCN complex\", \"Allosteric path linking nucleotide site to raptor interface not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Membrane tethering of the Rag GTPases was addressed by showing Lam2 (LAMTOR2 homolog) physically interacts with Npr2 and Gtr1 and tethers GDP-bound Gtr1 to the vacuole to suppress TORC1.\",\n      \"evidence\": \"Co-IP, vacuolar localization imaging, Rps6 phosphorylation readout, and epistasis in fission yeast\",\n      \"pmids\": [\"27227887\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian Ragulator-dependent tethering of RagC not directly tested here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Regulation of RRAGC at the transcriptional level was established by showing EHMT2 directly represses RRAGC via H3K9 dimethylation at the locus in a ROS-dependent manner.\",\n      \"evidence\": \"ChIP for EHMT2 occupancy, RNA-seq, sgRNA loss-of-function, and ROS-scavenger treatment in hepatocellular carcinoma cells\",\n      \"pmids\": [\"32684241\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of RRAGC derepression on mTORC1 not quantified here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Germline RRAGC variation as a developmental disease mechanism was established by showing de novo missense variants constitutively activate mTORC1 with increased cell size and decoupling of mTOR localization from metabolic state; raptor was confirmed as the actionable downstream node.\",\n      \"evidence\": \"Patient-derived fibroblasts and HEK293 models, p70S6K/TFEB readouts, localization imaging; raptor-depleting cardamonin sensitivity with shRNA epistasis and xenograft validation\",\n      \"pmids\": [\"37057673\", \"37749558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab for each study\", \"Long-term organismal consequences not modeled\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The architecture of the amino acid-sensing hub was resolved by a cryo-EM structure of the SEAC-EGOC supercomplex, showing SEAC binds active GTP-loaded EGOC and that its GAP activity is essential for amino acid-dependent TORC1 regulation.\",\n      \"evidence\": \"Cryo-EM structure determination, in vitro GAP assay, and SEAC subunit deletion epistasis in yeast (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.10.05.616782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian equivalent supercomplex not structurally resolved\", \"Preprint, not peer-reviewed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How oncogenic and developmental RRAGC mutations structurally lock the heterodimer into a raptor-competent, FLCN-resistant conformation, and whether RagC has Gtr1-independent roles, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental structure of mutant mammalian RagC heterodimer with raptor or FLCN\", \"Gtr2-specific Golgi/exocytic function (idx 13) lacks direct biochemical mechanism\", \"Whether transcriptional repression of RRAGC alters tumor mTORC1 output is untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [5, 12]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 7, 10]},\n      {\"term_id\": \"GO:0005773\", \"supporting_discovery_ids\": [5, 7, 8, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-165159\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"complexes\": [\"Rag GTPase heterodimer (RagA/B-RagC)\", \"EGO complex (EGOC)\", \"TORC1/mTORC1\"],\n    \"partners\": [\"RPTOR\", \"FLCN\", \"RRAGA\", \"Kog1\", \"Lst4\", \"Lst7\", \"EHMT2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}