{"gene":"RRAGA","run_date":"2026-06-10T07:46:27","timeline":{"discoveries":[{"year":1995,"finding":"RagA (and RagBs) are novel Ras-related GTP-binding proteins that bind GTP in a specific and saturable manner; bound GTP is rapidly exchangeable but no intrinsic GTPase activity was detected. They share ~52% identity with yeast Gtr1p, defining a novel subfamily of Ras-homologous GTPases with an unusually large C-terminal domain.","method":"GST fusion protein GTP-binding assay (radiolabeled GTPγS), sequence alignment, recombinant protein biochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro biochemical assay with recombinant protein demonstrating GTP binding and exchange; replicated for multiple family members in same study with rigorous controls","pmids":["7499430"],"is_preprint":false},{"year":1998,"finding":"RagA is a functional homologue of S. cerevisiae Gtr1p and participates in the Ran/Gsp1-GTPase pathway: human RagA and RagBs rescued cold sensitivity of gtr1-11 yeast, and a dominant-negative RagA (T21L) partially suppressed both rcc1- and rna1-1 mutations. Wild-type RagA localizes to the cytoplasm, but the dominant-negative T21L form relocalizes to nuclear speckles co-localizing with SC-35, while constitutively active Q66L remains cytoplasmic — indicating nucleotide-state-dependent nucleocytoplasmic shuttling.","method":"Yeast complementation assay, genetic epistasis (suppressor analysis), fluorescence localization/immunostaining with SC-35 co-localization","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic complementation, epistasis, localization), functionally linking RagA nucleotide state to subcellular distribution and Ran pathway","pmids":["9394008"],"is_preprint":false},{"year":2010,"finding":"In C. elegans, raga-1 (RagA ortholog) acts in the TOR pathway to regulate lifespan and behavioral aging: loss-of-function extended vigorous locomotion late in life; gain-of-function curtailed behavioral vitality and shortened lifespan; dominant-negative lengthened lifespan. RNAi experiments placed raga-1 upstream in the TOR pathway.","method":"C. elegans genetics (loss-of-function, gain-of-function, dominant-negative mutants), RNAi epistasis, behavioral assays (locomotion frequency)","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic loss/gain-of-function with defined phenotypic readout and RNAi pathway placement, single lab","pmids":["20523893"],"is_preprint":false},{"year":2014,"finding":"RagA is essential for embryonic development and for mTORC1 activation by nutrients in mammals: RagA-null mouse embryos die at E10.5 with loss of mTORC1 activity, severe growth defects, and abrogation of nutrient regulation of mTORC1, while growth-factor sensitivity of mTORC1 is maintained. Deletion of RagA in adult mice is also lethal. RagA-specific deletion in liver increases PI3K/Akt signaling, establishing that RagA-dependent mTORC1 activity normally suppresses PI3K/Akt.","method":"Conditional and constitutive mouse knockout (RagA and RagB), primary cell mTORC1 activity assays (nutrient and growth factor stimulation), genetic epistasis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with multiple orthogonal readouts (embryonic lethality, mTORC1 activity, PI3K/Akt signaling), replicated across tissue-specific deletions","pmids":["24768164"],"is_preprint":false},{"year":2015,"finding":"Skp2 E3 ligase mediates K63-linked ubiquitination of RagA; this ubiquitination facilitates recruitment of the GATOR1 complex (a GAP for RagA) to RagA, promoting GTP hydrolysis and thereby attenuating mTORC1 lysosomal recruitment and activation. This constitutes a negative feedback loop activated by amino acids in an mTORC1-dependent manner to prevent mTORC1 hyperactivation.","method":"Co-immunoprecipitation, ubiquitination assays (K63-linkage specificity), mTORC1 lysosomal localization assay, loss-of-function and overexpression with downstream signaling readouts (autophagy, cell size, cilia growth)","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, defined ubiquitin linkage, multiple functional readouts (mTORC1 activity, autophagy, cilia, cell size), mechanistic pathway placement","pmids":["26051179"],"is_preprint":false},{"year":2015,"finding":"DYNLT (Tctex-1 dynein light chain) interacts with RagA via a β-strand in RagA's G3 box (nucleotide-binding region), forming a tripartite complex with dynein intermediate chain, thereby linking RagA to the dynein motor. Both microtubule-associated and cytoplasmic DYNLT can bind RagA equally.","method":"NMR spectroscopy mapping of binding residues, Co-IP/pulldown, identification of interacting domain by deletion mapping","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — NMR with binding-residue mapping plus pulldown, single lab, defines interaction surface","pmids":["26227614"],"is_preprint":false},{"year":2016,"finding":"RRAGA missense mutations (p.Leu60Arg) associated with autosomal dominant cataracts cause increased relocalization of RRAGA to lysosomes, up-regulated mTORC1 phosphorylation, down-regulated autophagy, and altered cell growth in human lens epithelial cells, mechanistically linking RRAGA gain-of-function to mTORC1 hyperactivation and cataract pathology.","method":"Functional studies in human lens epithelial cells: lysosomal localization imaging, mTORC1 phosphorylation assays, autophagy assays, cell growth assays, promoter activity assays","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in relevant cell type, single lab, no in vitro reconstitution","pmids":["27294265"],"is_preprint":false},{"year":2019,"finding":"RagA is required for mTORC1 translocation to lysosomal membranes: siRNA silencing of RagA in PC12 cells blocked LPS-induced mTORC1 lysosomal translocation and activation of p70S6K.","method":"siRNA knockdown, immunofluorescence for mTORC1 lysosomal co-localization, Western blot for p70S6K phosphorylation","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, single method per readout, clean KD with defined cellular phenotype (lysosomal mTORC1 localization)","pmids":["31711501"],"is_preprint":false},{"year":2019,"finding":"RagA interacts with WDR35/IFT121 (a hedgehog signaling/ciliary protein); overexpression of WDR35 decreases phosphorylation of ribosomal S6 protein in a RagA-, RagB-, and RagC-dependent manner, suggesting WDR35 is an upstream negative regulator of mTORC1 acting through RagA.","method":"Co-immunoprecipitation, overexpression with S6 phosphorylation readout, genetic dependence (RagA/B/C requirement)","journal":"Genes to cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP plus downstream phosphorylation assay, single lab, no mechanistic dissection of interaction","pmids":["30570184"],"is_preprint":false},{"year":2023,"finding":"RAGA (RagA) interacts with CD47 and promotes CD47 lysosomal localization and degradation via the endocytosis/lysosome pathway; disruption of RAGA blocks CD47 degradation, leading to CD47 accumulation and increased plasma membrane CD47 expression, thereby reducing phagocytic clearance of cancer cells.","method":"Co-immunoprecipitation, lysosomal localization assay, RAGA loss-of-function, phagocytosis assay, CD47 protein stability assay","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional localization and degradation assays with loss-of-function, multiple readouts, single lab","pmids":["36823443"],"is_preprint":false},{"year":2023,"finding":"In Drosophila gut, RagA knockdown alone induces intestinal thickening and foregastric enlargement. RagA knockdown rescues intestinal thinning and decreased secretory cells in nprl2 mutants (genetic epistasis placing RagA downstream of Nprl2 for these phenotypes), but does not rescue the enlarged forestomach of nprl2 mutants, indicating Nprl2 regulates forestomach development through a RagA-independent mechanism.","method":"Drosophila genetics (RagA RNAi knockdown, nprl2 mutants, double mutant epistasis), immunofluorescence for intestinal morphology and cell composition","journal":"Sheng wu gong cheng xue bao = Chinese journal of biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with two orthogonal phenotypic readouts (morphology and cell composition), single lab","pmids":["37154336"],"is_preprint":false},{"year":2024,"finding":"Hyperactivation of mTORC1 regulator RAGA-1 in C. elegans preserved ribosomal proteins during starvation and accelerated growth recovery after short starvation, but reduced survival under prolonged starvation, demonstrating that RAGA-1-dependent mTORC1 activity controls autophagy-dependent ribosomal protein turnover and balances starvation survival versus recovery speed.","method":"Live imaging, proteomics (proteome quantification), C. elegans RAGA-1 gain-of-function genetics, starvation survival assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — combined live imaging, proteomics, and genetics in C. elegans, preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"In renal tubular epithelial cells, RagA/B deletion inhibits mTORC1 but triggers renal cystogenesis driven by TFEB nuclear translocation; Rag GTPases (including RagA) suppress TFEB in vivo independently of mTORC1, establishing that Rag GTPases are the primary suppressors of TFEB in this context rather than acting solely through mTORC1.","method":"Conditional RagA/B knockout in mouse renal tubular epithelial cells, mTORC1 activity assays, TFEB nuclear localization assays, cystogenesis phenotype, genetic epistasis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional knockout with multiple readouts (cystogenesis, mTORC1, TFEB localization), preprint, single lab","pmids":[],"is_preprint":true}],"current_model":"RagA (RRAGA) is a Ras-related GTPase that binds and slowly exchanges GTP without intrinsic GTPase activity; in its GTP-loaded state it recruits mTORC1 to the lysosomal surface to enable nutrient (amino acid)-dependent mTORC1 activation, while GATOR1 (recruited via Skp2-mediated K63-linked ubiquitination of RagA) acts as a GAP to hydrolyze RagA-GTP and terminate signaling; RagA also suppresses TFEB nuclear translocation independently of mTORC1, interacts with DYNLT dynein light chain and WDR35/IFT121, and promotes lysosomal degradation of CD47, with its nucleotide-bound state governing its nucleocytoplasmic distribution."},"narrative":{"mechanistic_narrative":"RRAGA (RagA) is a Ras-related GTP-binding protein that functions as the master nutrient sensor controlling mTORC1 activation at the lysosome and broader TOR-dependent control of growth, autophagy, and aging [PMID:7499430, PMID:24768164]. Biochemically it binds GTP in a specific, saturable, and rapidly exchangeable manner but lacks detectable intrinsic GTPase activity, defining a novel Ras-homologous subfamily with an unusually large C-terminal domain [PMID:7499430]. In its GTP-loaded state RagA recruits mTORC1 to the lysosomal surface to enable amino-acid-dependent mTORC1 activation, and loss of RagA abolishes nutrient regulation of mTORC1 while leaving growth-factor sensitivity intact, causing embryonic lethality and growth defects in mice; RagA-dependent mTORC1 activity in turn suppresses PI3K/Akt signaling [PMID:24768164, PMID:31711501]. Signaling is terminated by a negative feedback loop in which Skp2 catalyzes K63-linked ubiquitination of RagA to recruit the GATOR1 GAP complex, driving GTP hydrolysis and attenuating mTORC1 recruitment [PMID:26051179]. The nucleotide-bound state also governs RagA's nucleocytoplasmic distribution, with dominant-negative RagA relocalizing to nuclear speckles co-localizing with SC-35 [PMID:9394008]. Beyond mTORC1, RagA acts as the primary in vivo suppressor of TFEB nuclear translocation independently of mTORC1, links to the dynein motor through DYNLT binding at its G3 nucleotide-binding box [PMID:26227614], and promotes endolysosomal degradation of CD47 to enhance phagocytic clearance of cancer cells [PMID:36823443]. A gain-of-function RRAGA missense mutation (p.Leu60Arg) causing autosomal dominant cataract drives increased lysosomal localization, mTORC1 hyperactivation, and suppressed autophagy in lens epithelial cells [PMID:27294265].","teleology":[{"year":1995,"claim":"Established RagA as a biochemical entity: a Ras-related protein that binds and exchanges GTP but, unlike canonical GTPases, lacks intrinsic hydrolytic activity, predicting it would require an external GAP.","evidence":"GST-fusion radiolabeled GTPγS binding assays and sequence alignment with recombinant protein","pmids":["7499430"],"confidence":"High","gaps":["No cellular function assigned at this stage","GAP and exchange factors unidentified","Role of the large C-terminal domain undefined"]},{"year":1998,"claim":"Linked RagA's nucleotide state to its subcellular distribution and placed it functionally in the Ran/Gsp1 GTPase pathway via yeast complementation, the first connection between RagA conformation and localization.","evidence":"Yeast complementation of gtr1-11, genetic suppressor analysis, and SC-35 co-localization imaging of T21L and Q66L mutants","pmids":["9394008"],"confidence":"High","gaps":["Mammalian relevance of Ran-pathway link not demonstrated","mTORC1 role not yet known","Mechanism of nuclear speckle relocalization unexplained"]},{"year":2010,"claim":"Demonstrated in vivo that RagA orthologs act upstream in the TOR pathway to control lifespan and behavioral aging, tying nucleotide-state mutants to organismal physiology.","evidence":"C. elegans loss-, gain-, and dominant-negative genetics with RNAi epistasis and locomotion assays","pmids":["20523893"],"confidence":"Medium","gaps":["Molecular mechanism downstream of TOR not dissected","Single model organism","Lysosomal recruitment mechanism not addressed"]},{"year":2014,"claim":"Defined RagA as essential and nutrient-specific for mammalian mTORC1 activation, separating amino-acid from growth-factor inputs and revealing feedback suppression of PI3K/Akt.","evidence":"Constitutive and tissue-specific mouse knockouts with mTORC1 and PI3K/Akt signaling readouts","pmids":["24768164"],"confidence":"High","gaps":["How amino acid signals load GTP onto RagA not resolved","Mechanism of PI3K/Akt suppression unclear"]},{"year":2015,"claim":"Identified the negative-feedback circuit that turns RagA signaling off: Skp2-mediated K63 ubiquitination recruits the GATOR1 GAP to drive RagA-GTP hydrolysis, answering how the GTPase-activity-less RagA is inactivated.","evidence":"Reciprocal Co-IP, K63-linkage-specific ubiquitination assays, and mTORC1 lysosomal localization with autophagy/cell-size readouts","pmids":["26051179"],"confidence":"High","gaps":["Stoichiometry and ubiquitination site mapping incomplete","Deubiquitinase counterbalance not identified"]},{"year":2015,"claim":"Mapped a direct physical link between RagA and the dynein motor, suggesting motor-based positioning of RagA via its nucleotide-binding region.","evidence":"NMR binding-residue mapping at the G3 box plus Co-IP/pulldown defining a tripartite complex with dynein intermediate chain","pmids":["26227614"],"confidence":"Medium","gaps":["Functional consequence of dynein binding for mTORC1 signaling untested","Single lab, no in vivo validation"]},{"year":2016,"claim":"Provided a human disease link, showing a RRAGA gain-of-function mutation causes mTORC1 hyperactivation and autophagy suppression underlying autosomal dominant cataract.","evidence":"Functional assays in human lens epithelial cells: lysosomal imaging, mTORC1 phosphorylation, autophagy and growth assays","pmids":["27294265"],"confidence":"Medium","gaps":["No in vitro reconstitution of mutant GTPase behavior","Single lab"]},{"year":2019,"claim":"Extended the lysosomal recruitment role to inflammatory signaling and identified candidate upstream regulators acting through RagA.","evidence":"siRNA knockdown with mTORC1/p70S6K readouts (PC12 cells); Co-IP of WDR35/IFT121 with Rag-dependent S6 phosphorylation","pmids":["31711501","30570184"],"confidence":"Low","gaps":["WDR35 link rests on a single Co-IP without mechanistic dissection","Direct vs indirect WDR35-RagA interaction unresolved"]},{"year":2023,"claim":"Revealed an mTORC1-independent function of RagA in cargo turnover, driving endolysosomal degradation of CD47 to control phagocytic clearance.","evidence":"Co-IP, lysosomal localization and CD47 stability assays, RAGA loss-of-function and phagocytosis assays","pmids":["36823443"],"confidence":"Medium","gaps":["Mechanism coupling RagA to CD47 endocytosis unclear","Whether GTP state controls CD47 degradation untested"]},{"year":2025,"claim":"Established Rag GTPases including RagA as the primary in vivo suppressors of TFEB, distinct from their mTORC1 role, with loss triggering renal cystogenesis.","evidence":"Conditional RagA/B mouse renal knockout with mTORC1, TFEB localization, and cystogenesis readouts (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Direct biochemical basis of mTORC1-independent TFEB suppression undefined"]},{"year":null,"claim":"The molecular events that load GTP onto RagA in response to amino acids, and how a single GTPase coordinates its mTORC1-dependent and mTORC1-independent (TFEB, CD47) outputs, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified amino-acid-responsive GEF for RagA in the corpus","Structural basis for selecting downstream effectors unknown","Integration of dynein-based positioning with signaling output untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,12]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[4,6,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9]}],"complexes":["Rag GTPase complex"],"partners":["MTOR","SKP2","GATOR1","DYNLT1","WDR35","CD47"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7L523","full_name":"Ras-related GTP-binding protein A","aliases":["Adenovirus E3 14.7 kDa-interacting protein 1","FIP-1"],"length_aa":313,"mass_kda":36.6,"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:25936802, PubMed:31601708, PubMed:31601764, PubMed:38103557). Forms heterodimeric Rag complexes with RagC/RRAGC or RagD/RRAGD and cycles between an inactive GDP-bound and an active GTP-bound form: RagA/RRAGA is in its active form when GTP-bound RagA/RRAGA forms a complex with GDP-bound RagC/RRAGC (or RagD/RRAGD) and in an inactive form when GDP-bound RagA/RRAGA heterodimerizes with GTP-bound RagC/RRAGC (or RagD/RRAGD) (PubMed:20381137, PubMed:24095279, PubMed:25936802, PubMed:31601708, PubMed:31601764, PubMed:32868926). In its GTP-bound active form, promotes the recruitment of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB (PubMed:20381137, PubMed:25936802, PubMed:31601708, PubMed:31601764). Involved in the RCC1/Ran-GTPase pathway (PubMed:9394008). May play a direct role in a TNF signaling pathway leading to induction of cell death (PubMed:8995684) (Microbial infection) May alternatively act as a cellular target for adenovirus E3-14.7K, an inhibitor of TNF functions, thereby affecting cell death","subcellular_location":"Cytoplasm; Nucleus; Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q7L523/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RRAGA","classification":"Not Classified","n_dependent_lines":398,"n_total_lines":1208,"dependency_fraction":0.3294701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RRAGA","total_profiled":1310},"omim":[{"mim_id":"621247","title":"CLEAVAGE AND POLYADENYLATION SPECIFICITY FACTOR 7; CPSF7","url":"https://www.omim.org/entry/621247"},{"mim_id":"618834","title":"LATE ENDOSOMAL/LYSOSOMAL ADAPTOR, MAPK AND MTOR ACTIVATOR 4; LAMTOR4","url":"https://www.omim.org/entry/618834"},{"mim_id":"618082","title":"WD REPEAT-CONTAINING PROTEIN 33; WDR33","url":"https://www.omim.org/entry/618082"},{"mim_id":"616599","title":"BLOC1-RELATED COMPLEX, SUBUNIT 6; BORCS6","url":"https://www.omim.org/entry/616599"},{"mim_id":"614191","title":"DEP DOMAIN-CONTAINING PROTEIN 5; DEPDC5","url":"https://www.omim.org/entry/614191"}],"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/RRAGA"},"hgnc":{"alias_symbol":["RAGA","FIP-1"],"prev_symbol":[]},"alphafold":{"accession":"Q7L523","domains":[{"cath_id":"3.40.50.300","chopping":"5-178","consensus_level":"high","plddt":95.7136,"start":5,"end":178},{"cath_id":"3.30.450.190","chopping":"184-300","consensus_level":"high","plddt":93.9964,"start":184,"end":300}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L523","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L523-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L523-F1-predicted_aligned_error_v6.png","plddt_mean":92.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RRAGA","jax_strain_url":"https://www.jax.org/strain/search?query=RRAGA"},"sequence":{"accession":"Q7L523","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7L523.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7L523/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L523"}},"corpus_meta":[{"pmid":"7499430","id":"PMC_7499430","title":"Cloning of a novel family of mammalian GTP-binding proteins (RagA, RagBs, RagB1) with remote similarity to the Ras-related GTPases.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7499430","citation_count":110,"is_preprint":false},{"pmid":"24768164","id":"PMC_24768164","title":"RagA, but not RagB, is essential for embryonic development and adult mice.","date":"2014","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/24768164","citation_count":81,"is_preprint":false},{"pmid":"9394008","id":"PMC_9394008","title":"RagA is a functional homologue of S. cerevisiae Gtr1p involved in the Ran/Gsp1-GTPase pathway.","date":"1998","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/9394008","citation_count":80,"is_preprint":false},{"pmid":"26051179","id":"PMC_26051179","title":"Skp2-Mediated RagA Ubiquitination Elicits a Negative Feedback to Prevent Amino-Acid-Dependent mTORC1 Hyperactivation by Recruiting GATOR1.","date":"2015","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/26051179","citation_count":76,"is_preprint":false},{"pmid":"20523893","id":"PMC_20523893","title":"Manipulation of behavioral decline in Caenorhabditis elegans with the Rag GTPase raga-1.","date":"2010","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20523893","citation_count":73,"is_preprint":false},{"pmid":"17965357","id":"PMC_17965357","title":"Characterization of RagA and RagB in Porphyromonas gingivalis: study using gene-deletion mutants.","date":"2007","source":"Journal of medical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/17965357","citation_count":71,"is_preprint":false},{"pmid":"9358168","id":"PMC_9358168","title":"RAGA: RNA sequence alignment by genetic algorithm.","date":"1997","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/9358168","citation_count":45,"is_preprint":false},{"pmid":"27294265","id":"PMC_27294265","title":"Mutations of RagA GTPase in mTORC1 Pathway Are Associated with Autosomal Dominant Cataracts.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27294265","citation_count":29,"is_preprint":false},{"pmid":"31711501","id":"PMC_31711501","title":"Potential link between the RagA-mTOR-p70S6K axis and depressive-behaviors during bacterial liposaccharide challenge.","date":"2019","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/31711501","citation_count":14,"is_preprint":false},{"pmid":"34032024","id":"PMC_34032024","title":"The RagA and RagB proteins of Porphyromonas gingivalis.","date":"2021","source":"Molecular oral microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34032024","citation_count":13,"is_preprint":false},{"pmid":"34707778","id":"PMC_34707778","title":"Botanical Drug Puerarin Ameliorates Liposaccharide-Induced Depressive Behaviors in Mice via Inhibiting RagA/mTOR/p70S6K Pathways.","date":"2021","source":"Oxidative medicine and cellular 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mTORC1","date":"2025-07-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.24.664930","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.17.676758","title":"Proteomic and Kinetic Characterization of Prion Seeding in Distinct Human CJD Strains Unveils Early Diagnostic Biomarkers","date":"2025-09-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.17.676758","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.28.609383","title":"Autophagy-dependent proteome remodelling and ribosome decline balance starvation survival and recovery speed in  <i>C. 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They share ~52% identity with yeast Gtr1p, defining a novel subfamily of Ras-homologous GTPases with an unusually large C-terminal domain.\",\n      \"method\": \"GST fusion protein GTP-binding assay (radiolabeled GTPγS), sequence alignment, recombinant protein biochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro biochemical assay with recombinant protein demonstrating GTP binding and exchange; replicated for multiple family members in same study with rigorous controls\",\n      \"pmids\": [\"7499430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"RagA is a functional homologue of S. cerevisiae Gtr1p and participates in the Ran/Gsp1-GTPase pathway: human RagA and RagBs rescued cold sensitivity of gtr1-11 yeast, and a dominant-negative RagA (T21L) partially suppressed both rcc1- and rna1-1 mutations. Wild-type RagA localizes to the cytoplasm, but the dominant-negative T21L form relocalizes to nuclear speckles co-localizing with SC-35, while constitutively active Q66L remains cytoplasmic — indicating nucleotide-state-dependent nucleocytoplasmic shuttling.\",\n      \"method\": \"Yeast complementation assay, genetic epistasis (suppressor analysis), fluorescence localization/immunostaining with SC-35 co-localization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic complementation, epistasis, localization), functionally linking RagA nucleotide state to subcellular distribution and Ran pathway\",\n      \"pmids\": [\"9394008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In C. elegans, raga-1 (RagA ortholog) acts in the TOR pathway to regulate lifespan and behavioral aging: loss-of-function extended vigorous locomotion late in life; gain-of-function curtailed behavioral vitality and shortened lifespan; dominant-negative lengthened lifespan. RNAi experiments placed raga-1 upstream in the TOR pathway.\",\n      \"method\": \"C. elegans genetics (loss-of-function, gain-of-function, dominant-negative mutants), RNAi epistasis, behavioral assays (locomotion frequency)\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic loss/gain-of-function with defined phenotypic readout and RNAi pathway placement, single lab\",\n      \"pmids\": [\"20523893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RagA is essential for embryonic development and for mTORC1 activation by nutrients in mammals: RagA-null mouse embryos die at E10.5 with loss of mTORC1 activity, severe growth defects, and abrogation of nutrient regulation of mTORC1, while growth-factor sensitivity of mTORC1 is maintained. Deletion of RagA in adult mice is also lethal. RagA-specific deletion in liver increases PI3K/Akt signaling, establishing that RagA-dependent mTORC1 activity normally suppresses PI3K/Akt.\",\n      \"method\": \"Conditional and constitutive mouse knockout (RagA and RagB), primary cell mTORC1 activity assays (nutrient and growth factor stimulation), genetic epistasis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with multiple orthogonal readouts (embryonic lethality, mTORC1 activity, PI3K/Akt signaling), replicated across tissue-specific deletions\",\n      \"pmids\": [\"24768164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Skp2 E3 ligase mediates K63-linked ubiquitination of RagA; this ubiquitination facilitates recruitment of the GATOR1 complex (a GAP for RagA) to RagA, promoting GTP hydrolysis and thereby attenuating mTORC1 lysosomal recruitment and activation. This constitutes a negative feedback loop activated by amino acids in an mTORC1-dependent manner to prevent mTORC1 hyperactivation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays (K63-linkage specificity), mTORC1 lysosomal localization assay, loss-of-function and overexpression with downstream signaling readouts (autophagy, cell size, cilia growth)\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, defined ubiquitin linkage, multiple functional readouts (mTORC1 activity, autophagy, cilia, cell size), mechanistic pathway placement\",\n      \"pmids\": [\"26051179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DYNLT (Tctex-1 dynein light chain) interacts with RagA via a β-strand in RagA's G3 box (nucleotide-binding region), forming a tripartite complex with dynein intermediate chain, thereby linking RagA to the dynein motor. Both microtubule-associated and cytoplasmic DYNLT can bind RagA equally.\",\n      \"method\": \"NMR spectroscopy mapping of binding residues, Co-IP/pulldown, identification of interacting domain by deletion mapping\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — NMR with binding-residue mapping plus pulldown, single lab, defines interaction surface\",\n      \"pmids\": [\"26227614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RRAGA missense mutations (p.Leu60Arg) associated with autosomal dominant cataracts cause increased relocalization of RRAGA to lysosomes, up-regulated mTORC1 phosphorylation, down-regulated autophagy, and altered cell growth in human lens epithelial cells, mechanistically linking RRAGA gain-of-function to mTORC1 hyperactivation and cataract pathology.\",\n      \"method\": \"Functional studies in human lens epithelial cells: lysosomal localization imaging, mTORC1 phosphorylation assays, autophagy assays, cell growth assays, promoter activity assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in relevant cell type, single lab, no in vitro reconstitution\",\n      \"pmids\": [\"27294265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RagA is required for mTORC1 translocation to lysosomal membranes: siRNA silencing of RagA in PC12 cells blocked LPS-induced mTORC1 lysosomal translocation and activation of p70S6K.\",\n      \"method\": \"siRNA knockdown, immunofluorescence for mTORC1 lysosomal co-localization, Western blot for p70S6K phosphorylation\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, single method per readout, clean KD with defined cellular phenotype (lysosomal mTORC1 localization)\",\n      \"pmids\": [\"31711501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RagA interacts with WDR35/IFT121 (a hedgehog signaling/ciliary protein); overexpression of WDR35 decreases phosphorylation of ribosomal S6 protein in a RagA-, RagB-, and RagC-dependent manner, suggesting WDR35 is an upstream negative regulator of mTORC1 acting through RagA.\",\n      \"method\": \"Co-immunoprecipitation, overexpression with S6 phosphorylation readout, genetic dependence (RagA/B/C requirement)\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP plus downstream phosphorylation assay, single lab, no mechanistic dissection of interaction\",\n      \"pmids\": [\"30570184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RAGA (RagA) interacts with CD47 and promotes CD47 lysosomal localization and degradation via the endocytosis/lysosome pathway; disruption of RAGA blocks CD47 degradation, leading to CD47 accumulation and increased plasma membrane CD47 expression, thereby reducing phagocytic clearance of cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, lysosomal localization assay, RAGA loss-of-function, phagocytosis assay, CD47 protein stability assay\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional localization and degradation assays with loss-of-function, multiple readouts, single lab\",\n      \"pmids\": [\"36823443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In Drosophila gut, RagA knockdown alone induces intestinal thickening and foregastric enlargement. RagA knockdown rescues intestinal thinning and decreased secretory cells in nprl2 mutants (genetic epistasis placing RagA downstream of Nprl2 for these phenotypes), but does not rescue the enlarged forestomach of nprl2 mutants, indicating Nprl2 regulates forestomach development through a RagA-independent mechanism.\",\n      \"method\": \"Drosophila genetics (RagA RNAi knockdown, nprl2 mutants, double mutant epistasis), immunofluorescence for intestinal morphology and cell composition\",\n      \"journal\": \"Sheng wu gong cheng xue bao = Chinese journal of biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with two orthogonal phenotypic readouts (morphology and cell composition), single lab\",\n      \"pmids\": [\"37154336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hyperactivation of mTORC1 regulator RAGA-1 in C. elegans preserved ribosomal proteins during starvation and accelerated growth recovery after short starvation, but reduced survival under prolonged starvation, demonstrating that RAGA-1-dependent mTORC1 activity controls autophagy-dependent ribosomal protein turnover and balances starvation survival versus recovery speed.\",\n      \"method\": \"Live imaging, proteomics (proteome quantification), C. elegans RAGA-1 gain-of-function genetics, starvation survival assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — combined live imaging, proteomics, and genetics in C. elegans, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In renal tubular epithelial cells, RagA/B deletion inhibits mTORC1 but triggers renal cystogenesis driven by TFEB nuclear translocation; Rag GTPases (including RagA) suppress TFEB in vivo independently of mTORC1, establishing that Rag GTPases are the primary suppressors of TFEB in this context rather than acting solely through mTORC1.\",\n      \"method\": \"Conditional RagA/B knockout in mouse renal tubular epithelial cells, mTORC1 activity assays, TFEB nuclear localization assays, cystogenesis phenotype, genetic epistasis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional knockout with multiple readouts (cystogenesis, mTORC1, TFEB localization), preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RagA (RRAGA) is a Ras-related GTPase that binds and slowly exchanges GTP without intrinsic GTPase activity; in its GTP-loaded state it recruits mTORC1 to the lysosomal surface to enable nutrient (amino acid)-dependent mTORC1 activation, while GATOR1 (recruited via Skp2-mediated K63-linked ubiquitination of RagA) acts as a GAP to hydrolyze RagA-GTP and terminate signaling; RagA also suppresses TFEB nuclear translocation independently of mTORC1, interacts with DYNLT dynein light chain and WDR35/IFT121, and promotes lysosomal degradation of CD47, with its nucleotide-bound state governing its nucleocytoplasmic distribution.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RRAGA (RagA) is a Ras-related GTP-binding protein that functions as the master nutrient sensor controlling mTORC1 activation at the lysosome and broader TOR-dependent control of growth, autophagy, and aging [#0, #3]. Biochemically it binds GTP in a specific, saturable, and rapidly exchangeable manner but lacks detectable intrinsic GTPase activity, defining a novel Ras-homologous subfamily with an unusually large C-terminal domain [#0]. In its GTP-loaded state RagA recruits mTORC1 to the lysosomal surface to enable amino-acid-dependent mTORC1 activation, and loss of RagA abolishes nutrient regulation of mTORC1 while leaving growth-factor sensitivity intact, causing embryonic lethality and growth defects in mice; RagA-dependent mTORC1 activity in turn suppresses PI3K/Akt signaling [#3, #7]. Signaling is terminated by a negative feedback loop in which Skp2 catalyzes K63-linked ubiquitination of RagA to recruit the GATOR1 GAP complex, driving GTP hydrolysis and attenuating mTORC1 recruitment [#4]. The nucleotide-bound state also governs RagA's nucleocytoplasmic distribution, with dominant-negative RagA relocalizing to nuclear speckles co-localizing with SC-35 [#1]. Beyond mTORC1, RagA acts as the primary in vivo suppressor of TFEB nuclear translocation independently of mTORC1 [#12], links to the dynein motor through DYNLT binding at its G3 nucleotide-binding box [#5], and promotes endolysosomal degradation of CD47 to enhance phagocytic clearance of cancer cells [#9]. A gain-of-function RRAGA missense mutation (p.Leu60Arg) causing autosomal dominant cataract drives increased lysosomal localization, mTORC1 hyperactivation, and suppressed autophagy in lens epithelial cells [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established RagA as a biochemical entity: a Ras-related protein that binds and exchanges GTP but, unlike canonical GTPases, lacks intrinsic hydrolytic activity, predicting it would require an external GAP.\",\n      \"evidence\": \"GST-fusion radiolabeled GTPγS binding assays and sequence alignment with recombinant protein\",\n      \"pmids\": [\"7499430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No cellular function assigned at this stage\", \"GAP and exchange factors unidentified\", \"Role of the large C-terminal domain undefined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Linked RagA's nucleotide state to its subcellular distribution and placed it functionally in the Ran/Gsp1 GTPase pathway via yeast complementation, the first connection between RagA conformation and localization.\",\n      \"evidence\": \"Yeast complementation of gtr1-11, genetic suppressor analysis, and SC-35 co-localization imaging of T21L and Q66L mutants\",\n      \"pmids\": [\"9394008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian relevance of Ran-pathway link not demonstrated\", \"mTORC1 role not yet known\", \"Mechanism of nuclear speckle relocalization unexplained\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated in vivo that RagA orthologs act upstream in the TOR pathway to control lifespan and behavioral aging, tying nucleotide-state mutants to organismal physiology.\",\n      \"evidence\": \"C. elegans loss-, gain-, and dominant-negative genetics with RNAi epistasis and locomotion assays\",\n      \"pmids\": [\"20523893\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism downstream of TOR not dissected\", \"Single model organism\", \"Lysosomal recruitment mechanism not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined RagA as essential and nutrient-specific for mammalian mTORC1 activation, separating amino-acid from growth-factor inputs and revealing feedback suppression of PI3K/Akt.\",\n      \"evidence\": \"Constitutive and tissue-specific mouse knockouts with mTORC1 and PI3K/Akt signaling readouts\",\n      \"pmids\": [\"24768164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How amino acid signals load GTP onto RagA not resolved\", \"Mechanism of PI3K/Akt suppression unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the negative-feedback circuit that turns RagA signaling off: Skp2-mediated K63 ubiquitination recruits the GATOR1 GAP to drive RagA-GTP hydrolysis, answering how the GTPase-activity-less RagA is inactivated.\",\n      \"evidence\": \"Reciprocal Co-IP, K63-linkage-specific ubiquitination assays, and mTORC1 lysosomal localization with autophagy/cell-size readouts\",\n      \"pmids\": [\"26051179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and ubiquitination site mapping incomplete\", \"Deubiquitinase counterbalance not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped a direct physical link between RagA and the dynein motor, suggesting motor-based positioning of RagA via its nucleotide-binding region.\",\n      \"evidence\": \"NMR binding-residue mapping at the G3 box plus Co-IP/pulldown defining a tripartite complex with dynein intermediate chain\",\n      \"pmids\": [\"26227614\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of dynein binding for mTORC1 signaling untested\", \"Single lab, no in vivo validation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided a human disease link, showing a RRAGA gain-of-function mutation causes mTORC1 hyperactivation and autophagy suppression underlying autosomal dominant cataract.\",\n      \"evidence\": \"Functional assays in human lens epithelial cells: lysosomal imaging, mTORC1 phosphorylation, autophagy and growth assays\",\n      \"pmids\": [\"27294265\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of mutant GTPase behavior\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the lysosomal recruitment role to inflammatory signaling and identified candidate upstream regulators acting through RagA.\",\n      \"evidence\": \"siRNA knockdown with mTORC1/p70S6K readouts (PC12 cells); Co-IP of WDR35/IFT121 with Rag-dependent S6 phosphorylation\",\n      \"pmids\": [\"31711501\", \"30570184\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"WDR35 link rests on a single Co-IP without mechanistic dissection\", \"Direct vs indirect WDR35-RagA interaction unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed an mTORC1-independent function of RagA in cargo turnover, driving endolysosomal degradation of CD47 to control phagocytic clearance.\",\n      \"evidence\": \"Co-IP, lysosomal localization and CD47 stability assays, RAGA loss-of-function and phagocytosis assays\",\n      \"pmids\": [\"36823443\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling RagA to CD47 endocytosis unclear\", \"Whether GTP state controls CD47 degradation untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established Rag GTPases including RagA as the primary in vivo suppressors of TFEB, distinct from their mTORC1 role, with loss triggering renal cystogenesis.\",\n      \"evidence\": \"Conditional RagA/B mouse renal knockout with mTORC1, TFEB localization, and cystogenesis readouts (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Direct biochemical basis of mTORC1-independent TFEB suppression undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular events that load GTP onto RagA in response to amino acids, and how a single GTPase coordinates its mTORC1-dependent and mTORC1-independent (TFEB, CD47) outputs, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No identified amino-acid-responsive GEF for RagA in the corpus\", \"Structural basis for selecting downstream effectors unknown\", \"Integration of dynein-based positioning with signaling output untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [4, 6, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-165159\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\"Rag GTPase complex\"],\n    \"partners\": [\"MTOR\", \"SKP2\", \"GATOR1\", \"DYNLT1\", \"WDR35\", \"CD47\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}