{"gene":"CASTOR2","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2016,"finding":"CASTOR1 homodimerizes and heterodimerizes with CASTOR2; CASTOR1 interacts with GATOR2 and is required for arginine deprivation to inhibit mTORC1. Arginine binds CASTOR1 with a Kd of ~30 μM, disrupting the CASTOR1-GATOR2 complex and thereby activating mTORC1.","method":"Co-immunoprecipitation, biochemical binding assays, mutagenesis, cell-based mTORC1 activity assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including binding assays, Co-IP, and functional rescue; high-citation foundational paper","pmids":["26972053"],"is_preprint":false},{"year":2019,"finding":"CASTOR2 overexpression inhibits mTORC1 activation, abolishes cell proliferation and colony formation in KSHV-transformed cells. KSHV suppresses CASTOR2 expression to activate mTORC1, and KSHV miRNAs (miR-K4-5p and miR-K1-5p) directly target CASTOR1 to suppress its expression, indirectly derepressing mTORC1.","method":"Overexpression/knockdown experiments, reporter assays for miRNA targeting, colony formation assays, mTORC1 activity readouts","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2–3 — functional overexpression/KD with cellular phenotype and miRNA target validation, single lab","pmids":["31305263"],"is_preprint":false},{"year":2026,"finding":"CASTOR2 binds arginine similarly to CASTOR1 but with lower sensitivity, responding to high arginine concentrations whereas CASTOR1 responds to low arginine levels. Both CASTOR1 and CASTOR2 interact with the GATOR2 component Mios and inhibit its binding to GATOR1. Arginine binding to CASTOR1/2 induces conformational changes at the ACT2-ACT4 domain interface, causing dissociation from Mios. In C2C12 cells, CASTOR2 regulates mTORC1 and myogenesis in response to high arginine availability.","method":"Biochemical binding assays, structural analysis of conformational changes, Co-IP with Mios/GATOR1/GATOR2, mutagenesis, C2C12 cell-based mTORC1 and myogenesis assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 — reconstitution-level biochemistry with structural and mutagenesis validation, plus cellular functional assays in a single rigorous study","pmids":["41506264"],"is_preprint":false}],"current_model":"CASTOR2 is a cytosolic arginine sensor that homodimerizes or heterodimerizes with CASTOR1, binds arginine (responding at high concentrations), interacts with the GATOR2 component Mios to inhibit GATOR1 binding, and upon arginine binding undergoes ACT domain conformational changes that release Mios, thereby allowing GATOR2 to promote Rag GTPase activation and mTORC1 signaling; in muscle cells, CASTOR2 fine-tunes mTORC1 activity and myogenesis in response to high arginine availability."},"narrative":{"teleology":[{"year":2016,"claim":"The identification of CASTOR1 as an arginine sensor for mTORC1 established that CASTOR1 homodimerizes and heterodimerizes with CASTOR2, and that arginine binding disrupts the CASTOR1–GATOR2 interaction, linking the CASTOR proteins to nutrient-dependent mTORC1 regulation.","evidence":"Co-immunoprecipitation, biochemical arginine-binding assays, mutagenesis, and cell-based mTORC1 readouts in HEK293T cells","pmids":["26972053"],"confidence":"High","gaps":["Whether CASTOR2 itself binds arginine and at what affinity was not determined","The structural basis for arginine-induced dissociation from GATOR2 was unresolved","CASTOR2-specific physiological roles remained undefined"]},{"year":2019,"claim":"Demonstrating that CASTOR2 overexpression inhibits mTORC1 and cell proliferation in KSHV-transformed cells established CASTOR2 as a functionally relevant negative regulator of mTORC1 in a disease context.","evidence":"Overexpression and knockdown experiments, colony formation assays, and mTORC1 activity readouts in KSHV-transformed cells","pmids":["31305263"],"confidence":"Medium","gaps":["CASTOR2's mechanism of mTORC1 inhibition (direct GATOR2 binding vs. indirect) was not biochemically dissected","Endogenous CASTOR2 loss-of-function phenotype in non-viral contexts was not tested","Whether CASTOR2 acts independently of CASTOR1 in this system was unclear"]},{"year":2026,"claim":"Biochemical and structural characterization revealed that CASTOR2 binds arginine with lower sensitivity than CASTOR1, interacts with the GATOR2 subunit Mios, and undergoes ACT-domain conformational changes upon arginine binding that release Mios, establishing CASTOR2 as a high-arginine-concentration sensor that regulates mTORC1 and myogenesis.","evidence":"Biochemical binding assays, structural analysis of ACT2–ACT4 conformational changes, Co-IP with Mios/GATOR1/GATOR2, mutagenesis, and C2C12 myogenesis assays","pmids":["41506264"],"confidence":"High","gaps":["Full atomic-resolution structure of the CASTOR2–Mios complex is not yet available","In vivo physiological consequences of CASTOR2 loss in muscle tissue have not been demonstrated","How CASTOR1 and CASTOR2 coordinate their differential arginine sensitivities within the same cell remains uncharacterized"]},{"year":null,"claim":"The in vivo tissue-specific roles of CASTOR2, the structural basis of differential arginine sensitivity between CASTOR1 and CASTOR2, and the physiological significance of CASTOR1–CASTOR2 heterodimers versus homodimers remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No animal knockout models for CASTOR2 have been reported","Heterodimerization stoichiometry and its functional consequences are undefined","Whether CASTOR2 senses other amino acids or metabolites has not been tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2]}],"pathway":[],"complexes":[],"partners":["CASTOR1","MIOS"],"other_free_text":[]},"mechanistic_narrative":"CASTOR2 functions as a cytosolic arginine sensor that tunes mTORC1 signaling in response to high arginine concentrations. CASTOR2 homodimerizes and heterodimerizes with CASTOR1, and both proteins interact with the GATOR2 component Mios to inhibit GATOR2–GATOR1 binding; arginine binding induces conformational changes at the ACT2–ACT4 domain interface that release Mios, thereby permitting GATOR2 to activate Rag GTPases and mTORC1 [PMID:26972053, PMID:41506264]. Compared with CASTOR1, CASTOR2 has lower arginine sensitivity and responds at high arginine levels, functioning in muscle cells to regulate mTORC1 activity and myogenesis [PMID:41506264]. Overexpression of CASTOR2 inhibits mTORC1 activation and suppresses proliferation in KSHV-transformed cells, and KSHV downregulates CASTOR2 expression to sustain mTORC1 signaling [PMID:31305263]."},"prefetch_data":{"uniprot":{"accession":"A6NHX0","full_name":"Cytosolic arginine sensor for mTORC1 subunit 2","aliases":["Cellular arginine sensor for mTORC1 protein 2","GATS-like protein 2"],"length_aa":329,"mass_kda":36.1,"function":"Functions as a negative regulator of the TORC1 signaling pathway through the GATOR complex. As part of homodimers or heterodimers with CASTOR1, directly binds and inhibits the GATOR subcomplex GATOR2 and thereby mTORC1. Does not directly bind arginine, but binding of arginine to CASTOR1 disrupts the interaction of CASTOR2-containing heterodimers with GATOR2 which can in turn activate mTORC1 and the TORC1 signaling pathway","subcellular_location":"Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/A6NHX0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CASTOR2","classification":"Not Classified","n_dependent_lines":50,"n_total_lines":1208,"dependency_fraction":0.041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CASTOR2","total_profiled":1310},"omim":[{"mim_id":"620307","title":"WD REPEAT-CONTAINING PROTEIN 24; WDR24","url":"https://www.omim.org/entry/620307"},{"mim_id":"617418","title":"WD REPEAT-CONTAINING PROTEIN 59; WDR59","url":"https://www.omim.org/entry/617418"},{"mim_id":"617034","title":"CELLULAR ARGININE SENSOR FOR MTORC1 PROTEIN 1; CASTOR1","url":"https://www.omim.org/entry/617034"},{"mim_id":"617033","title":"CELLULAR ARGININE SENSOR FOR MTORC1 PROTEIN 2; CASTOR2","url":"https://www.omim.org/entry/617033"},{"mim_id":"601231","title":"MECHANISTIC TARGET OF RAPAMYCIN; MTOR","url":"https://www.omim.org/entry/601231"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":61.7}],"url":"https://www.proteinatlas.org/search/CASTOR2"},"hgnc":{"alias_symbol":[],"prev_symbol":["GATSL1","GATSL2"]},"alphafold":{"accession":"A6NHX0","domains":[{"cath_id":"3.30.2130.10","chopping":"1-154","consensus_level":"medium","plddt":90.7777,"start":1,"end":154},{"cath_id":"3.30.2130.10","chopping":"178-211_222-326","consensus_level":"medium","plddt":92.1367,"start":178,"end":326}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A6NHX0","model_url":"https://alphafold.ebi.ac.uk/files/AF-A6NHX0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A6NHX0-F1-predicted_aligned_error_v6.png","plddt_mean":88.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CASTOR2","jax_strain_url":"https://www.jax.org/strain/search?query=CASTOR2"},"sequence":{"accession":"A6NHX0","fasta_url":"https://rest.uniprot.org/uniprotkb/A6NHX0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A6NHX0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A6NHX0"}},"corpus_meta":[{"pmid":"26972053","id":"PMC_26972053","title":"The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway.","date":"2016","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26972053","citation_count":659,"is_preprint":false},{"pmid":"35061305","id":"PMC_35061305","title":"FOXO1 cooperates with C/EBPδ and ATF4 to regulate skeletal muscle atrophy transcriptional program during fasting.","date":"2022","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/35061305","citation_count":47,"is_preprint":false},{"pmid":"34234117","id":"PMC_34234117","title":"Cross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34234117","citation_count":36,"is_preprint":false},{"pmid":"31305263","id":"PMC_31305263","title":"Kaposi sarcoma-associated herpesvirus miRNAs suppress CASTOR1-mediated mTORC1 inhibition to promote tumorigenesis.","date":"2019","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/31305263","citation_count":35,"is_preprint":false},{"pmid":"32532099","id":"PMC_32532099","title":"Transcriptome Functional Analysis of Mammary Gland of Cows in Heat Stress and Thermoneutral Condition.","date":"2020","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/32532099","citation_count":30,"is_preprint":false},{"pmid":"31537867","id":"PMC_31537867","title":"Identification of differentially expressed genes and fusion genes associated with malignant progression of spinal cord gliomas by transcriptome analysis.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31537867","citation_count":6,"is_preprint":false},{"pmid":"39659991","id":"PMC_39659991","title":"Dietary protein re-alimentation following restriction improves protein deposition via changing amino acid metabolism and transcriptional profiling of muscle tissue in growing beef bulls.","date":"2024","source":"Animal nutrition (Zhongguo xu mu shou yi xue hui)","url":"https://pubmed.ncbi.nlm.nih.gov/39659991","citation_count":6,"is_preprint":false},{"pmid":"41506264","id":"PMC_41506264","title":"CASTOR1 and CASTOR2 respond to different arginine levels to regulate mTORC1 activity.","date":"2026","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/41506264","citation_count":0,"is_preprint":false},{"pmid":"41404116","id":"PMC_41404116","title":"Integrated metabolomic and transcriptomic analysis reveals digestive tract adaptations to high altitude in Bayanbulak sheep.","date":"2025","source":"Frontiers in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/41404116","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6418,"output_tokens":965,"usd":0.016865},"stage2":{"model":"claude-opus-4-6","input_tokens":4155,"output_tokens":2908,"usd":0.140212},"total_usd":0.157077,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"CASTOR1 homodimerizes and heterodimerizes with CASTOR2; CASTOR1 interacts with GATOR2 and is required for arginine deprivation to inhibit mTORC1. Arginine binds CASTOR1 with a Kd of ~30 μM, disrupting the CASTOR1-GATOR2 complex and thereby activating mTORC1.\",\n      \"method\": \"Co-immunoprecipitation, biochemical binding assays, mutagenesis, cell-based mTORC1 activity assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including binding assays, Co-IP, and functional rescue; high-citation foundational paper\",\n      \"pmids\": [\"26972053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CASTOR2 overexpression inhibits mTORC1 activation, abolishes cell proliferation and colony formation in KSHV-transformed cells. KSHV suppresses CASTOR2 expression to activate mTORC1, and KSHV miRNAs (miR-K4-5p and miR-K1-5p) directly target CASTOR1 to suppress its expression, indirectly derepressing mTORC1.\",\n      \"method\": \"Overexpression/knockdown experiments, reporter assays for miRNA targeting, colony formation assays, mTORC1 activity readouts\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — functional overexpression/KD with cellular phenotype and miRNA target validation, single lab\",\n      \"pmids\": [\"31305263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CASTOR2 binds arginine similarly to CASTOR1 but with lower sensitivity, responding to high arginine concentrations whereas CASTOR1 responds to low arginine levels. Both CASTOR1 and CASTOR2 interact with the GATOR2 component Mios and inhibit its binding to GATOR1. Arginine binding to CASTOR1/2 induces conformational changes at the ACT2-ACT4 domain interface, causing dissociation from Mios. In C2C12 cells, CASTOR2 regulates mTORC1 and myogenesis in response to high arginine availability.\",\n      \"method\": \"Biochemical binding assays, structural analysis of conformational changes, Co-IP with Mios/GATOR1/GATOR2, mutagenesis, C2C12 cell-based mTORC1 and myogenesis assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstitution-level biochemistry with structural and mutagenesis validation, plus cellular functional assays in a single rigorous study\",\n      \"pmids\": [\"41506264\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CASTOR2 is a cytosolic arginine sensor that homodimerizes or heterodimerizes with CASTOR1, binds arginine (responding at high concentrations), interacts with the GATOR2 component Mios to inhibit GATOR1 binding, and upon arginine binding undergoes ACT domain conformational changes that release Mios, thereby allowing GATOR2 to promote Rag GTPase activation and mTORC1 signaling; in muscle cells, CASTOR2 fine-tunes mTORC1 activity and myogenesis in response to high arginine availability.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CASTOR2 functions as a cytosolic arginine sensor that tunes mTORC1 signaling in response to high arginine concentrations. CASTOR2 homodimerizes and heterodimerizes with CASTOR1, and both proteins interact with the GATOR2 component Mios to inhibit GATOR2–GATOR1 binding; arginine binding induces conformational changes at the ACT2–ACT4 domain interface that release Mios, thereby permitting GATOR2 to activate Rag GTPases and mTORC1 [PMID:26972053, PMID:41506264]. Compared with CASTOR1, CASTOR2 has lower arginine sensitivity and responds at high arginine levels, functioning in muscle cells to regulate mTORC1 activity and myogenesis [PMID:41506264]. Overexpression of CASTOR2 inhibits mTORC1 activation and suppresses proliferation in KSHV-transformed cells, and KSHV downregulates CASTOR2 expression to sustain mTORC1 signaling [PMID:31305263].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"The identification of CASTOR1 as an arginine sensor for mTORC1 established that CASTOR1 homodimerizes and heterodimerizes with CASTOR2, and that arginine binding disrupts the CASTOR1–GATOR2 interaction, linking the CASTOR proteins to nutrient-dependent mTORC1 regulation.\",\n      \"evidence\": \"Co-immunoprecipitation, biochemical arginine-binding assays, mutagenesis, and cell-based mTORC1 readouts in HEK293T cells\",\n      \"pmids\": [\"26972053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether CASTOR2 itself binds arginine and at what affinity was not determined\",\n        \"The structural basis for arginine-induced dissociation from GATOR2 was unresolved\",\n        \"CASTOR2-specific physiological roles remained undefined\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that CASTOR2 overexpression inhibits mTORC1 and cell proliferation in KSHV-transformed cells established CASTOR2 as a functionally relevant negative regulator of mTORC1 in a disease context.\",\n      \"evidence\": \"Overexpression and knockdown experiments, colony formation assays, and mTORC1 activity readouts in KSHV-transformed cells\",\n      \"pmids\": [\"31305263\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"CASTOR2's mechanism of mTORC1 inhibition (direct GATOR2 binding vs. indirect) was not biochemically dissected\",\n        \"Endogenous CASTOR2 loss-of-function phenotype in non-viral contexts was not tested\",\n        \"Whether CASTOR2 acts independently of CASTOR1 in this system was unclear\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Biochemical and structural characterization revealed that CASTOR2 binds arginine with lower sensitivity than CASTOR1, interacts with the GATOR2 subunit Mios, and undergoes ACT-domain conformational changes upon arginine binding that release Mios, establishing CASTOR2 as a high-arginine-concentration sensor that regulates mTORC1 and myogenesis.\",\n      \"evidence\": \"Biochemical binding assays, structural analysis of ACT2–ACT4 conformational changes, Co-IP with Mios/GATOR1/GATOR2, mutagenesis, and C2C12 myogenesis assays\",\n      \"pmids\": [\"41506264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full atomic-resolution structure of the CASTOR2–Mios complex is not yet available\",\n        \"In vivo physiological consequences of CASTOR2 loss in muscle tissue have not been demonstrated\",\n        \"How CASTOR1 and CASTOR2 coordinate their differential arginine sensitivities within the same cell remains uncharacterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The in vivo tissue-specific roles of CASTOR2, the structural basis of differential arginine sensitivity between CASTOR1 and CASTOR2, and the physiological significance of CASTOR1–CASTOR2 heterodimers versus homodimers remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No animal knockout models for CASTOR2 have been reported\",\n        \"Heterodimerization stoichiometry and its functional consequences are undefined\",\n        \"Whether CASTOR2 senses other amino acids or metabolites has not been tested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CASTOR1\", \"Mios\"],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to fix the pathway term_id. The Reactome pathway should be `R-HSA-162582` for Signal Transduction. Let me also reconsider — the mTORC1 pathway is fundamentally about signal transduction. Let me correct:\n\n```json\n{\n  \"mechanistic_narrative\": \"CASTOR2 functions as a cytosolic arginine sensor that tunes mTORC1 signaling in response to high arginine concentrations. CASTOR2 homodimerizes and heterodimerizes with CASTOR1, and both proteins interact with the GATOR2 component Mios to inhibit GATOR2–GATOR1 binding; arginine binding induces conformational changes at the ACT2–ACT4 domain interface that release Mios, thereby permitting GATOR2 to activate Rag GTPases and mTORC1 [PMID:26972053, PMID:41506264]. Compared with CASTOR1, CASTOR2 has lower arginine sensitivity and responds at high arginine levels, functioning in muscle cells to regulate mTORC1 activity and myogenesis [PMID:41506264]. Overexpression of CASTOR2 inhibits mTORC1 activation and suppresses proliferation in KSHV-transformed cells, and KSHV downregulates CASTOR2 expression to sustain mTORC1 signaling [PMID:31305263].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"The identification of CASTOR1 as an arginine sensor for mTORC1 established that CASTOR1 homodimerizes and heterodimerizes with CASTOR2, and that arginine binding disrupts the CASTOR1–GATOR2 interaction, linking the CASTOR proteins to nutrient-dependent mTORC1 regulation.\",\n      \"evidence\": \"Co-immunoprecipitation, biochemical arginine-binding assays, mutagenesis, and cell-based mTORC1 readouts in HEK293T cells\",\n      \"pmids\": [\"26972053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether CASTOR2 itself binds arginine and at what affinity was not determined\",\n        \"The structural basis for arginine-induced dissociation from GATOR2 was unresolved\",\n        \"CASTOR2-specific physiological roles remained undefined\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that CASTOR2 overexpression inhibits mTORC1 and cell proliferation in KSHV-transformed cells established CASTOR2 as a functionally relevant negative regulator of mTORC1 in a disease context.\",\n      \"evidence\": \"Overexpression and knockdown experiments, colony formation assays, and mTORC1 activity readouts in KSHV-transformed cells\",\n      \"pmids\": [\"31305263\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"CASTOR2's mechanism of mTORC1 inhibition (direct GATOR2 binding vs. indirect) was not biochemically dissected\",\n        \"Endogenous CASTOR2 loss-of-function phenotype in non-viral contexts was not tested\",\n        \"Whether CASTOR2 acts independently of CASTOR1 in this system was unclear\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Biochemical and structural characterization revealed that CASTOR2 binds arginine with lower sensitivity than CASTOR1, interacts with the GATOR2 subunit Mios, and undergoes ACT-domain conformational changes upon arginine binding that release Mios, establishing CASTOR2 as a high-arginine-concentration sensor that regulates mTORC1 and myogenesis.\",\n      \"evidence\": \"Biochemical binding assays, structural analysis of ACT2–ACT4 conformational changes, Co-IP with Mios/GATOR1/GATOR2, mutagenesis, and C2C12 myogenesis assays\",\n      \"pmids\": [\"41506264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full atomic-resolution structure of the CASTOR2–Mios complex is not yet available\",\n        \"In vivo physiological consequences of CASTOR2 loss in muscle tissue have not been demonstrated\",\n        \"How CASTOR1 and CASTOR2 coordinate their differential arginine sensitivities within the same cell remains uncharacterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The in vivo tissue-specific roles of CASTOR2, the structural basis of differential arginine sensitivity between CASTOR1 and CASTOR2, and the physiological significance of CASTOR1–CASTOR2 heterodimers versus homodimers remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No animal knockout models for CASTOR2 have been reported\",\n        \"Heterodimerization stoichiometry and its functional consequences are undefined\",\n        \"Whether CASTOR2 senses other amino acids or metabolites has not been tested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CASTOR1\", \"Mios\"],\n    \"other_free_text\": []\n  }\n}\n```"}