{"gene":"CASTOR2","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2016,"finding":"CASTOR1 homodimerizes and can heterodimerize with CASTOR2; CASTOR1 interacts with GATOR2 and arginine binding to CASTOR1 (Kd ~30 μM) disrupts the CASTOR1-GATOR2 complex, establishing CASTOR1 as a cytosolic arginine sensor that mediates arginine-deprivation repression of mTORC1.","method":"Co-immunoprecipitation, in vitro binding assays, isothermal titration calorimetry, site-directed mutagenesis, genetic rescue experiments in cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding assays with Kd measurement, mutagenesis, co-IP, and functional rescue in cells; highly cited foundational study","pmids":["26972053"],"is_preprint":false},{"year":2019,"finding":"KSHV-encoded miRNAs miR-K4-5p (and likely miR-K1-5p) directly target CASTOR1 to suppress its expression; suppression of both CASTOR1 and CASTOR2 by KSHV activates mTORC1, and overexpression of CASTOR2 attenuates mTORC1 activation and abolishes proliferation and colony formation of KSHV-transformed cells.","method":"miRNA target reporter assays, knockdown/overexpression experiments, colony formation assays, immunoblotting for mTORC1 pathway readouts","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression and knockdown with defined cellular phenotype, miRNA targeting validated, single lab","pmids":["31305263"],"is_preprint":false},{"year":2026,"finding":"CASTOR2 binds arginine similarly to CASTOR1 but responds to higher arginine concentrations, while CASTOR1 responds to low arginine levels; both interact with the GATOR2 component Mios and inhibit Mios binding to GATOR1; arginine binding induces conformational changes at the ACT2-ACT4 domain interface causing CASTOR2 dissociation from Mios. In C2C12 muscle cells, CASTOR2 regulates mTORC1 and myogenesis in response to high arginine availability.","method":"Biochemical binding assays, structural/conformational analysis, co-immunoprecipitation, loss-of-function experiments in C2C12 cells with mTORC1 activity and myogenesis readouts","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding, structural conformational data, co-IP with GATOR2 component, functional cell-based assays; single lab but multiple orthogonal methods","pmids":["41506264"],"is_preprint":false}],"current_model":"CASTOR2 is a cytosolic arginine sensor that heterodimerizes with CASTOR1 and, at high arginine concentrations, binds arginine to undergo conformational changes at its ACT domain interface, causing dissociation from the GATOR2 component Mios and thereby relieving GATOR2-mediated inhibition of GATOR1, ultimately permitting mTORC1 activation; in muscle cells CASTOR2 fine-tunes mTORC1 activity and myogenesis in response to high arginine availability."},"narrative":{"mechanistic_narrative":"CASTOR2 is a cytosolic arginine sensor that couples intracellular arginine availability to mTORC1 signaling through the GATOR2 complex [PMID:41506264]. It heterodimerizes with the related sensor CASTOR1 [PMID:26972053] and, like CASTOR1, binds arginine directly, but it is tuned to respond at higher arginine concentrations whereas CASTOR1 reports low arginine [PMID:41506264]. Both sensors interact with the GATOR2 component Mios and restrain Mios binding to GATOR1; arginine binding drives a conformational change at the ACT2–ACT4 domain interface that releases CASTOR2 from Mios, relieving GATOR2-mediated inhibition and thereby permitting mTORC1 activation [PMID:41506264]. In C2C12 muscle cells this sensing function tunes mTORC1 activity and myogenesis to high arginine availability [PMID:41506264]. CASTOR2 expression also constrains mTORC1-driven proliferation: in KSHV-transformed cells, viral suppression of CASTOR1/CASTOR2 activates mTORC1, and restoring CASTOR2 attenuates this activation and blocks colony formation [PMID:31305263].","teleology":[{"year":2016,"claim":"Established that CASTOR proteins act as cytosolic arginine sensors upstream of mTORC1 and that CASTOR2 participates by heterodimerizing with the arginine-binding sensor CASTOR1.","evidence":"Co-IP, in vitro binding with ITC Kd measurement, mutagenesis, and genetic rescue in cells","pmids":["26972053"],"confidence":"High","gaps":["Arginine binding and GATOR2 regulation were defined for CASTOR1, not directly for CASTOR2","Physiological role of the CASTOR1-CASTOR2 heterodimer not resolved","No distinct affinity or functional readout assigned to CASTOR2 itself"]},{"year":2019,"claim":"Demonstrated a disease-relevant consequence of CASTOR2 function by showing that its loss permits mTORC1 activation and oncogenic proliferation, while its restoration suppresses transformation.","evidence":"miRNA target reporter assays, knockdown/overexpression, colony formation, and mTORC1 immunoblotting in KSHV-transformed cells","pmids":["31305263"],"confidence":"Medium","gaps":["Single-lab functional study without structural or direct arginine-binding characterization of CASTOR2","Whether CASTOR2 acts independently or only via CASTOR1 heterodimers not dissected","Mechanism of mTORC1 suppression inferred from pathway readouts rather than reconstitution"]},{"year":2026,"claim":"Defined CASTOR2 as a bona fide arginine sensor with a distinct concentration set-point and resolved the mechanistic basis by which arginine binding triggers GATOR2 release.","evidence":"Biochemical arginine-binding assays, ACT-domain conformational analysis, co-IP with Mios, and loss-of-function in C2C12 cells with mTORC1 and myogenesis readouts","pmids":["41506264"],"confidence":"High","gaps":["No high-resolution structure of the arginine-bound CASTOR2–Mios complex","Quantitative arginine affinity (Kd) for CASTOR2 not specified","In vivo relevance beyond C2C12 muscle cells not established"]},{"year":null,"claim":"How CASTOR2 and CASTOR1 divide labor across the arginine concentration range in intact tissues, and what determines the relative roles of homodimers versus heterodimers, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of CASTOR2 with bound arginine","Tissue-specific contribution of CASTOR2 versus CASTOR1 not mapped","Regulation of CASTOR2 expression beyond viral miRNA targeting unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2]}],"complexes":[],"partners":["CASTOR1","MIOS"],"other_free_text":[]}},"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":671,"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":52,"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":38,"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":37,"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":31,"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":"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":"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":7181,"output_tokens":958,"usd":0.017957,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7419,"output_tokens":1769,"usd":0.04066,"stage2_stop_reason":"end_turn"},"total_usd":0.058617,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"CASTOR1 homodimerizes and can heterodimerize with CASTOR2; CASTOR1 interacts with GATOR2 and arginine binding to CASTOR1 (Kd ~30 μM) disrupts the CASTOR1-GATOR2 complex, establishing CASTOR1 as a cytosolic arginine sensor that mediates arginine-deprivation repression of mTORC1.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assays, isothermal titration calorimetry, site-directed mutagenesis, genetic rescue experiments in cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding assays with Kd measurement, mutagenesis, co-IP, and functional rescue in cells; highly cited foundational study\",\n      \"pmids\": [\"26972053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KSHV-encoded miRNAs miR-K4-5p (and likely miR-K1-5p) directly target CASTOR1 to suppress its expression; suppression of both CASTOR1 and CASTOR2 by KSHV activates mTORC1, and overexpression of CASTOR2 attenuates mTORC1 activation and abolishes proliferation and colony formation of KSHV-transformed cells.\",\n      \"method\": \"miRNA target reporter assays, knockdown/overexpression experiments, colony formation assays, immunoblotting for mTORC1 pathway readouts\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression and knockdown with defined cellular phenotype, miRNA targeting validated, single lab\",\n      \"pmids\": [\"31305263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CASTOR2 binds arginine similarly to CASTOR1 but responds to higher arginine concentrations, while CASTOR1 responds to low arginine levels; both interact with the GATOR2 component Mios and inhibit Mios binding to GATOR1; arginine binding induces conformational changes at the ACT2-ACT4 domain interface causing CASTOR2 dissociation from Mios. In C2C12 muscle cells, CASTOR2 regulates mTORC1 and myogenesis in response to high arginine availability.\",\n      \"method\": \"Biochemical binding assays, structural/conformational analysis, co-immunoprecipitation, loss-of-function experiments in C2C12 cells with mTORC1 activity and myogenesis readouts\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding, structural conformational data, co-IP with GATOR2 component, functional cell-based assays; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41506264\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CASTOR2 is a cytosolic arginine sensor that heterodimerizes with CASTOR1 and, at high arginine concentrations, binds arginine to undergo conformational changes at its ACT domain interface, causing dissociation from the GATOR2 component Mios and thereby relieving GATOR2-mediated inhibition of GATOR1, ultimately permitting mTORC1 activation; in muscle cells CASTOR2 fine-tunes mTORC1 activity and myogenesis in response to high arginine availability.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CASTOR2 is a cytosolic arginine sensor that couples intracellular arginine availability to mTORC1 signaling through the GATOR2 complex [#2]. It heterodimerizes with the related sensor CASTOR1 [#0] and, like CASTOR1, binds arginine directly, but it is tuned to respond at higher arginine concentrations whereas CASTOR1 reports low arginine [#2]. Both sensors interact with the GATOR2 component Mios and restrain Mios binding to GATOR1; arginine binding drives a conformational change at the ACT2–ACT4 domain interface that releases CASTOR2 from Mios, relieving GATOR2-mediated inhibition and thereby permitting mTORC1 activation [#2]. In C2C12 muscle cells this sensing function tunes mTORC1 activity and myogenesis to high arginine availability [#2]. CASTOR2 expression also constrains mTORC1-driven proliferation: in KSHV-transformed cells, viral suppression of CASTOR1/CASTOR2 activates mTORC1, and restoring CASTOR2 attenuates this activation and blocks colony formation [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that CASTOR proteins act as cytosolic arginine sensors upstream of mTORC1 and that CASTOR2 participates by heterodimerizing with the arginine-binding sensor CASTOR1.\",\n      \"evidence\": \"Co-IP, in vitro binding with ITC Kd measurement, mutagenesis, and genetic rescue in cells\",\n      \"pmids\": [\"26972053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Arginine binding and GATOR2 regulation were defined for CASTOR1, not directly for CASTOR2\",\n        \"Physiological role of the CASTOR1-CASTOR2 heterodimer not resolved\",\n        \"No distinct affinity or functional readout assigned to CASTOR2 itself\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated a disease-relevant consequence of CASTOR2 function by showing that its loss permits mTORC1 activation and oncogenic proliferation, while its restoration suppresses transformation.\",\n      \"evidence\": \"miRNA target reporter assays, knockdown/overexpression, colony formation, and mTORC1 immunoblotting in KSHV-transformed cells\",\n      \"pmids\": [\"31305263\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab functional study without structural or direct arginine-binding characterization of CASTOR2\",\n        \"Whether CASTOR2 acts independently or only via CASTOR1 heterodimers not dissected\",\n        \"Mechanism of mTORC1 suppression inferred from pathway readouts rather than reconstitution\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined CASTOR2 as a bona fide arginine sensor with a distinct concentration set-point and resolved the mechanistic basis by which arginine binding triggers GATOR2 release.\",\n      \"evidence\": \"Biochemical arginine-binding assays, ACT-domain conformational analysis, co-IP with Mios, and loss-of-function in C2C12 cells with mTORC1 and myogenesis readouts\",\n      \"pmids\": [\"41506264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of the arginine-bound CASTOR2–Mios complex\",\n        \"Quantitative arginine affinity (Kd) for CASTOR2 not specified\",\n        \"In vivo relevance beyond C2C12 muscle cells not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CASTOR2 and CASTOR1 divide labor across the arginine concentration range in intact tissues, and what determines the relative roles of homodimers versus heterodimers, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of CASTOR2 with bound arginine\",\n        \"Tissue-specific contribution of CASTOR2 versus CASTOR1 not mapped\",\n        \"Regulation of CASTOR2 expression beyond viral miRNA targeting unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CASTOR1\", \"MIOS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}