{"gene":"NR2C2AP","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2002,"finding":"TRA16 (NR2C2AP) was identified as a nuclear co-repressor that interacts with TR4 (NR2C2) via TR4's DNA-binding domain and ligand-binding domain, suppressing TR4-mediated transactivation. The suppression mechanism involves decreased binding between TR4 protein and TR4 response elements on target genes, as shown by EMSA.","method":"Mammalian two-hybrid system, co-immunoprecipitation, electrophoretic mobility shift assay (EMSA), reporter gene transactivation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and mammalian two-hybrid with EMSA functional validation, multiple orthogonal methods in a single focused study","pmids":["12486131"],"is_preprint":false},{"year":2002,"finding":"TRA16 (NR2C2AP) selectively suppresses TR4-mediated transactivation but shows only slight influence on androgen receptor, glucocorticoid receptor, and progesterone receptor transactivation, indicating receptor-selective repressor activity.","method":"Reporter gene transactivation assay comparing multiple nuclear receptors","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, single method (reporter assay) but clear functional specificity demonstrated","pmids":["12486131"],"is_preprint":false},{"year":2002,"finding":"TRA16 (NR2C2AP) is predominantly localized in the nucleus of cells.","method":"Subcellular localization assay (described in functional characterization context)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, localization reported without detailed imaging methodology described in abstract","pmids":["12486131"],"is_preprint":false},{"year":2012,"finding":"TRA16 (NR2C2AP) physically interacts with TR2 (NR2C1) and blocks TR2's inhibitory effect on ERβ-mediated transcription, thereby enhancing ERβ transactivation.","method":"Mammalian two-hybrid, reporter gene assay, co-immunoprecipitation, immunocytofluorescence in Cos-1 cells","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple orthogonal methods (Co-IP, two-hybrid, reporter assay) but single lab","pmids":["23129017"],"is_preprint":false},{"year":2012,"finding":"TRA16 (NR2C2AP) overexpression in Cos-1 cells enhanced cell proliferation.","method":"Cell proliferation assay following TRA16 introduction into Cos-1 cells","journal":"Oncology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method, no mechanistic pathway placement beyond receptor interactions","pmids":["23129017"],"is_preprint":false}],"current_model":"NR2C2AP (TRA16) is a nuclear co-repressor that physically binds TR4 (NR2C2) through its DNA-binding and ligand-binding domains, selectively suppressing TR4-mediated transactivation by reducing TR4 binding to its response elements; it also interacts with TR2 (NR2C1) to relieve TR2-mediated repression of ERβ, thereby enhancing ERβ transcriptional activity."},"narrative":{"mechanistic_narrative":"NR2C2AP (TRA16) is a nuclear protein that functions as a selective modulator of testicular orphan nuclear receptor signaling within the NR2C subfamily [PMID:12486131, PMID:23129017]. It acts as a co-repressor of TR4 (NR2C2), binding the receptor through both its DNA-binding and ligand-binding domains and suppressing TR4-mediated transactivation by decreasing TR4 occupancy at its response elements [PMID:12486131]. This repressor activity is receptor-selective, with only slight effects on androgen, glucocorticoid, and progesterone receptors [PMID:12486131]. NR2C2AP also physically engages the related receptor TR2 (NR2C1), where it blocks TR2's inhibitory effect on ERβ-mediated transcription and thereby enhances ERβ transactivation [PMID:23129017]. Beyond these nuclear-receptor interactions, no broader pathway placement or structural mechanism has been characterized in the available corpus.","teleology":[{"year":2002,"claim":"Establishing how NR2C2AP controls TR4 signaling answered whether a dedicated repressor restrains this orphan nuclear receptor and by what molecular route.","evidence":"Mammalian two-hybrid, reciprocal co-immunoprecipitation, EMSA, and reporter transactivation assays mapping interaction to TR4's DNA-binding and ligand-binding domains","pmids":["12486131"],"confidence":"High","gaps":["No identification of additional co-repressor complex partners recruited by NR2C2AP","Direct target genes of TR4 modulated in vivo not defined","No structural detail of the TR4-NR2C2AP interface"]},{"year":2002,"claim":"Comparing multiple nuclear receptors established that NR2C2AP repression is receptor-selective rather than a general transcriptional dampener.","evidence":"Reporter gene transactivation assays comparing TR4 against androgen, glucocorticoid, and progesterone receptors","pmids":["12486131"],"confidence":"Medium","gaps":["Selectivity tested only against a limited panel of steroid receptors","Basis of selectivity at the sequence/domain level not resolved"]},{"year":2002,"claim":"Localizing NR2C2AP placed it in the nucleus, consistent with a role in transcriptional regulation.","evidence":"Subcellular localization assay reported within the functional characterization study","pmids":["12486131"],"confidence":"Medium","gaps":["Imaging methodology not detailed","Whether localization changes upon receptor binding not addressed"]},{"year":2012,"claim":"Extending the receptor repertoire showed NR2C2AP also acts on TR2 to indirectly potentiate ERβ activity, broadening its role beyond TR4 repression.","evidence":"Mammalian two-hybrid, co-immunoprecipitation, immunocytofluorescence, and reporter assays in Cos-1 cells","pmids":["23129017"],"confidence":"Medium","gaps":["Single-lab evidence without reciprocal validation in a second cell system","Domain mapping of the TR2 interaction not performed","Physiological ERβ targets affected not identified"]},{"year":2012,"claim":"Overexpression linked NR2C2AP to a cellular proliferation phenotype, hinting at a downstream consequence of its receptor modulation.","evidence":"Cell proliferation assay after NR2C2AP introduction into Cos-1 cells","pmids":["23129017"],"confidence":"Low","gaps":["Single method, single cell line without loss-of-function confirmation","Causal link between proliferation and receptor modulation not established","No in vivo or disease-relevant validation"]},{"year":null,"claim":"It remains unknown whether NR2C2AP nucleates a defined co-repressor complex and what endogenous gene programs it controls through TR4, TR2, and ERβ.","evidence":"","pmids":[],"confidence":"Low","gaps":["No identified co-repressor complex subunits","No genome-wide target gene mapping","No structural model of receptor binding"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,3]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3]}],"complexes":[],"partners":["NR2C2","NR2C1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86WQ0","full_name":"Nuclear receptor 2C2-associated protein","aliases":["TR4 orphan receptor-associated 16 kDa protein"],"length_aa":139,"mass_kda":15.9,"function":"May act as a repressor of NR2C2-mediated transactivation by suppressing the binding between NR2C2/TR4 and the TR4-response element in target genes","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q86WQ0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NR2C2AP","classification":"Not Classified","n_dependent_lines":566,"n_total_lines":1208,"dependency_fraction":0.4685430463576159},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NR2C2AP","total_profiled":1310},"omim":[{"mim_id":"608719","title":"TR4-ASSOCIATED PROTEIN, 16-KD","url":"https://www.omim.org/entry/608719"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NR2C2AP"},"hgnc":{"alias_symbol":["TRA16"],"prev_symbol":[]},"alphafold":{"accession":"Q86WQ0","domains":[{"cath_id":"2.60.120.260","chopping":"12-139","consensus_level":"high","plddt":97.2135,"start":12,"end":139}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86WQ0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86WQ0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86WQ0-F1-predicted_aligned_error_v6.png","plddt_mean":96.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NR2C2AP","jax_strain_url":"https://www.jax.org/strain/search?query=NR2C2AP"},"sequence":{"accession":"Q86WQ0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86WQ0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86WQ0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86WQ0"}},"corpus_meta":[{"pmid":"12486131","id":"PMC_12486131","title":"Identification of a novel testicular orphan receptor-4 (TR4)-associated protein as repressor for the selective suppression of TR4-mediated transactivation.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12486131","citation_count":20,"is_preprint":false},{"pmid":"23129017","id":"PMC_23129017","title":"Testicular orphan nuclear receptor 4-associated protein 16 promotes non-small cell lung carcinoma by activating estrogen receptor β and blocking testicular orphan nuclear receptor 2.","date":"2012","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/23129017","citation_count":8,"is_preprint":false},{"pmid":"29105400","id":"PMC_29105400","title":"Effects of Klf4 and c-Myc Knockdown on Pluripotency Maintenance in Porcine Induced Pluripotent Stem Cell.","date":"2017","source":"Cell journal","url":"https://pubmed.ncbi.nlm.nih.gov/29105400","citation_count":6,"is_preprint":false},{"pmid":"24507670","id":"PMC_24507670","title":"Establishment and identification of induced pluripotent stem cells in liver cancer patients.","date":"2014","source":"Asian Pacific journal of tropical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24507670","citation_count":2,"is_preprint":false},{"pmid":"17940562","id":"PMC_17940562","title":"[Expression of TR4-associated protein in non-small cell lung cancer].","date":"2007","source":"Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/17940562","citation_count":2,"is_preprint":false},{"pmid":"40432923","id":"PMC_40432923","title":"Pan-cancer analysis reveals TRA16 as a master regulator of human carcinogenesis.","date":"2025","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40432923","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5061,"output_tokens":1031,"usd":0.015324,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7595,"output_tokens":1801,"usd":0.0415,"stage2_stop_reason":"end_turn"},"total_usd":0.056824,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"TRA16 (NR2C2AP) was identified as a nuclear co-repressor that interacts with TR4 (NR2C2) via TR4's DNA-binding domain and ligand-binding domain, suppressing TR4-mediated transactivation. The suppression mechanism involves decreased binding between TR4 protein and TR4 response elements on target genes, as shown by EMSA.\",\n      \"method\": \"Mammalian two-hybrid system, co-immunoprecipitation, electrophoretic mobility shift assay (EMSA), reporter gene transactivation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and mammalian two-hybrid with EMSA functional validation, multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"12486131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TRA16 (NR2C2AP) selectively suppresses TR4-mediated transactivation but shows only slight influence on androgen receptor, glucocorticoid receptor, and progesterone receptor transactivation, indicating receptor-selective repressor activity.\",\n      \"method\": \"Reporter gene transactivation assay comparing multiple nuclear receptors\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, single method (reporter assay) but clear functional specificity demonstrated\",\n      \"pmids\": [\"12486131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TRA16 (NR2C2AP) is predominantly localized in the nucleus of cells.\",\n      \"method\": \"Subcellular localization assay (described in functional characterization context)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, localization reported without detailed imaging methodology described in abstract\",\n      \"pmids\": [\"12486131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRA16 (NR2C2AP) physically interacts with TR2 (NR2C1) and blocks TR2's inhibitory effect on ERβ-mediated transcription, thereby enhancing ERβ transactivation.\",\n      \"method\": \"Mammalian two-hybrid, reporter gene assay, co-immunoprecipitation, immunocytofluorescence in Cos-1 cells\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple orthogonal methods (Co-IP, two-hybrid, reporter assay) but single lab\",\n      \"pmids\": [\"23129017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRA16 (NR2C2AP) overexpression in Cos-1 cells enhanced cell proliferation.\",\n      \"method\": \"Cell proliferation assay following TRA16 introduction into Cos-1 cells\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method, no mechanistic pathway placement beyond receptor interactions\",\n      \"pmids\": [\"23129017\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NR2C2AP (TRA16) is a nuclear co-repressor that physically binds TR4 (NR2C2) through its DNA-binding and ligand-binding domains, selectively suppressing TR4-mediated transactivation by reducing TR4 binding to its response elements; it also interacts with TR2 (NR2C1) to relieve TR2-mediated repression of ERβ, thereby enhancing ERβ transcriptional activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NR2C2AP (TRA16) is a nuclear protein that functions as a selective modulator of testicular orphan nuclear receptor signaling within the NR2C subfamily [#0, #3]. It acts as a co-repressor of TR4 (NR2C2), binding the receptor through both its DNA-binding and ligand-binding domains and suppressing TR4-mediated transactivation by decreasing TR4 occupancy at its response elements [#0]. This repressor activity is receptor-selective, with only slight effects on androgen, glucocorticoid, and progesterone receptors [#1]. NR2C2AP also physically engages the related receptor TR2 (NR2C1), where it blocks TR2's inhibitory effect on ERβ-mediated transcription and thereby enhances ERβ transactivation [#3]. Beyond these nuclear-receptor interactions, no broader pathway placement or structural mechanism has been characterized in the available corpus.\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing how NR2C2AP controls TR4 signaling answered whether a dedicated repressor restrains this orphan nuclear receptor and by what molecular route.\",\n      \"evidence\": \"Mammalian two-hybrid, reciprocal co-immunoprecipitation, EMSA, and reporter transactivation assays mapping interaction to TR4's DNA-binding and ligand-binding domains\",\n      \"pmids\": [\"12486131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No identification of additional co-repressor complex partners recruited by NR2C2AP\", \"Direct target genes of TR4 modulated in vivo not defined\", \"No structural detail of the TR4-NR2C2AP interface\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Comparing multiple nuclear receptors established that NR2C2AP repression is receptor-selective rather than a general transcriptional dampener.\",\n      \"evidence\": \"Reporter gene transactivation assays comparing TR4 against androgen, glucocorticoid, and progesterone receptors\",\n      \"pmids\": [\"12486131\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity tested only against a limited panel of steroid receptors\", \"Basis of selectivity at the sequence/domain level not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Localizing NR2C2AP placed it in the nucleus, consistent with a role in transcriptional regulation.\",\n      \"evidence\": \"Subcellular localization assay reported within the functional characterization study\",\n      \"pmids\": [\"12486131\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Imaging methodology not detailed\", \"Whether localization changes upon receptor binding not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extending the receptor repertoire showed NR2C2AP also acts on TR2 to indirectly potentiate ERβ activity, broadening its role beyond TR4 repression.\",\n      \"evidence\": \"Mammalian two-hybrid, co-immunoprecipitation, immunocytofluorescence, and reporter assays in Cos-1 cells\",\n      \"pmids\": [\"23129017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab evidence without reciprocal validation in a second cell system\", \"Domain mapping of the TR2 interaction not performed\", \"Physiological ERβ targets affected not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Overexpression linked NR2C2AP to a cellular proliferation phenotype, hinting at a downstream consequence of its receptor modulation.\",\n      \"evidence\": \"Cell proliferation assay after NR2C2AP introduction into Cos-1 cells\",\n      \"pmids\": [\"23129017\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single method, single cell line without loss-of-function confirmation\", \"Causal link between proliferation and receptor modulation not established\", \"No in vivo or disease-relevant validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether NR2C2AP nucleates a defined co-repressor complex and what endogenous gene programs it controls through TR4, TR2, and ERβ.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No identified co-repressor complex subunits\", \"No genome-wide target gene mapping\", \"No structural model of receptor binding\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NR2C2\", \"NR2C1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}