{"gene":"TBXA2R","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2016,"finding":"TBXA2R knockdown causes dramatic cell killing in triple-negative breast cancer (TNBC) cells, and TBXA2R enhances TNBC cell migration and invasion by activating Rho signalling; these phenotypes are reversed by Rho-associated Kinase (ROCK) inhibitors. TBXA2R also protects TNBC cells from DNA damage by negatively regulating reactive oxygen species levels. TBXA2R mRNA and promoter activities are up-regulated following BRCA1 knockdown, with c-Myc required for BRCA1-mediated transcriptional repression of TBXA2R.","method":"siRNA knockdown with cell viability, migration, and invasion assays; Rho signalling reporter assays; ROCK inhibitor rescue experiments; ROS measurement; BRCA1 knockdown with promoter/reporter assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (KD phenotype, pathway rescue, promoter regulation) in single lab; no structural or in vitro reconstitution","pmids":["27487152"],"is_preprint":false},{"year":2026,"finding":"TBXA2R activates ERM (ezrin, radixin, moesin) proteins to drive motility, invasion, and metastatic colonization of TNBC cells. Mechanistically, TBXA2R engages Gαq/11 and Gα12/13 subfamilies, then the Rho subfamily of Rho GTPases, and their Ser/Thr kinase effectors SLK and LOK to phosphorylate/activate ERMs. TBXA2R promotes TNBC metastatic colonization in vivo in an ERM-dependent manner.","method":"GPCR signalling pathway dissection (G-protein subtype-specific assays), Rho GTPase activation assays, SLK/LOK kinase activity assays, ERM phosphorylation assays, in vitro migration/invasion assays, in vivo metastasis colonization model, genetic rescue/loss-of-function","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (G-protein subtype mapping, kinase identification, in vitro functional assays, in vivo metastasis model) establishing a complete signalling axis in a single rigorous study","pmids":["41844278"],"is_preprint":false},{"year":2010,"finding":"The TBXA2R -4684T allele is associated with lower TBXA2R promoter activity compared to the -4684C allele; ETS-like gene transcription factor-1 (ELK-1) co-transfection further decreases promoter activity driven by the -4684T construct. EMSA showed the -4684T allele produces a specific shifted band with greater protein-binding affinity than the -4684C allele, indicating differential transcription factor binding at this SNP affects TBXA2R expression.","method":"Dual-luciferase reporter assay for promoter activity; electrophoretic mobility shift assay (EMSA) with nuclear extracts from HMC-1 mast cell line; ELK-1 co-transfection","journal":"Clinical and experimental allergy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal in vitro methods (reporter assay + EMSA) in single lab establishing functional consequence of promoter SNP","pmids":["21070398"],"is_preprint":false},{"year":1993,"finding":"The human TBXA2R gene was mapped to chromosome 19p13.3 by somatic cell hybrid PCR and linkage analysis, placing it closest to marker D19S120 between D19S120 and PMS207 at the telomeric end of 19p13.3.","method":"PCR amplification in monochoromosomal human/rodent somatic cell hybrids; multipoint linkage analysis in CEPH families (LOD score 19.55 at θ=0.05)","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct chromosomal mapping by somatic cell hybrids confirmed by multipoint linkage analysis with high LOD score","pmids":["8288221"],"is_preprint":false},{"year":1996,"finding":"The rat Tbxa2r gene was mapped to chromosome 7q11 by fluorescence in situ hybridization; the cloned rat kidney Tbxa2r cDNA was shown to be expressed in the renal glomerulus, vasculature, and transitional cell epithelium of renal pelvis.","method":"Fluorescence in situ hybridization (FISH); cDNA cloning; tissue expression analysis","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct FISH mapping and cloning with tissue localization data in single study","pmids":["8646890"],"is_preprint":false},{"year":2018,"finding":"Naturally occurring rare loss-of-function variants in TBXA2R (encoding the TPα receptor, an α-isoform GPCR) are associated with bleeding phenotypes and abnormal platelet function, providing structure-function information about critical residues required for TPα-dependent thrombus formation.","method":"Clinical characterization of patients with naturally occurring TBXA2R variants; functional platelet assays; structure-function analysis of GPCR variants","journal":"Platelets","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — review synthesizing multiple patient variant studies with functional platelet assays; not a single original experiment but synthesizes replicated patient data","pmids":["30089223"],"is_preprint":false}],"current_model":"TBXA2R (thromboxane A2 receptor, TPα) is a Gαq/11- and Gα12/13-coupled GPCR that, upon activation, engages Rho GTPases and their kinase effectors SLK/LOK to phosphorylate ERM proteins, driving cancer cell motility, invasion, and metastatic colonization; in platelets, TPα signalling is essential for thrombus formation, as demonstrated by loss-of-function variants causing bleeding; BRCA1 transcriptionally represses TBXA2R via c-Myc, and a promoter SNP (-4684T>C) modulates ELK-1-dependent TBXA2R expression; the gene maps to human chromosome 19p13.3."},"narrative":{"mechanistic_narrative":"TBXA2R encodes the thromboxane A2 receptor (TPα), a G-protein-coupled receptor that couples extracellular stimulus to cytoskeletal remodeling and cell motility through Rho-family GTPase signalling [PMID:41844278, PMID:27487152]. Upon activation, TPα engages the Gαq/11 and Gα12/13 subfamilies, which in turn activate Rho GTPases and their Ser/Thr kinase effectors SLK and LOK to phosphorylate and activate ERM (ezrin/radixin/moesin) proteins; this axis drives migration, invasion, and ERM-dependent metastatic colonization of triple-negative breast cancer cells in vivo [PMID:41844278]. Consistent with this pro-tumorigenic role, TBXA2R knockdown is lethal to TNBC cells, and Rho signalling and its phenotypic outputs are reversed by ROCK inhibitors, while TBXA2R additionally protects these cells from DNA damage by limiting reactive oxygen species [PMID:27487152]. TBXA2R expression is transcriptionally constrained: BRCA1 represses the gene through c-Myc, and a promoter SNP (-4684T>C) alters ELK-1-dependent transcription factor binding to set promoter activity [PMID:27487152, PMID:21070398]. In platelets, TPα signalling is required for thrombus formation, as naturally occurring rare loss-of-function variants cause bleeding phenotypes and abnormal platelet function [PMID:30089223].","teleology":[{"year":1993,"claim":"Establishing the chromosomal location of the human gene provided the genomic anchor needed to link TBXA2R to phenotypes and regulatory elements.","evidence":"PCR in monochromosomal somatic cell hybrids and multipoint linkage analysis in CEPH families","pmids":["8288221"],"confidence":"High","gaps":["Does not address receptor function or signalling","No tissue-level expression data"]},{"year":1996,"claim":"Mapping and cloning the rodent ortholog with tissue expression analysis extended the receptor's relevance beyond platelets to renal vasculature and epithelium.","evidence":"FISH mapping and cDNA cloning with renal tissue expression analysis in rat","pmids":["8646890"],"confidence":"Medium","gaps":["Functional role in kidney not tested","No signalling mechanism defined"]},{"year":2010,"claim":"Identifying a functional promoter SNP showed that TBXA2R expression is set by differential transcription factor binding, explaining a source of expression variation.","evidence":"Luciferase promoter assays and EMSA with mast cell nuclear extracts plus ELK-1 co-transfection","pmids":["21070398"],"confidence":"Medium","gaps":["Direct ELK-1 binding at the SNP not confirmed beyond mobility shift","Physiological consequence of allelic expression difference untested"]},{"year":2016,"claim":"Demonstrating that TBXA2R drives TNBC migration/invasion via Rho/ROCK and is repressed by BRCA1 reframed the receptor as a pro-tumorigenic signalling node under transcriptional control.","evidence":"siRNA knockdown with viability/migration/invasion assays, Rho reporter and ROCK inhibitor rescue, ROS measurement, and BRCA1 knockdown promoter assays","pmids":["27487152"],"confidence":"Medium","gaps":["Single-lab phenotypic work without in vivo validation at this stage","Mechanistic link between receptor and Rho not resolved to specific effectors"]},{"year":2018,"claim":"Linking rare loss-of-function variants to bleeding established that TPα signalling is causally required for normal platelet-dependent thrombus formation.","evidence":"Clinical characterization of patients with TBXA2R variants, platelet function assays, and GPCR structure-function analysis","pmids":["30089223"],"confidence":"Medium","gaps":["Synthesizes patient data rather than a single controlled experiment","Per-residue structure-function mapping incomplete"]},{"year":2026,"claim":"Dissecting the full Gαq/11–Gα12/13 → Rho → SLK/LOK → ERM axis defined the complete signalling chain by which TPα drives invasion and metastatic colonization.","evidence":"G-protein subtype-specific assays, Rho GTPase activation, SLK/LOK kinase and ERM phosphorylation assays, in vitro invasion, and in vivo metastasis model with genetic rescue","pmids":["41844278"],"confidence":"High","gaps":["Whether the same axis operates in platelets or kidney not tested","Upstream agonist/ligand context in tumors not defined"]},{"year":null,"claim":"How TBXA2R signalling outputs are differentially deployed across cell types (platelet thrombus formation versus cancer cell invasion versus renal function) remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the receptor in the corpus","Tissue-specific effector wiring not compared directly"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[5]}],"complexes":[],"partners":["SLK","LOK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P21731","full_name":"Thromboxane A2 receptor","aliases":["Prostanoid TP receptor"],"length_aa":343,"mass_kda":37.4,"function":"Receptor for thromboxane A2 (TXA2), a potent stimulator of platelet aggregation. The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system. In the kidney, the binding of TXA2 to glomerular TP receptors causes intense vasoconstriction. Activates phospholipase C Activates adenylyl cyclase Inhibits adenylyl cyclase","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P21731/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TBXA2R","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TBXA2R","total_profiled":1310},"omim":[{"mim_id":"615125","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 13C; ANKRD13C","url":"https://www.omim.org/entry/615125"},{"mim_id":"614009","title":"BLEEDING DISORDER, PLATELET-TYPE, 13, SUSCEPTIBILITY TO; BDPLT13","url":"https://www.omim.org/entry/614009"},{"mim_id":"231200","title":"BERNARD-SOULIER SYNDROME; BSS","url":"https://www.omim.org/entry/231200"},{"mim_id":"190196","title":"TRANSGLUTAMINASE 2; TGM2","url":"https://www.omim.org/entry/190196"},{"mim_id":"188070","title":"THROMBOXANE A2 RECEPTOR, PLATELET; TBXA2R","url":"https://www.omim.org/entry/188070"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":34.6}],"url":"https://www.proteinatlas.org/search/TBXA2R"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P21731","domains":[{"cath_id":"1.20.1070.10","chopping":"24-316","consensus_level":"high","plddt":90.9778,"start":24,"end":316}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P21731","model_url":"https://alphafold.ebi.ac.uk/files/AF-P21731-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P21731-F1-predicted_aligned_error_v6.png","plddt_mean":86.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TBXA2R","jax_strain_url":"https://www.jax.org/strain/search?query=TBXA2R"},"sequence":{"accession":"P21731","fasta_url":"https://rest.uniprot.org/uniprotkb/P21731.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P21731/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P21731"}},"corpus_meta":[{"pmid":"16250911","id":"PMC_16250911","title":"Expression of thromboxane synthase, TBXAS1 and the thromboxane A2 receptor, TBXA2R, in human breast cancer.","date":"2005","source":"International seminars in surgical oncology : ISSO","url":"https://pubmed.ncbi.nlm.nih.gov/16250911","citation_count":49,"is_preprint":false},{"pmid":"18031559","id":"PMC_18031559","title":"TBXA2R gene polymorphism and responsiveness to leukotriene receptor antagonist in children with asthma.","date":"2007","source":"Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18031559","citation_count":30,"is_preprint":false},{"pmid":"27641736","id":"PMC_27641736","title":"Associations of MDR1, TBXA2R, PLA2G7, and PEAR1 genetic polymorphisms with the platelet activity in Chinese ischemic stroke patients receiving aspirin therapy.","date":"2016","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/27641736","citation_count":30,"is_preprint":false},{"pmid":"21070398","id":"PMC_21070398","title":"Association of thromboxane A2 receptor (TBXA2R) gene polymorphism in patients with aspirin-intolerant acute urticaria.","date":"2010","source":"Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21070398","citation_count":27,"is_preprint":false},{"pmid":"22017802","id":"PMC_22017802","title":"Association of ORMDL3, STAT6 and TBXA2R gene polymorphisms with asthma.","date":"2011","source":"International journal of immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/22017802","citation_count":23,"is_preprint":false},{"pmid":"27487152","id":"PMC_27487152","title":"Thromboxane A2 receptor (TBXA2R) is a potent survival factor for triple negative breast cancers (TNBCs).","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27487152","citation_count":22,"is_preprint":false},{"pmid":"25483406","id":"PMC_25483406","title":"Regulatory SNPs and transcriptional factor binding sites in ADRBK1, AKT3, ATF3, DIO2, TBXA2R and VEGFA.","date":"2014","source":"Transcription","url":"https://pubmed.ncbi.nlm.nih.gov/25483406","citation_count":21,"is_preprint":false},{"pmid":"30089223","id":"PMC_30089223","title":"TBXA2R gene variants associated with bleeding.","date":"2018","source":"Platelets","url":"https://pubmed.ncbi.nlm.nih.gov/30089223","citation_count":17,"is_preprint":false},{"pmid":"25821496","id":"PMC_25821496","title":"Xueshuan Xinmaining Tablet Treats Blood Stasis through Regulating the Expression of F13a1, Car1, and Tbxa2r.","date":"2015","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/25821496","citation_count":16,"is_preprint":false},{"pmid":"8288221","id":"PMC_8288221","title":"Linkage mapping of the human thromboxane A2 receptor (TBXA2R) to chromosome 19p13.3 using transcribed 3' untranslated DNA sequence polymorphisms.","date":"1993","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8288221","citation_count":13,"is_preprint":false},{"pmid":"29588858","id":"PMC_29588858","title":"Single nucleotide polymorphisms in asthma candidate genes TBXA2R, ADAM33 FCER1B and ORMDL3 in Pakistani asthmatics a case control study.","date":"2018","source":"Asthma research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/29588858","citation_count":13,"is_preprint":false},{"pmid":"30179800","id":"PMC_30179800","title":"TBXA2R rs4523 G allele is associated with decreased susceptibility to Kawasaki disease.","date":"2018","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/30179800","citation_count":9,"is_preprint":false},{"pmid":"8646890","id":"PMC_8646890","title":"Assignment of the gene for rat thromboxane receptor (Tbxa2r) to chromosome 7q11 by fluorescence in situ hybridization.","date":"1996","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8646890","citation_count":7,"is_preprint":false},{"pmid":"32971583","id":"PMC_32971583","title":"Association of TBXA2R, P2Y12 and ADD1 genes polymorphisms with ischemic stroke susceptibility: A metaanalysis.","date":"2020","source":"Clinical and investigative medicine. Medecine clinique et experimentale","url":"https://pubmed.ncbi.nlm.nih.gov/32971583","citation_count":6,"is_preprint":false},{"pmid":"36936944","id":"PMC_36936944","title":"In silico analysis of single nucleotide polymorphism (rs34377097) of TBXA2R gene and pollen induced bronchial asthma susceptibility in West Bengal population, India.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36936944","citation_count":4,"is_preprint":false},{"pmid":"39465093","id":"PMC_39465093","title":"The Impact of TBXA2R Gene Variants on the Risk of Aspirin-Induced Upper Gastrointestinal Bleeding: A Case-Control Study.","date":"2024","source":"Hospital pharmacy","url":"https://pubmed.ncbi.nlm.nih.gov/39465093","citation_count":2,"is_preprint":false},{"pmid":"41844278","id":"PMC_41844278","title":"TBXA2R activates ERMs to drive motility, invasion, and metastatic colonization of TNBC cells.","date":"2026","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/41844278","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10983,"output_tokens":1792,"usd":0.029915,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8639,"output_tokens":2158,"usd":0.048572,"stage2_stop_reason":"end_turn"},"total_usd":0.078487,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"TBXA2R knockdown causes dramatic cell killing in triple-negative breast cancer (TNBC) cells, and TBXA2R enhances TNBC cell migration and invasion by activating Rho signalling; these phenotypes are reversed by Rho-associated Kinase (ROCK) inhibitors. TBXA2R also protects TNBC cells from DNA damage by negatively regulating reactive oxygen species levels. TBXA2R mRNA and promoter activities are up-regulated following BRCA1 knockdown, with c-Myc required for BRCA1-mediated transcriptional repression of TBXA2R.\",\n      \"method\": \"siRNA knockdown with cell viability, migration, and invasion assays; Rho signalling reporter assays; ROCK inhibitor rescue experiments; ROS measurement; BRCA1 knockdown with promoter/reporter assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (KD phenotype, pathway rescue, promoter regulation) in single lab; no structural or in vitro reconstitution\",\n      \"pmids\": [\"27487152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TBXA2R activates ERM (ezrin, radixin, moesin) proteins to drive motility, invasion, and metastatic colonization of TNBC cells. Mechanistically, TBXA2R engages Gαq/11 and Gα12/13 subfamilies, then the Rho subfamily of Rho GTPases, and their Ser/Thr kinase effectors SLK and LOK to phosphorylate/activate ERMs. TBXA2R promotes TNBC metastatic colonization in vivo in an ERM-dependent manner.\",\n      \"method\": \"GPCR signalling pathway dissection (G-protein subtype-specific assays), Rho GTPase activation assays, SLK/LOK kinase activity assays, ERM phosphorylation assays, in vitro migration/invasion assays, in vivo metastasis colonization model, genetic rescue/loss-of-function\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (G-protein subtype mapping, kinase identification, in vitro functional assays, in vivo metastasis model) establishing a complete signalling axis in a single rigorous study\",\n      \"pmids\": [\"41844278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The TBXA2R -4684T allele is associated with lower TBXA2R promoter activity compared to the -4684C allele; ETS-like gene transcription factor-1 (ELK-1) co-transfection further decreases promoter activity driven by the -4684T construct. EMSA showed the -4684T allele produces a specific shifted band with greater protein-binding affinity than the -4684C allele, indicating differential transcription factor binding at this SNP affects TBXA2R expression.\",\n      \"method\": \"Dual-luciferase reporter assay for promoter activity; electrophoretic mobility shift assay (EMSA) with nuclear extracts from HMC-1 mast cell line; ELK-1 co-transfection\",\n      \"journal\": \"Clinical and experimental allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal in vitro methods (reporter assay + EMSA) in single lab establishing functional consequence of promoter SNP\",\n      \"pmids\": [\"21070398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The human TBXA2R gene was mapped to chromosome 19p13.3 by somatic cell hybrid PCR and linkage analysis, placing it closest to marker D19S120 between D19S120 and PMS207 at the telomeric end of 19p13.3.\",\n      \"method\": \"PCR amplification in monochoromosomal human/rodent somatic cell hybrids; multipoint linkage analysis in CEPH families (LOD score 19.55 at θ=0.05)\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct chromosomal mapping by somatic cell hybrids confirmed by multipoint linkage analysis with high LOD score\",\n      \"pmids\": [\"8288221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The rat Tbxa2r gene was mapped to chromosome 7q11 by fluorescence in situ hybridization; the cloned rat kidney Tbxa2r cDNA was shown to be expressed in the renal glomerulus, vasculature, and transitional cell epithelium of renal pelvis.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH); cDNA cloning; tissue expression analysis\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct FISH mapping and cloning with tissue localization data in single study\",\n      \"pmids\": [\"8646890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Naturally occurring rare loss-of-function variants in TBXA2R (encoding the TPα receptor, an α-isoform GPCR) are associated with bleeding phenotypes and abnormal platelet function, providing structure-function information about critical residues required for TPα-dependent thrombus formation.\",\n      \"method\": \"Clinical characterization of patients with naturally occurring TBXA2R variants; functional platelet assays; structure-function analysis of GPCR variants\",\n      \"journal\": \"Platelets\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — review synthesizing multiple patient variant studies with functional platelet assays; not a single original experiment but synthesizes replicated patient data\",\n      \"pmids\": [\"30089223\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TBXA2R (thromboxane A2 receptor, TPα) is a Gαq/11- and Gα12/13-coupled GPCR that, upon activation, engages Rho GTPases and their kinase effectors SLK/LOK to phosphorylate ERM proteins, driving cancer cell motility, invasion, and metastatic colonization; in platelets, TPα signalling is essential for thrombus formation, as demonstrated by loss-of-function variants causing bleeding; BRCA1 transcriptionally represses TBXA2R via c-Myc, and a promoter SNP (-4684T>C) modulates ELK-1-dependent TBXA2R expression; the gene maps to human chromosome 19p13.3.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TBXA2R encodes the thromboxane A2 receptor (TPα), a G-protein-coupled receptor that couples extracellular stimulus to cytoskeletal remodeling and cell motility through Rho-family GTPase signalling [#1, #0]. Upon activation, TPα engages the Gαq/11 and Gα12/13 subfamilies, which in turn activate Rho GTPases and their Ser/Thr kinase effectors SLK and LOK to phosphorylate and activate ERM (ezrin/radixin/moesin) proteins; this axis drives migration, invasion, and ERM-dependent metastatic colonization of triple-negative breast cancer cells in vivo [#1]. Consistent with this pro-tumorigenic role, TBXA2R knockdown is lethal to TNBC cells, and Rho signalling and its phenotypic outputs are reversed by ROCK inhibitors, while TBXA2R additionally protects these cells from DNA damage by limiting reactive oxygen species [#0]. TBXA2R expression is transcriptionally constrained: BRCA1 represses the gene through c-Myc, and a promoter SNP (-4684T>C) alters ELK-1-dependent transcription factor binding to set promoter activity [#0, #2]. In platelets, TPα signalling is required for thrombus formation, as naturally occurring rare loss-of-function variants cause bleeding phenotypes and abnormal platelet function [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing the chromosomal location of the human gene provided the genomic anchor needed to link TBXA2R to phenotypes and regulatory elements.\",\n      \"evidence\": \"PCR in monochromosomal somatic cell hybrids and multipoint linkage analysis in CEPH families\",\n      \"pmids\": [\"8288221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address receptor function or signalling\", \"No tissue-level expression data\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Mapping and cloning the rodent ortholog with tissue expression analysis extended the receptor's relevance beyond platelets to renal vasculature and epithelium.\",\n      \"evidence\": \"FISH mapping and cDNA cloning with renal tissue expression analysis in rat\",\n      \"pmids\": [\"8646890\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role in kidney not tested\", \"No signalling mechanism defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying a functional promoter SNP showed that TBXA2R expression is set by differential transcription factor binding, explaining a source of expression variation.\",\n      \"evidence\": \"Luciferase promoter assays and EMSA with mast cell nuclear extracts plus ELK-1 co-transfection\",\n      \"pmids\": [\"21070398\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ELK-1 binding at the SNP not confirmed beyond mobility shift\", \"Physiological consequence of allelic expression difference untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating that TBXA2R drives TNBC migration/invasion via Rho/ROCK and is repressed by BRCA1 reframed the receptor as a pro-tumorigenic signalling node under transcriptional control.\",\n      \"evidence\": \"siRNA knockdown with viability/migration/invasion assays, Rho reporter and ROCK inhibitor rescue, ROS measurement, and BRCA1 knockdown promoter assays\",\n      \"pmids\": [\"27487152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab phenotypic work without in vivo validation at this stage\", \"Mechanistic link between receptor and Rho not resolved to specific effectors\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linking rare loss-of-function variants to bleeding established that TPα signalling is causally required for normal platelet-dependent thrombus formation.\",\n      \"evidence\": \"Clinical characterization of patients with TBXA2R variants, platelet function assays, and GPCR structure-function analysis\",\n      \"pmids\": [\"30089223\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Synthesizes patient data rather than a single controlled experiment\", \"Per-residue structure-function mapping incomplete\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Dissecting the full Gαq/11–Gα12/13 → Rho → SLK/LOK → ERM axis defined the complete signalling chain by which TPα drives invasion and metastatic colonization.\",\n      \"evidence\": \"G-protein subtype-specific assays, Rho GTPase activation, SLK/LOK kinase and ERM phosphorylation assays, in vitro invasion, and in vivo metastasis model with genetic rescue\",\n      \"pmids\": [\"41844278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same axis operates in platelets or kidney not tested\", \"Upstream agonist/ligand context in tumors not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TBXA2R signalling outputs are differentially deployed across cell types (platelet thrombus formation versus cancer cell invasion versus renal function) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the receptor in the corpus\", \"Tissue-specific effector wiring not compared directly\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SLK\", \"LOK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}