{"gene":"BDKRB2","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1992,"finding":"Human BDKRB2 encodes a 364 amino acid, seven-transmembrane domain G-protein coupled receptor that binds bradykinin with high affinity (KD = 0.13 nM) and is pharmacologically characterized as a BK-2 subtype receptor; the antagonist Hoe 140 has IC50 = 65 pM for the cloned receptor expressed in COS-7 cells.","method":"cDNA cloning, COS-7 cell transfection, saturation binding analysis, pharmacological characterization with selective antagonist","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct functional reconstitution in heterologous cells with quantitative binding assays and pharmacological validation; foundational cloning paper replicated across species","pmids":["1314587"],"is_preprint":false},{"year":1994,"finding":"The human BDKRB2 gene contains three exons (first two noncoding, third containing the full coding region for the 364 aa / 7-TM protein), is a single-copy gene, and maps to chromosome 14q32; the 5' flanking region contains a TATA box and putative transcription factor binding sites.","method":"Genomic library cloning, sequencing, Southern blot, in situ hybridization, RT-PCR","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct structural characterization of the gene by sequencing and chromosomal localization by in situ hybridization, multiple orthogonal methods in one study","pmids":["7835885"],"is_preprint":false},{"year":1994,"finding":"In cultured rat myenteric neurons, BK increases cytosolic calcium via Bk-2 receptors coupled to both extracellular calcium influx and intracellular calcium release; the extracellular calcium influx component is mediated by a prostaglandin-dependent pathway, as BK stimulates PGE2 production and indomethacin blocks the calcium influx component.","method":"Calcium imaging with selective receptor antagonists, calcium-free buffer experiments, indomethacin treatment, PGE2 measurement in isolated ganglia","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal pharmacological approaches in single lab establishing receptor subtype and downstream signaling mechanism","pmids":["7965750"],"is_preprint":false},{"year":2013,"finding":"In Bdkrb2-/- mice, elevated angiotensin-(1-7) and its receptor Mas produce increased plasma nitric oxide and prostacyclin, leading to acquired platelet function defects (reduced spreading, reduced collagen-induced integrin αIIbβ3 activation and P-selectin expression) and delayed thrombosis; the platelet phenotype depends on the host (non-hematopoietic) environment rather than bone marrow progenitors, as shown by reciprocal bone marrow transplantation.","method":"Bdkrb2 knockout mice, pharmacological blockade (A-779, L-NAME, nimesulide), bone marrow transplantation, platelet spreading assays, flow cytometry for integrin activation and P-selectin, plasma NO and prostacyclin measurement","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout combined with pharmacological rescue, bone marrow transplantation epistasis, and multiple orthogonal platelet function assays establishing pathway and cellular mechanism","pmids":["23386129"],"is_preprint":false},{"year":2013,"finding":"BdkrB2 interacts genetically with p53 in kidney development: BdkrB2 is a transcriptional target of p53 (p53-mediated transcriptional activation), and BdkrB2 inactivation upregulates checkpoint kinase 1 (Chk1), which phosphorylates p53 on Ser23, potentiating p53-mediated apoptosis and repression of terminal epithelial differentiation in salt-stressed Bdkrb2-/- embryos leading to renal dysgenesis.","method":"Bdkrb2 knockout mouse model with gestational salt stress, molecular analysis of Chk1 levels and p53 phosphorylation","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic epistasis in knockout mice with defined molecular readouts (Chk1 levels, p53 phosphorylation), single lab report","pmids":["23152407"],"is_preprint":false},{"year":2011,"finding":"BDKRB2 functions downstream of IRX1 transcriptional repression to promote angiogenesis and vasculogenic mimicry in gastric cancer; siRNA knockdown of BDKRB2 or its downstream effector PAK1 inhibits tube formation, cell proliferation, cell migration, and invasion in vitro.","method":"IRX1 overexpression, BDKRB2 siRNA knockdown, PAK1 siRNA knockdown, in vitro angiogenesis assay, chick embryo angiogenesis assay, transwell migration/invasion assay, cell proliferation assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (siRNA) with multiple orthogonal functional readouts in single lab, establishing BDKRB2 as downstream effector of IRX1 with PAK1 as further downstream target","pmids":["21602894"],"is_preprint":false},{"year":2017,"finding":"NMI promotes BDKRB2 expression and mediates ERK1/2 (MAPK/ERK pathway) activation in hepatocellular carcinoma; NMI depletion decreases HCC cell proliferation and invasiveness while NMI overexpression enhances them, with BDKRB2 as a downstream target.","method":"NMI siRNA knockdown, NMI stable overexpression, in vitro proliferation/invasion assays, in vivo nude mouse tumor model, Western blotting for ERK1/2 activation, bidirectional perturbation of NMI expression","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional perturbation (KD and OE) with in vitro and in vivo readouts, single lab","pmids":["28077802"],"is_preprint":false},{"year":2014,"finding":"miR-129-1-3p directly targets the BDKRB2 3'UTR and negatively regulates BDKRB2 expression, thereby inhibiting gastric cancer cell migration.","method":"miR-129-1-3p mimic/inhibitor transfection, transwell migration assay, qRT-PCR for BDKRB2 expression, luciferase reporter assay for direct targeting of BDKRB2 3'UTR","journal":"Medical oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validation by luciferase reporter assay plus functional migration assay, single lab","pmids":["25008064"],"is_preprint":false},{"year":2019,"finding":"Bradykinin acting via BDKRB2 promotes VEGF expression in cervical cancer cell lines and enhances HUVEC angiogenesis; BDKRB2 knockdown reduces these effects while BDKRB2 overexpression enhances them, and the BK antagonist HOE140 opposes BK-induced VEGF upregulation.","method":"BK treatment of CC cell lines, BDKRB2 siRNA knockdown, BDKRB2 overexpression, HUVEC tube formation assay, VEGF expression measurement, HOE140 antagonist treatment","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (KD and OE) plus pharmacological antagonist, multiple readouts, single lab","pmids":["31059006"],"is_preprint":false}],"current_model":"BDKRB2 encodes a seven-transmembrane G-protein coupled receptor that binds bradykinin with high affinity, mobilizes both intracellular calcium and prostaglandin-dependent extracellular calcium influx, promotes nitric oxide and prostacyclin production, regulates platelet function and thrombosis through a non-cell-autonomous (host environment) mechanism, activates MAPK/ERK signaling via downstream targets including PAK1, upregulates VEGF to promote angiogenesis, and participates in a bidirectional genetic interaction with p53/Chk1 in kidney development."},"narrative":{"mechanistic_narrative":"BDKRB2 encodes a seven-transmembrane G-protein coupled receptor that binds bradykinin with high affinity and constitutes the pharmacologically defined BK-2 receptor subtype [PMID:1314587]. Upon activation, the receptor couples to dual calcium signaling: direct intracellular calcium release and a prostaglandin-dependent extracellular calcium influx, the latter driven by receptor-stimulated PGE2 production [PMID:7965750]. Through this signaling, BDKRB2 regulates vascular and hemostatic physiology; in its absence, a compensatory angiotensin-(1-7)/Mas axis elevates plasma nitric oxide and prostacyclin, producing a host-environment-dependent platelet function defect and delayed thrombosis [PMID:23386129]. In cancer contexts, bradykinin-engaged BDKRB2 drives angiogenesis by upregulating VEGF and promoting endothelial tube formation, effects opposed by the antagonist HOE140 [PMID:31059006], and it acts as a downstream effector of IRX1 repression to promote angiogenesis, vasculogenic mimicry, migration, and invasion via the downstream target PAK1 [PMID:21602894]. BDKRB2 expression is positively driven by NMI with concomitant ERK1/2 activation [PMID:28077802] and negatively controlled by miR-129-1-3p targeting its 3'UTR [PMID:25008064]. In kidney development, BDKRB2 is a transcriptional target of p53 and engages a feedback loop in which its inactivation upregulates Chk1, potentiating p53-mediated apoptosis under salt stress [PMID:23152407].","teleology":[{"year":1992,"claim":"Established the molecular identity of the bradykinin BK-2 receptor by cloning and reconstituting a high-affinity, antagonist-sensitive GPCR, resolving what protein mediates BK-2 pharmacology.","evidence":"cDNA cloning, COS-7 transfection, saturation binding and pharmacological characterization with Hoe 140","pmids":["1314587"],"confidence":"High","gaps":["No structural data on the receptor","G-protein coupling identity not defined in this study"]},{"year":1994,"claim":"Defined the gene architecture and chromosomal locus, confirming BDKRB2 as a single-copy three-exon gene at 14q32 and grounding its transcriptional regulation.","evidence":"Genomic library cloning, sequencing, Southern blot, in situ hybridization, RT-PCR","pmids":["7835885"],"confidence":"High","gaps":["Promoter regulatory elements identified only as putative","No functional validation of transcription factor binding sites"]},{"year":1994,"claim":"Resolved the downstream signaling logic of the receptor by showing it mobilizes calcium through both intracellular release and a prostaglandin-dependent influx pathway.","evidence":"Calcium imaging with antagonists, calcium-free buffer, indomethacin, and PGE2 measurement in rat myenteric neurons","pmids":["7965750"],"confidence":"Medium","gaps":["Demonstrated in rat neurons only","Specific prostaglandin synthase and effector channels not identified"]},{"year":2011,"claim":"Placed BDKRB2 in an oncogenic transcriptional circuit, showing it acts downstream of IRX1 repression and upstream of PAK1 to drive angiogenesis and invasion.","evidence":"IRX1 overexpression, BDKRB2 and PAK1 siRNA knockdown, angiogenesis, migration, invasion and proliferation assays in gastric cancer","pmids":["21602894"],"confidence":"Medium","gaps":["Mechanism linking BDKRB2 to PAK1 not defined","Single lab, in vitro and chick embryo models"]},{"year":2013,"claim":"Revealed a non-cell-autonomous role for BDKRB2 in hemostasis, showing receptor loss triggers an angiotensin-(1-7)/Mas-driven NO and prostacyclin elevation that impairs platelets via the host environment.","evidence":"Bdkrb2 knockout mice, pharmacological blockade, reciprocal bone marrow transplantation, platelet function assays, plasma NO/prostacyclin measurement","pmids":["23386129"],"confidence":"High","gaps":["Does not define how chronic receptor loss elevates the Mas axis","Human relevance of the platelet phenotype untested"]},{"year":2013,"claim":"Connected BDKRB2 to a p53/Chk1 feedback loop in organogenesis, establishing it as a p53 transcriptional target whose loss potentiates p53-driven apoptosis in the developing kidney.","evidence":"Bdkrb2 knockout mouse with gestational salt stress, analysis of Chk1 levels and p53 Ser23 phosphorylation","pmids":["23152407"],"confidence":"Medium","gaps":["Direct p53 binding to the Bdkrb2 promoter not shown","Mechanism by which receptor loss raises Chk1 unknown"]},{"year":2014,"claim":"Identified a post-transcriptional brake on BDKRB2, with miR-129-1-3p directly targeting its 3'UTR to limit migration.","evidence":"miRNA mimic/inhibitor, luciferase 3'UTR reporter, transwell migration, qRT-PCR in gastric cancer","pmids":["25008064"],"confidence":"Medium","gaps":["Endogenous miRNA regulation in vivo not assessed","Single cancer context"]},{"year":2017,"claim":"Linked an upstream activator to BDKRB2 signaling, showing NMI promotes BDKRB2 expression and ERK1/2 activation to drive HCC proliferation and invasion.","evidence":"NMI knockdown and overexpression, ERK1/2 Western blots, in vitro assays and nude mouse tumor model","pmids":["28077802"],"confidence":"Medium","gaps":["Mechanism of NMI-driven BDKRB2 upregulation unclear","Direct receptor-to-ERK coupling not dissected"]},{"year":2019,"claim":"Defined BDKRB2 as a bradykinin-responsive driver of VEGF-mediated angiogenesis in cancer, with antagonist sensitivity confirming receptor specificity.","evidence":"BK treatment, BDKRB2 knockdown/overexpression, HOE140 antagonist, HUVEC tube formation, VEGF measurement in cervical cancer cells","pmids":["31059006"],"confidence":"Medium","gaps":["Signaling intermediates between receptor and VEGF not mapped","In vitro only"]},{"year":null,"claim":"The G-protein coupling specificity and structural basis of ligand recognition that connect receptor activation to its divergent calcium, ERK, VEGF, and platelet outputs remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the receptor in the corpus","Heterotrimeric G-protein partners not identified","Tissue-specific determinants of pathway choice unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[3]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P30411","full_name":"B2 bradykinin receptor","aliases":[],"length_aa":391,"mass_kda":44.5,"function":"Receptor for bradykinin. It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P30411/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BDKRB2","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/BDKRB2","total_profiled":1310},"omim":[{"mim_id":"616604","title":"CHROMOSOME 14q32 DUPLICATION SYNDROME, 700-KB","url":"https://www.omim.org/entry/616604"},{"mim_id":"609589","title":"MICROTUBULE-ASSOCIATED SCAFFOLD PROTEIN 1; MTUS1","url":"https://www.omim.org/entry/609589"},{"mim_id":"608729","title":"ANGIOTENSIN II RECEPTOR-ASSOCIATED PROTEIN; AGTRAP","url":"https://www.omim.org/entry/608729"},{"mim_id":"606039","title":"HYDROXYCARBOXYLIC ACID RECEPTOR 3; HCAR3","url":"https://www.omim.org/entry/606039"},{"mim_id":"604775","title":"TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY A, MEMBER 1; TRPA1","url":"https://www.omim.org/entry/604775"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"urinary bladder","ntpm":38.4}],"url":"https://www.proteinatlas.org/search/BDKRB2"},"hgnc":{"alias_symbol":["BK-2"],"prev_symbol":[]},"alphafold":{"accession":"P30411","domains":[{"cath_id":"1.20.1070.10","chopping":"52-351","consensus_level":"medium","plddt":89.5498,"start":52,"end":351}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P30411","model_url":"https://alphafold.ebi.ac.uk/files/AF-P30411-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P30411-F1-predicted_aligned_error_v6.png","plddt_mean":79.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BDKRB2","jax_strain_url":"https://www.jax.org/strain/search?query=BDKRB2"},"sequence":{"accession":"P30411","fasta_url":"https://rest.uniprot.org/uniprotkb/P30411.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P30411/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P30411"}},"corpus_meta":[{"pmid":"1314587","id":"PMC_1314587","title":"Cloning and pharmacological 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the antagonist Hoe 140 has IC50 = 65 pM for the cloned receptor expressed in COS-7 cells.\",\n      \"method\": \"cDNA cloning, COS-7 cell transfection, saturation binding analysis, pharmacological characterization with selective antagonist\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct functional reconstitution in heterologous cells with quantitative binding assays and pharmacological validation; foundational cloning paper replicated across species\",\n      \"pmids\": [\"1314587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The human BDKRB2 gene contains three exons (first two noncoding, third containing the full coding region for the 364 aa / 7-TM protein), is a single-copy gene, and maps to chromosome 14q32; the 5' flanking region contains a TATA box and putative transcription factor binding sites.\",\n      \"method\": \"Genomic library cloning, sequencing, Southern blot, in situ hybridization, RT-PCR\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct structural characterization of the gene by sequencing and chromosomal localization by in situ hybridization, multiple orthogonal methods in one study\",\n      \"pmids\": [\"7835885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"In cultured rat myenteric neurons, BK increases cytosolic calcium via Bk-2 receptors coupled to both extracellular calcium influx and intracellular calcium release; the extracellular calcium influx component is mediated by a prostaglandin-dependent pathway, as BK stimulates PGE2 production and indomethacin blocks the calcium influx component.\",\n      \"method\": \"Calcium imaging with selective receptor antagonists, calcium-free buffer experiments, indomethacin treatment, PGE2 measurement in isolated ganglia\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal pharmacological approaches in single lab establishing receptor subtype and downstream signaling mechanism\",\n      \"pmids\": [\"7965750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In Bdkrb2-/- mice, elevated angiotensin-(1-7) and its receptor Mas produce increased plasma nitric oxide and prostacyclin, leading to acquired platelet function defects (reduced spreading, reduced collagen-induced integrin αIIbβ3 activation and P-selectin expression) and delayed thrombosis; the platelet phenotype depends on the host (non-hematopoietic) environment rather than bone marrow progenitors, as shown by reciprocal bone marrow transplantation.\",\n      \"method\": \"Bdkrb2 knockout mice, pharmacological blockade (A-779, L-NAME, nimesulide), bone marrow transplantation, platelet spreading assays, flow cytometry for integrin activation and P-selectin, plasma NO and prostacyclin measurement\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout combined with pharmacological rescue, bone marrow transplantation epistasis, and multiple orthogonal platelet function assays establishing pathway and cellular mechanism\",\n      \"pmids\": [\"23386129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BdkrB2 interacts genetically with p53 in kidney development: BdkrB2 is a transcriptional target of p53 (p53-mediated transcriptional activation), and BdkrB2 inactivation upregulates checkpoint kinase 1 (Chk1), which phosphorylates p53 on Ser23, potentiating p53-mediated apoptosis and repression of terminal epithelial differentiation in salt-stressed Bdkrb2-/- embryos leading to renal dysgenesis.\",\n      \"method\": \"Bdkrb2 knockout mouse model with gestational salt stress, molecular analysis of Chk1 levels and p53 phosphorylation\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic epistasis in knockout mice with defined molecular readouts (Chk1 levels, p53 phosphorylation), single lab report\",\n      \"pmids\": [\"23152407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BDKRB2 functions downstream of IRX1 transcriptional repression to promote angiogenesis and vasculogenic mimicry in gastric cancer; siRNA knockdown of BDKRB2 or its downstream effector PAK1 inhibits tube formation, cell proliferation, cell migration, and invasion in vitro.\",\n      \"method\": \"IRX1 overexpression, BDKRB2 siRNA knockdown, PAK1 siRNA knockdown, in vitro angiogenesis assay, chick embryo angiogenesis assay, transwell migration/invasion assay, cell proliferation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (siRNA) with multiple orthogonal functional readouts in single lab, establishing BDKRB2 as downstream effector of IRX1 with PAK1 as further downstream target\",\n      \"pmids\": [\"21602894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NMI promotes BDKRB2 expression and mediates ERK1/2 (MAPK/ERK pathway) activation in hepatocellular carcinoma; NMI depletion decreases HCC cell proliferation and invasiveness while NMI overexpression enhances them, with BDKRB2 as a downstream target.\",\n      \"method\": \"NMI siRNA knockdown, NMI stable overexpression, in vitro proliferation/invasion assays, in vivo nude mouse tumor model, Western blotting for ERK1/2 activation, bidirectional perturbation of NMI expression\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional perturbation (KD and OE) with in vitro and in vivo readouts, single lab\",\n      \"pmids\": [\"28077802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"miR-129-1-3p directly targets the BDKRB2 3'UTR and negatively regulates BDKRB2 expression, thereby inhibiting gastric cancer cell migration.\",\n      \"method\": \"miR-129-1-3p mimic/inhibitor transfection, transwell migration assay, qRT-PCR for BDKRB2 expression, luciferase reporter assay for direct targeting of BDKRB2 3'UTR\",\n      \"journal\": \"Medical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validation by luciferase reporter assay plus functional migration assay, single lab\",\n      \"pmids\": [\"25008064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Bradykinin acting via BDKRB2 promotes VEGF expression in cervical cancer cell lines and enhances HUVEC angiogenesis; BDKRB2 knockdown reduces these effects while BDKRB2 overexpression enhances them, and the BK antagonist HOE140 opposes BK-induced VEGF upregulation.\",\n      \"method\": \"BK treatment of CC cell lines, BDKRB2 siRNA knockdown, BDKRB2 overexpression, HUVEC tube formation assay, VEGF expression measurement, HOE140 antagonist treatment\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (KD and OE) plus pharmacological antagonist, multiple readouts, single lab\",\n      \"pmids\": [\"31059006\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BDKRB2 encodes a seven-transmembrane G-protein coupled receptor that binds bradykinin with high affinity, mobilizes both intracellular calcium and prostaglandin-dependent extracellular calcium influx, promotes nitric oxide and prostacyclin production, regulates platelet function and thrombosis through a non-cell-autonomous (host environment) mechanism, activates MAPK/ERK signaling via downstream targets including PAK1, upregulates VEGF to promote angiogenesis, and participates in a bidirectional genetic interaction with p53/Chk1 in kidney development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BDKRB2 encodes a seven-transmembrane G-protein coupled receptor that binds bradykinin with high affinity and constitutes the pharmacologically defined BK-2 receptor subtype [#0]. Upon activation, the receptor couples to dual calcium signaling: direct intracellular calcium release and a prostaglandin-dependent extracellular calcium influx, the latter driven by receptor-stimulated PGE2 production [#2]. Through this signaling, BDKRB2 regulates vascular and hemostatic physiology; in its absence, a compensatory angiotensin-(1-7)/Mas axis elevates plasma nitric oxide and prostacyclin, producing a host-environment-dependent platelet function defect and delayed thrombosis [#3]. In cancer contexts, bradykinin-engaged BDKRB2 drives angiogenesis by upregulating VEGF and promoting endothelial tube formation, effects opposed by the antagonist HOE140 [#8], and it acts as a downstream effector of IRX1 repression to promote angiogenesis, vasculogenic mimicry, migration, and invasion via the downstream target PAK1 [#5]. BDKRB2 expression is positively driven by NMI with concomitant ERK1/2 activation [#6] and negatively controlled by miR-129-1-3p targeting its 3'UTR [#7]. In kidney development, BDKRB2 is a transcriptional target of p53 and engages a feedback loop in which its inactivation upregulates Chk1, potentiating p53-mediated apoptosis under salt stress [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established the molecular identity of the bradykinin BK-2 receptor by cloning and reconstituting a high-affinity, antagonist-sensitive GPCR, resolving what protein mediates BK-2 pharmacology.\",\n      \"evidence\": \"cDNA cloning, COS-7 transfection, saturation binding and pharmacological characterization with Hoe 140\",\n      \"pmids\": [\"1314587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural data on the receptor\", \"G-protein coupling identity not defined in this study\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Defined the gene architecture and chromosomal locus, confirming BDKRB2 as a single-copy three-exon gene at 14q32 and grounding its transcriptional regulation.\",\n      \"evidence\": \"Genomic library cloning, sequencing, Southern blot, in situ hybridization, RT-PCR\",\n      \"pmids\": [\"7835885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Promoter regulatory elements identified only as putative\", \"No functional validation of transcription factor binding sites\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Resolved the downstream signaling logic of the receptor by showing it mobilizes calcium through both intracellular release and a prostaglandin-dependent influx pathway.\",\n      \"evidence\": \"Calcium imaging with antagonists, calcium-free buffer, indomethacin, and PGE2 measurement in rat myenteric neurons\",\n      \"pmids\": [\"7965750\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Demonstrated in rat neurons only\", \"Specific prostaglandin synthase and effector channels not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed BDKRB2 in an oncogenic transcriptional circuit, showing it acts downstream of IRX1 repression and upstream of PAK1 to drive angiogenesis and invasion.\",\n      \"evidence\": \"IRX1 overexpression, BDKRB2 and PAK1 siRNA knockdown, angiogenesis, migration, invasion and proliferation assays in gastric cancer\",\n      \"pmids\": [\"21602894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking BDKRB2 to PAK1 not defined\", \"Single lab, in vitro and chick embryo models\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a non-cell-autonomous role for BDKRB2 in hemostasis, showing receptor loss triggers an angiotensin-(1-7)/Mas-driven NO and prostacyclin elevation that impairs platelets via the host environment.\",\n      \"evidence\": \"Bdkrb2 knockout mice, pharmacological blockade, reciprocal bone marrow transplantation, platelet function assays, plasma NO/prostacyclin measurement\",\n      \"pmids\": [\"23386129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define how chronic receptor loss elevates the Mas axis\", \"Human relevance of the platelet phenotype untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected BDKRB2 to a p53/Chk1 feedback loop in organogenesis, establishing it as a p53 transcriptional target whose loss potentiates p53-driven apoptosis in the developing kidney.\",\n      \"evidence\": \"Bdkrb2 knockout mouse with gestational salt stress, analysis of Chk1 levels and p53 Ser23 phosphorylation\",\n      \"pmids\": [\"23152407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct p53 binding to the Bdkrb2 promoter not shown\", \"Mechanism by which receptor loss raises Chk1 unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified a post-transcriptional brake on BDKRB2, with miR-129-1-3p directly targeting its 3'UTR to limit migration.\",\n      \"evidence\": \"miRNA mimic/inhibitor, luciferase 3'UTR reporter, transwell migration, qRT-PCR in gastric cancer\",\n      \"pmids\": [\"25008064\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous miRNA regulation in vivo not assessed\", \"Single cancer context\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked an upstream activator to BDKRB2 signaling, showing NMI promotes BDKRB2 expression and ERK1/2 activation to drive HCC proliferation and invasion.\",\n      \"evidence\": \"NMI knockdown and overexpression, ERK1/2 Western blots, in vitro assays and nude mouse tumor model\",\n      \"pmids\": [\"28077802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of NMI-driven BDKRB2 upregulation unclear\", \"Direct receptor-to-ERK coupling not dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined BDKRB2 as a bradykinin-responsive driver of VEGF-mediated angiogenesis in cancer, with antagonist sensitivity confirming receptor specificity.\",\n      \"evidence\": \"BK treatment, BDKRB2 knockdown/overexpression, HOE140 antagonist, HUVEC tube formation, VEGF measurement in cervical cancer cells\",\n      \"pmids\": [\"31059006\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling intermediates between receptor and VEGF not mapped\", \"In vitro only\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The G-protein coupling specificity and structural basis of ligand recognition that connect receptor activation to its divergent calcium, ERK, VEGF, and platelet outputs remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the receptor in the corpus\", \"Heterotrimeric G-protein partners not identified\", \"Tissue-specific determinants of pathway choice unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}