{"gene":"PLXNB3","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2023,"finding":"PLXNB3 expression is induced by hypoxia and is a direct transcriptional target gene of hypoxia-inducible factor 1 (HIF-1) in human breast cancer cells. PLXNB3 protein is required for hypoxia-induced MET/SRC/focal adhesion kinase (FAK) signaling and MET/SRC/STAT3/NANOG signaling cascades, and for hypoxia-induced breast cancer cell migration, invasion, cancer stem cell specification, tumor formation, and lung metastasis in orthotopic mouse models.","method":"siRNA knockdown, orthotopic breast cancer mouse models, reporter assays for HIF-1 target gene validation, pathway analysis of MET/SRC/FAK and MET/SRC/STAT3/NANOG signaling","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA KD, in vivo mouse models, pathway signaling assays), consistent with review paper (PMID:37768037) describing the same mechanism","pmids":["36857181","37768037"],"is_preprint":false},{"year":2009,"finding":"The missense mutation R538H in the extracellular domain of PLXNB3 prevents binding of its ligand Sema5A, establishing that PLXNB3 functions as a receptor for Sema5A.","method":"Functional binding assay in cellular models using cancer-associated somatic mutations; ligand-receptor binding assay","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct functional assay in cellular model, single lab, single method reported in abstract","pmids":["19462467"],"is_preprint":false},{"year":2023,"finding":"M2-type tumor-associated macrophage (TAM)-derived SEMA5A binds to tumor cell-expressed PLXNB3 to promote pancreatic adenocarcinoma (PDAC) tumor cell proliferation and outgrowth via enhancement of aerobic glycolysis (Warburg effect).","method":"In vivo intrasplenic injection mouse models, KPC mouse models, in vitro mechanistic studies of SEMA5A-PLXNB3 axis and glycolysis","journal":"Journal of immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse models plus mechanistic glycolysis assays, single lab","pmids":["36741230"],"is_preprint":false},{"year":2022,"finding":"PLXNB3 is a cell surface glycoprotein enriched in triple-negative breast cancer (TNBC) cells, and its knockdown by siRNA or CRISPR-Cas9 editing impairs TNBC cell line growth, invasion, and migration in vitro and in vivo.","method":"N-glycoproteomics, siRNA knockdown, CRISPR-Cas9 editing, in vitro invasion/migration assays, in vivo models","journal":"Journal of proteome research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (glycoproteomics, siRNA, CRISPR-Cas9, in vivo), single lab","pmids":["35981243"],"is_preprint":false},{"year":2022,"finding":"A pathogenic PLXNB3 mutation (p.E1440V) inhibits cell migration and proliferation in AC16 and HEK293T cells and affects activity of key factors in the Notch signaling pathway, myocardial contraction pathway, and neurodevelopmental pathways, linking PLXNB3 to congenital heart disease with neurodevelopmental disabilities.","method":"Scratch wound assay, Ki-67 flow cytometry, RT-qPCR of pathway genes, whole-exome sequencing, AlphaFold/PyRosetta structural modeling","journal":"Translational pediatrics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional cell-based assays with multiple readouts, single lab, structural modeling is computational","pmids":["36506778"],"is_preprint":false},{"year":2015,"finding":"A KIAA1199/PLXNB3/SEMA5A/CTGF axis was proposed to enhance cell proliferation and angiogenesis in fibroblast-like synoviocytes; PLXNB3 knockdown and overexpression experiments were used to dissect contributions of this pathway.","method":"KIAA1199 knockdown and overexpression, MTT proliferation assay, tube formation assay, western blotting, qPCR","journal":"Arthritis research & therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement is proposed based on expression and knockdown data, PLXNB3-specific mechanistic detail is limited in the abstract","pmids":["26022278"],"is_preprint":false}],"current_model":"PLXNB3 is a transmembrane semaphorin receptor (for Sema4D/Sema5A) that is transcriptionally induced by HIF-1 under hypoxia; upon activation it stimulates MET receptor tyrosine kinase, leading to downstream SRC/FAK signaling (promoting cancer cell migration and invasion) and SRC/STAT3/NANOG signaling (promoting cancer stem cell specification and self-renewal), while in pancreatic cancer the SEMA5A–PLXNB3 axis drives tumor outgrowth by enhancing aerobic glycolysis."},"narrative":{"mechanistic_narrative":"PLXNB3 is a transmembrane semaphorin receptor that drives tumor cell migration, invasion, and growth across multiple cancer types [PMID:36857181, PMID:37768037, PMID:35981243]. It functions as a cell-surface receptor for Sema5A, as defined by the R538H extracellular-domain mutation that abolishes ligand binding [PMID:19462467]. In breast cancer, PLXNB3 is a direct HIF-1 transcriptional target induced under hypoxia, and it is required for hypoxia-driven MET/SRC/FAK signaling (promoting migration and invasion) and MET/SRC/STAT3/NANOG signaling (promoting cancer stem cell specification), as well as for tumor formation and lung metastasis in vivo [PMID:36857181, PMID:37768037]. PLXNB3 is enriched as a cell-surface glycoprotein in triple-negative breast cancer, where its depletion impairs growth, invasion, and migration [PMID:35981243]. In pancreatic adenocarcinoma, tumor-associated macrophage-derived SEMA5A engages tumor-cell PLXNB3 to enhance aerobic glycolysis and tumor outgrowth [PMID:36741230]. A pathogenic missense variant (p.E1440V) links PLXNB3 to congenital heart disease with neurodevelopmental disability through effects on cell migration and proliferation [PMID:36506778]. Beyond these receptor and signaling roles, the biochemical mechanism by which PLXNB3 couples to MET remains uncharacterized in the available corpus.","teleology":[{"year":2009,"claim":"Establishing what ligand PLXNB3 recognizes, this work showed it acts as a receptor for Sema5A by identifying an extracellular missense mutation that blocks ligand binding.","evidence":"Functional ligand-receptor binding assay in cellular models using a cancer-associated R538H mutation","pmids":["19462467"],"confidence":"Medium","gaps":["Single lab, single binding method reported in abstract","Downstream signaling consequences of Sema5A binding not addressed here","Sema4D as an alternative ligand not tested"]},{"year":2015,"claim":"An early attempt to place PLXNB3 in a signaling axis proposed a KIAA1199/PLXNB3/SEMA5A/CTGF pathway promoting proliferation and angiogenesis in synoviocytes.","evidence":"KIAA1199 knockdown/overexpression with MTT proliferation and tube-formation assays, western blot, qPCR","pmids":["26022278"],"confidence":"Low","gaps":["Pathway placement is proposed from expression/knockdown correlation, not direct mechanism","PLXNB3-specific molecular detail is limited","Direct PLXNB3-CTGF link not demonstrated"]},{"year":2022,"claim":"To define PLXNB3's role in aggressive breast cancer, glycoproteomics and genetic depletion established it as a cell-surface glycoprotein enriched in TNBC and functionally required for tumor cell growth and invasion.","evidence":"N-glycoproteomics, siRNA and CRISPR-Cas9 depletion, in vitro invasion/migration assays and in vivo models","pmids":["35981243"],"confidence":"High","gaps":["Receptor ligand and downstream effectors not resolved in this study","Single lab","Mechanism of growth/invasion control not detailed"]},{"year":2022,"claim":"Extending PLXNB3 beyond cancer, a pathogenic p.E1440V variant was linked to congenital heart disease with neurodevelopmental disability through impaired migration and proliferation.","evidence":"Scratch wound and Ki-67 assays in AC16/HEK293T cells, RT-qPCR of pathway genes, whole-exome sequencing, computational structural modeling","pmids":["36506778"],"confidence":"Medium","gaps":["Structural impact is computationally modeled, not experimentally resolved","Causality in disease rests on exome association plus cell assays","Notch/myocardial pathway effects are correlative readouts"]},{"year":2023,"claim":"Defining the upstream regulation and downstream signaling of PLXNB3, this work showed it is a direct HIF-1 target required for hypoxia-driven MET/SRC/FAK and MET/SRC/STAT3/NANOG cascades and for metastasis and cancer stem cell specification.","evidence":"siRNA knockdown, HIF-1 reporter target validation, pathway signaling assays, orthotopic breast cancer mouse models","pmids":["36857181","37768037"],"confidence":"High","gaps":["Biochemical mechanism coupling PLXNB3 to MET activation not defined","Role of Sema5A/Sema4D ligand in this hypoxic context not established","Direct physical PLXNB3-MET interaction not shown"]},{"year":2023,"claim":"Identifying a tumor-microenvironment ligand source, this work showed macrophage-derived SEMA5A engages tumor PLXNB3 to drive pancreatic cancer outgrowth via enhanced aerobic glycolysis.","evidence":"Intrasplenic injection and KPC mouse models plus in vitro glycolysis assays of the SEMA5A-PLXNB3 axis","pmids":["36741230"],"confidence":"Medium","gaps":["Signaling intermediates linking PLXNB3 to glycolytic reprogramming not mapped","Single lab","Direct SEMA5A-PLXNB3 binding not re-demonstrated in this context"]},{"year":null,"claim":"The proximal biochemical mechanism by which PLXNB3 transduces semaphorin binding into MET activation and metabolic reprogramming remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the PLXNB3-MET interface","No identified GAP/effector activity for PLXNB3 intracellular domain in the corpus","Mechanism linking receptor activation to glycolysis unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,3,4]}],"complexes":[],"partners":["SEMA5A","MET"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9ULL4","full_name":"Plexin-B3","aliases":[],"length_aa":1909,"mass_kda":206.8,"function":"Receptor for SEMA5A that plays a role in axon guidance, invasive growth and cell migration. Stimulates neurite outgrowth and mediates Ca(2+)/Mg(2+)-dependent cell aggregation. In glioma cells, SEMA5A stimulation of PLXNB3 results in the disassembly of F-actin stress fibers, disruption of focal adhesions and cellular collapse as well as inhibition of cell migration and invasion through ARHGDIA-mediated inactivation of RAC1","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9ULL4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLXNB3","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PLXNB3","total_profiled":1310},"omim":[{"mim_id":"609297","title":"SEMAPHORIN 5A; SEMA5A","url":"https://www.omim.org/entry/609297"},{"mim_id":"301148","title":"RETINITIS PIGMENTOSA 99; RP99","url":"https://www.omim.org/entry/301148"},{"mim_id":"300371","title":"ATP-BINDING CASSETTE, SUBFAMILY D, MEMBER 1; ABCD1","url":"https://www.omim.org/entry/300371"},{"mim_id":"300214","title":"PLEXIN B3; PLXNB3","url":"https://www.omim.org/entry/300214"},{"mim_id":"300089","title":"ISOCITRATE DEHYDROGENASE, NAD(+), 3, NONCATALYTIC SUBUNIT GAMMA; IDH3G","url":"https://www.omim.org/entry/300089"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":85.1},{"tissue":"intestine","ntpm":56.5}],"url":"https://www.proteinatlas.org/search/PLXNB3"},"hgnc":{"alias_symbol":["PLEXR","PLEXB3"],"prev_symbol":["PLXN6"]},"alphafold":{"accession":"Q9ULL4","domains":[{"cath_id":"2.130.10.10","chopping":"44-223","consensus_level":"medium","plddt":85.8966,"start":44,"end":223},{"cath_id":"3.30.1680.10","chopping":"475-518","consensus_level":"medium","plddt":89.3314,"start":475,"end":518},{"cath_id":"2.60.40.10","chopping":"684-787","consensus_level":"medium","plddt":82.604,"start":684,"end":787},{"cath_id":"-","chopping":"794-831","consensus_level":"medium","plddt":83.7382,"start":794,"end":831},{"cath_id":"2.60.40.10","chopping":"837-925","consensus_level":"high","plddt":88.4096,"start":837,"end":925},{"cath_id":"2.60.40.10","chopping":"929-1013","consensus_level":"medium","plddt":87.6891,"start":929,"end":1013},{"cath_id":"2.60.40,2.60.40","chopping":"1017-1055_1083-1146","consensus_level":"medium","plddt":85.3024,"start":1017,"end":1146},{"cath_id":"2.60.40.10","chopping":"1150-1238","consensus_level":"medium","plddt":83.969,"start":1150,"end":1238}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULL4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULL4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULL4-F1-predicted_aligned_error_v6.png","plddt_mean":81.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLXNB3","jax_strain_url":"https://www.jax.org/strain/search?query=PLXNB3"},"sequence":{"accession":"Q9ULL4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULL4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULL4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULL4"}},"corpus_meta":[{"pmid":"15147296","id":"PMC_15147296","title":"Plexin-B 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Study.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32640719","citation_count":35,"is_preprint":false},{"pmid":"17033634","id":"PMC_17033634","title":"Plexin B3 is genetically associated with verbal performance and white matter volume in human brain.","date":"2006","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/17033634","citation_count":32,"is_preprint":false},{"pmid":"26022278","id":"PMC_26022278","title":"KIAA1199 as a potential diagnostic biomarker of rheumatoid arthritis related to angiogenesis.","date":"2015","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/26022278","citation_count":31,"is_preprint":false},{"pmid":"32675277","id":"PMC_32675277","title":"A Rare TP53 Mutation Predominant in Ashkenazi Jews Confers Risk of Multiple Cancers.","date":"2020","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/32675277","citation_count":26,"is_preprint":false},{"pmid":"22994209","id":"PMC_22994209","title":"Contiguous ABCD1 DXS1357E deletion syndrome: report of an autopsy case.","date":"2012","source":"Neuropathology : official journal of the Japanese Society of Neuropathology","url":"https://pubmed.ncbi.nlm.nih.gov/22994209","citation_count":23,"is_preprint":false},{"pmid":"37768037","id":"PMC_37768037","title":"Mechanisms of Breast Cancer Stem Cell Specification and Self-Renewal Mediated by Hypoxia-Inducible Factor 1.","date":"2023","source":"Stem cells translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37768037","citation_count":19,"is_preprint":false},{"pmid":"36964401","id":"PMC_36964401","title":"Plasma levels of neurology-related proteins are associated with cognitive performance in an older population with overweight/obesity and metabolic syndrome.","date":"2023","source":"GeroScience","url":"https://pubmed.ncbi.nlm.nih.gov/36964401","citation_count":15,"is_preprint":false},{"pmid":"39243324","id":"PMC_39243324","title":"Identification of Immune-Related Biomarkers of Schizophrenia in the Central Nervous System Using Bioinformatic Methods and Machine Learning Algorithms.","date":"2024","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/39243324","citation_count":14,"is_preprint":false},{"pmid":"36857181","id":"PMC_36857181","title":"Plexin-B3 expression stimulates MET signaling, breast cancer stem cell specification, and lung metastasis.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36857181","citation_count":13,"is_preprint":false},{"pmid":"36622372","id":"PMC_36622372","title":"Cardiorespiratory fitness and targeted proteomics involved in brain and cardiovascular health in children with overweight/obesity.","date":"2023","source":"European journal of sport 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PLXNB3 protein is required for hypoxia-induced MET/SRC/focal adhesion kinase (FAK) signaling and MET/SRC/STAT3/NANOG signaling cascades, and for hypoxia-induced breast cancer cell migration, invasion, cancer stem cell specification, tumor formation, and lung metastasis in orthotopic mouse models.\",\n      \"method\": \"siRNA knockdown, orthotopic breast cancer mouse models, reporter assays for HIF-1 target gene validation, pathway analysis of MET/SRC/FAK and MET/SRC/STAT3/NANOG signaling\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (siRNA KD, in vivo mouse models, pathway signaling assays), consistent with review paper (PMID:37768037) describing the same mechanism\",\n      \"pmids\": [\"36857181\", \"37768037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The missense mutation R538H in the extracellular domain of PLXNB3 prevents binding of its ligand Sema5A, establishing that PLXNB3 functions as a receptor for Sema5A.\",\n      \"method\": \"Functional binding assay in cellular models using cancer-associated somatic mutations; ligand-receptor binding assay\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct functional assay in cellular model, single lab, single method reported in abstract\",\n      \"pmids\": [\"19462467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"M2-type tumor-associated macrophage (TAM)-derived SEMA5A binds to tumor cell-expressed PLXNB3 to promote pancreatic adenocarcinoma (PDAC) tumor cell proliferation and outgrowth via enhancement of aerobic glycolysis (Warburg effect).\",\n      \"method\": \"In vivo intrasplenic injection mouse models, KPC mouse models, in vitro mechanistic studies of SEMA5A-PLXNB3 axis and glycolysis\",\n      \"journal\": \"Journal of immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse models plus mechanistic glycolysis assays, single lab\",\n      \"pmids\": [\"36741230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PLXNB3 is a cell surface glycoprotein enriched in triple-negative breast cancer (TNBC) cells, and its knockdown by siRNA or CRISPR-Cas9 editing impairs TNBC cell line growth, invasion, and migration in vitro and in vivo.\",\n      \"method\": \"N-glycoproteomics, siRNA knockdown, CRISPR-Cas9 editing, in vitro invasion/migration assays, in vivo models\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (glycoproteomics, siRNA, CRISPR-Cas9, in vivo), single lab\",\n      \"pmids\": [\"35981243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A pathogenic PLXNB3 mutation (p.E1440V) inhibits cell migration and proliferation in AC16 and HEK293T cells and affects activity of key factors in the Notch signaling pathway, myocardial contraction pathway, and neurodevelopmental pathways, linking PLXNB3 to congenital heart disease with neurodevelopmental disabilities.\",\n      \"method\": \"Scratch wound assay, Ki-67 flow cytometry, RT-qPCR of pathway genes, whole-exome sequencing, AlphaFold/PyRosetta structural modeling\",\n      \"journal\": \"Translational pediatrics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional cell-based assays with multiple readouts, single lab, structural modeling is computational\",\n      \"pmids\": [\"36506778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A KIAA1199/PLXNB3/SEMA5A/CTGF axis was proposed to enhance cell proliferation and angiogenesis in fibroblast-like synoviocytes; PLXNB3 knockdown and overexpression experiments were used to dissect contributions of this pathway.\",\n      \"method\": \"KIAA1199 knockdown and overexpression, MTT proliferation assay, tube formation assay, western blotting, qPCR\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement is proposed based on expression and knockdown data, PLXNB3-specific mechanistic detail is limited in the abstract\",\n      \"pmids\": [\"26022278\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLXNB3 is a transmembrane semaphorin receptor (for Sema4D/Sema5A) that is transcriptionally induced by HIF-1 under hypoxia; upon activation it stimulates MET receptor tyrosine kinase, leading to downstream SRC/FAK signaling (promoting cancer cell migration and invasion) and SRC/STAT3/NANOG signaling (promoting cancer stem cell specification and self-renewal), while in pancreatic cancer the SEMA5A–PLXNB3 axis drives tumor outgrowth by enhancing aerobic glycolysis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLXNB3 is a transmembrane semaphorin receptor that drives tumor cell migration, invasion, and growth across multiple cancer types [#0, #3]. It functions as a cell-surface receptor for Sema5A, as defined by the R538H extracellular-domain mutation that abolishes ligand binding [#1]. In breast cancer, PLXNB3 is a direct HIF-1 transcriptional target induced under hypoxia, and it is required for hypoxia-driven MET/SRC/FAK signaling (promoting migration and invasion) and MET/SRC/STAT3/NANOG signaling (promoting cancer stem cell specification), as well as for tumor formation and lung metastasis in vivo [#0]. PLXNB3 is enriched as a cell-surface glycoprotein in triple-negative breast cancer, where its depletion impairs growth, invasion, and migration [#3]. In pancreatic adenocarcinoma, tumor-associated macrophage-derived SEMA5A engages tumor-cell PLXNB3 to enhance aerobic glycolysis and tumor outgrowth [#2]. A pathogenic missense variant (p.E1440V) links PLXNB3 to congenital heart disease with neurodevelopmental disability through effects on cell migration and proliferation [#4]. Beyond these receptor and signaling roles, the biochemical mechanism by which PLXNB3 couples to MET remains uncharacterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing what ligand PLXNB3 recognizes, this work showed it acts as a receptor for Sema5A by identifying an extracellular missense mutation that blocks ligand binding.\",\n      \"evidence\": \"Functional ligand-receptor binding assay in cellular models using a cancer-associated R538H mutation\",\n      \"pmids\": [\"19462467\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single lab, single binding method reported in abstract\", \"Downstream signaling consequences of Sema5A binding not addressed here\", \"Sema4D as an alternative ligand not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"An early attempt to place PLXNB3 in a signaling axis proposed a KIAA1199/PLXNB3/SEMA5A/CTGF pathway promoting proliferation and angiogenesis in synoviocytes.\",\n      \"evidence\": \"KIAA1199 knockdown/overexpression with MTT proliferation and tube-formation assays, western blot, qPCR\",\n      \"pmids\": [\"26022278\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Pathway placement is proposed from expression/knockdown correlation, not direct mechanism\", \"PLXNB3-specific molecular detail is limited\", \"Direct PLXNB3-CTGF link not demonstrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"To define PLXNB3's role in aggressive breast cancer, glycoproteomics and genetic depletion established it as a cell-surface glycoprotein enriched in TNBC and functionally required for tumor cell growth and invasion.\",\n      \"evidence\": \"N-glycoproteomics, siRNA and CRISPR-Cas9 depletion, in vitro invasion/migration assays and in vivo models\",\n      \"pmids\": [\"35981243\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Receptor ligand and downstream effectors not resolved in this study\", \"Single lab\", \"Mechanism of growth/invasion control not detailed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extending PLXNB3 beyond cancer, a pathogenic p.E1440V variant was linked to congenital heart disease with neurodevelopmental disability through impaired migration and proliferation.\",\n      \"evidence\": \"Scratch wound and Ki-67 assays in AC16/HEK293T cells, RT-qPCR of pathway genes, whole-exome sequencing, computational structural modeling\",\n      \"pmids\": [\"36506778\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural impact is computationally modeled, not experimentally resolved\", \"Causality in disease rests on exome association plus cell assays\", \"Notch/myocardial pathway effects are correlative readouts\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defining the upstream regulation and downstream signaling of PLXNB3, this work showed it is a direct HIF-1 target required for hypoxia-driven MET/SRC/FAK and MET/SRC/STAT3/NANOG cascades and for metastasis and cancer stem cell specification.\",\n      \"evidence\": \"siRNA knockdown, HIF-1 reporter target validation, pathway signaling assays, orthotopic breast cancer mouse models\",\n      \"pmids\": [\"36857181\", \"37768037\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Biochemical mechanism coupling PLXNB3 to MET activation not defined\", \"Role of Sema5A/Sema4D ligand in this hypoxic context not established\", \"Direct physical PLXNB3-MET interaction not shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying a tumor-microenvironment ligand source, this work showed macrophage-derived SEMA5A engages tumor PLXNB3 to drive pancreatic cancer outgrowth via enhanced aerobic glycolysis.\",\n      \"evidence\": \"Intrasplenic injection and KPC mouse models plus in vitro glycolysis assays of the SEMA5A-PLXNB3 axis\",\n      \"pmids\": [\"36741230\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Signaling intermediates linking PLXNB3 to glycolytic reprogramming not mapped\", \"Single lab\", \"Direct SEMA5A-PLXNB3 binding not re-demonstrated in this context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The proximal biochemical mechanism by which PLXNB3 transduces semaphorin binding into MET activation and metabolic reprogramming remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of the PLXNB3-MET interface\", \"No identified GAP/effector activity for PLXNB3 intracellular domain in the corpus\", \"Mechanism linking receptor activation to glycolysis unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SEMA5A\", \"MET\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}