{"gene":"EFNB3","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2011,"finding":"Ephrin-B3 (EFNB3) acts as an essential component of the Reelin signaling pathway for neuronal migration: Reelin binds directly to the extracellular domain of ephrin-Bs including EFNB3, which associate at the neuronal membrane with VLDLR and ApoER2 receptors; clustering of ephrin-Bs recruits and promotes phosphorylation of Dab1, which is required for Reelin signaling; loss of ephrin-B function severely impairs Reelin-induced Dab1 phosphorylation; activation of ephrin-Bs can rescue reeler neuronal migration defects in the absence of Reelin.","method":"Co-immunoprecipitation, genetic compound mutants (Reln+/-;Efnb3-/- mice), triple ephrin-B1/B2/B3 knockouts, rescue experiments, Dab1 phosphorylation assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (biochemical binding, genetic epistasis, KO phenotype, rescue) in a single high-impact study","pmids":["21460838"],"is_preprint":false},{"year":2016,"finding":"EFNB3 knockout in female mice leads to increased blood pressure and augmented vascular smooth muscle cell (VSMC) contractility; EFNB3 deletion in VSMCs results in reduced myosin light chain kinase phosphorylation; estrogen augments VSMC contractility via a nongenomic GPER pathway while testosterone reduces it in the absence of EFNB3; these effects are absent in wild-type VSMCs, indicating EFNB3 normally buffers sex hormone effects on VSMC contractility.","method":"Efnb3 gene knockout mice, VSMC contractility assays, GPER knockdown assays, ovariectomy experiments, myosin light chain kinase phosphorylation assays","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular and in vivo phenotype, multiple orthogonal methods including pharmacological and genetic perturbations","pmids":["26851246"],"is_preprint":false},{"year":2016,"finding":"GRIP1, a glutamate receptor interacting protein in the EFNB3 reverse signaling pathway, regulates VSMC contractility; siRNA knockdown of GRIP1 in mouse VSMCs increases contractility, and Efnb3 KO mice show enhanced carotid artery constriction by echocardiography.","method":"siRNA knockdown of GRIP1 in VSMCs, Efnb3 KO mouse echocardiography, in vitro contractility assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional KD with cellular phenotype, supported by in vivo data, single lab","pmids":["27941904"],"is_preprint":false},{"year":2003,"finding":"Mouse EFNB3 expressed on T cells acts as a costimulatory ligand: solid-phase EFNB3-Fc in the presence of suboptimal anti-CD3 crosslinking enhances T-cell proliferation, activation marker expression, IFN-γ production, and cytotoxic T-cell activity; TCR and EFNB3 receptors co-congregate into lipid rafts upon crosslinking; EFNB3R costimulation augments p38 and p44/42 MAPK activation; the effect is insensitive to cyclosporin A, resembling CD28 costimulation.","method":"Solid-phase EFNB3-Fc stimulation assays, proliferation assays, cytokine measurements, lipid raft co-localization, MAPK activation assays, cyclosporin A pharmacological treatment","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional readouts with defined signaling outcomes, single lab","pmids":["13679370"],"is_preprint":false},{"year":2008,"finding":"Crystal structures of Nipah and Hendra virus attachment glycoproteins in complex with human EFNB2 revealed that EFNB3 (as analogous receptor) mediates viral attachment via an extensive protein-protein interface involving a crucial phenylalanine side chain on EFNB2/B3 that inserts into a hydrophobic pocket on the viral attachment protein; this is mechanistically distinct from sialic acid-based paramyxovirus attachment.","method":"X-ray crystallography of viral attachment glycoprotein–EFNB2 complex","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation of binding interface; foundational structural paper","pmids":["18488039"],"is_preprint":false},{"year":2024,"finding":"Structure-guided mutagenesis of NiV receptor-binding protein identified two regions (including residues N557 and Y581) critical for EFNB3 binding; NiV interaction with Y120 of EFNB3 is important for EFNB3 receptor usage; substitution of these residues severely impairs EFNB3-mediated entry by NiV pseudotyped viral particles.","method":"Structure-guided mutagenesis, EFNB3 binding assays, pseudotyped viral particle entry assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 — structure-guided mutagenesis with functional validation of specific receptor-binding residues","pmids":["38426726"],"is_preprint":false},{"year":2016,"finding":"Contrary to earlier claims, compound mutant Efnb3-/-;Reln+/- mice and triple Efnb1;2;3-/- mice do not show defects of cortical layering or elevated Dab1 levels, indicating that while protein-protein interactions between ephrin-Bs and Reelin have been confirmed, they do not affect the radial positioning of migrating neocortical pyramidal neurons.","method":"Efnb3-/-;Reln+/- compound mutants, triple Efnb1;2;3-/- knockout mice, cortical layering analysis, Dab1 protein level measurement","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with defined phenotypic readout, challenges prior claims using same genetic tools","pmids":["27882975"],"is_preprint":false},{"year":2021,"finding":"Ephrin-B3/EphBs forward signaling in the spinal cord regulates nociception: Efnb3 knockout mice show increased thermal and mechanical thresholds and aberrant thin myelin sheaths; PLP (proteolipid protein) expression is reduced in the L4-6 spinal cord of Efnb3-/- mice; intrathecal PLP siRNA increases pain thresholds in wild-type mice; AAV9-PLP overexpression rescues pain hypersensitivity in Efnb3-/- mice; Efnb3lacz mice (forward signaling intact, reverse signaling absent) show normal pain behavior, indicating the reverse signaling is responsible.","method":"Efnb3-/- and Efnb3lacz conditional knock-in mice, behavioral pain assays, western blot, immunofluorescence, intrathecal siRNA, AAV9 gene delivery","journal":"Fundamental & clinical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods including genetic rescue, single lab","pmids":["34904278"],"is_preprint":false},{"year":2022,"finding":"Continuous activation of EFNB3 reverse signaling in benign prostate fibroblasts induces a cancer-associated fibroblast (CAF) phenotype and pro-tumorigenic secretome; this effect is mediated through Src family kinase (SFK) activation; SFK inhibition suppresses EFNB3-induced α-SMA and Tenascin-C expression in vitro.","method":"Stable EFNB3 overexpression in BHPrS1 cells, SFK inhibitor treatment, CAF marker expression assays, in vitro and in vivo tumorigenicity assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2-3 — overexpression plus pharmacological inhibition with defined cellular phenotype, single lab","pmids":["35565468"],"is_preprint":false},{"year":2023,"finding":"Ephrin B3 promotes intestinal epithelial barrier dysfunction and inflammation in colitis via two pathways: (1) inactivation of the ITGB4/AKT signaling pathway promoting epithelial barrier dysfunction; (2) activation of the Gremlin-1/NF-κB signaling pathway increasing inflammatory factor release; Efnb3-/- mice showed reduced DSS-induced colitis and reduced susceptibility to colitis-associated colorectal cancer.","method":"Efnb3-/- mice, DSS-induced colitis model, AOM/DSS colorectal cancer model, label-free quantitative proteomics, western blotting","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — KO mice with defined phenotype, proteomics plus validated signaling pathways, single lab","pmids":["38142837"],"is_preprint":false},{"year":2025,"finding":"Ephrin B3 drives tumorigenesis in cutaneous squamous cell carcinoma via regulation of CK19 (cytokeratin 19), which in turn positively regulates the NOTCH1 signaling pathway; Efnb3 deficiency also mitigates inflammatory responses through the MAPK pathway in acute skin inflammation.","method":"Efnb3-/- mice in DMBA/TPA carcinogenesis model, EFNB3 knockdown in A431 cells, label-free proteomics, Reactome pathway analysis","journal":"Medical oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 — KO model with defined phenotype, proteomics-identified mechanism, single lab","pmids":["40711642"],"is_preprint":false},{"year":2019,"finding":"LHX1 transcription factor regulates the expression of Eph/ephrin family guidance receptors including those responsive to ephrin-B3 in POA-derived cortical interneurons, thereby modulating their directional migration and layer distribution.","method":"Conditional LHX1 knockout in POA-derived interneurons, live imaging of interneuron migration, layer distribution analysis","journal":"Cerebral cortex","confidence":"Low","confidence_rationale":"Tier 3 — EFNB3 mentioned as a downstream target but not specifically validated as a direct mechanistic effector","pmids":["29912395"],"is_preprint":false},{"year":1997,"finding":"EFNB3 (originally designated EPLG8/LERK-8) was cloned and mapped to human chromosome 17p11.2-p13.1; it encodes a transmembrane protein related to ephrin-B2 and another B-class ephrin, expressed predominantly in brain and expressed at highest levels in forebrain subregions.","method":"cDNA library screening, chromosomal mapping by PCR of somatic cell hybrid panels, Northern blot tissue expression analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct molecular cloning and chromosomal mapping with expression characterization","pmids":["9126477"],"is_preprint":false},{"year":2025,"finding":"A frameshift variant (2-bp duplication, c.643_644dup) in EFNB3 causes autosomal recessive congenital mirror movement disorder in Weimaraner dogs, resembling the phenotype of Efnb3-/- knockout mice, establishing EFNB3 as necessary for normal spinal midline barrier formation during neurodevelopment.","method":"Linkage and autozygosity mapping, whole-genome sequencing of 3 affected and 1489 control dogs, pathological investigations","journal":"Movement disorders","confidence":"Medium","confidence_rationale":"Tier 2 — natural loss-of-function variant with defined phenotype corroborated by known KO mouse phenotype","pmids":["40401490"],"is_preprint":false}],"current_model":"EFNB3 (ephrin-B3) is a GPI-anchored transmembrane ligand for EphB receptor tyrosine kinases that mediates bidirectional signaling: in the nervous system it acts as a co-receptor in the Reelin pathway by binding Reelin extracellularly and associating with VLDLR/ApoER2 to promote Dab1 phosphorylation and neuronal migration, and functions as a spinal midline barrier through forward EphB signaling to regulate myelination (via PLP) and nociception; in the vasculature, EFNB3 reverse signaling through GRIP1 suppresses VSMC contractility and blood pressure in a sex hormone-dependent manner; in the immune system it costimulates T cells by co-clustering with TCR into lipid rafts and activating p38/MAPK; in cancer contexts it drives CAF conversion via Src family kinases, promotes colitis/colorectal carcinogenesis via ITGB4/AKT and Gremlin-1/NF-κB pathways, and drives skin SCC via a CK19-NOTCH1 axis; and structurally, its G-H loop phenylalanine/tyrosine residues (particularly Y120) are exploited as an entry receptor by Nipah and Hendra viruses through high-affinity protein-protein interactions."},"narrative":{"teleology":[],"mechanism_profile":null,"mechanistic_narrative":"Parse failed — see logs"},"prefetch_data":{"uniprot":{"accession":"Q15768","full_name":"Ephrin-B3","aliases":["EPH-related receptor transmembrane ligand ELK-L3","EPH-related receptor tyrosine kinase ligand 8","LERK-8"],"length_aa":340,"mass_kda":35.8,"function":"Cell surface transmembrane ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development. Binds promiscuously Eph receptors residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. May play a pivotal role in forebrain function. Binds to, and induce the collapse of, commissural axons/growth cones in vitro. May play a role in constraining the orientation of longitudinally projecting axons (By similarity) (Microbial infection) Acts as a receptor for nipah virus and hendra virus","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q15768/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EFNB3","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/EFNB3","total_profiled":1310},"omim":[{"mim_id":"613776","title":"CHROMOSOME 17p13.1 DELETION SYNDROME","url":"https://www.omim.org/entry/613776"},{"mim_id":"602757","title":"EPHRIN RECEPTOR EphB6; EPHB6","url":"https://www.omim.org/entry/602757"},{"mim_id":"602600","title":"LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 8; LRP8","url":"https://www.omim.org/entry/602600"},{"mim_id":"602297","title":"EPHRIN B3; EFNB3","url":"https://www.omim.org/entry/602297"},{"mim_id":"600514","title":"REELIN; RELN","url":"https://www.omim.org/entry/600514"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":41.5}],"url":"https://www.proteinatlas.org/search/EFNB3"},"hgnc":{"alias_symbol":["LERK-8"],"prev_symbol":["EPLG8"]},"alphafold":{"accession":"Q15768","domains":[{"cath_id":"2.60.40.420","chopping":"34-160","consensus_level":"high","plddt":91.4965,"start":34,"end":160}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15768","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15768-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15768-F1-predicted_aligned_error_v6.png","plddt_mean":67.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EFNB3","jax_strain_url":"https://www.jax.org/strain/search?query=EFNB3"},"sequence":{"accession":"Q15768","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15768.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15768/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15768"}},"corpus_meta":[{"pmid":"18488039","id":"PMC_18488039","title":"Structural 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clustering of ephrin-Bs recruits and promotes phosphorylation of Dab1, which is required for Reelin signaling; loss of ephrin-B function severely impairs Reelin-induced Dab1 phosphorylation; activation of ephrin-Bs can rescue reeler neuronal migration defects in the absence of Reelin.\",\n      \"method\": \"Co-immunoprecipitation, genetic compound mutants (Reln+/-;Efnb3-/- mice), triple ephrin-B1/B2/B3 knockouts, rescue experiments, Dab1 phosphorylation assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (biochemical binding, genetic epistasis, KO phenotype, rescue) in a single high-impact study\",\n      \"pmids\": [\"21460838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EFNB3 knockout in female mice leads to increased blood pressure and augmented vascular smooth muscle cell (VSMC) contractility; EFNB3 deletion in VSMCs results in reduced myosin light chain kinase phosphorylation; estrogen augments VSMC contractility via a nongenomic GPER pathway while testosterone reduces it in the absence of EFNB3; these effects are absent in wild-type VSMCs, indicating EFNB3 normally buffers sex hormone effects on VSMC contractility.\",\n      \"method\": \"Efnb3 gene knockout mice, VSMC contractility assays, GPER knockdown assays, ovariectomy experiments, myosin light chain kinase phosphorylation assays\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular and in vivo phenotype, multiple orthogonal methods including pharmacological and genetic perturbations\",\n      \"pmids\": [\"26851246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GRIP1, a glutamate receptor interacting protein in the EFNB3 reverse signaling pathway, regulates VSMC contractility; siRNA knockdown of GRIP1 in mouse VSMCs increases contractility, and Efnb3 KO mice show enhanced carotid artery constriction by echocardiography.\",\n      \"method\": \"siRNA knockdown of GRIP1 in VSMCs, Efnb3 KO mouse echocardiography, in vitro contractility assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional KD with cellular phenotype, supported by in vivo data, single lab\",\n      \"pmids\": [\"27941904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mouse EFNB3 expressed on T cells acts as a costimulatory ligand: solid-phase EFNB3-Fc in the presence of suboptimal anti-CD3 crosslinking enhances T-cell proliferation, activation marker expression, IFN-γ production, and cytotoxic T-cell activity; TCR and EFNB3 receptors co-congregate into lipid rafts upon crosslinking; EFNB3R costimulation augments p38 and p44/42 MAPK activation; the effect is insensitive to cyclosporin A, resembling CD28 costimulation.\",\n      \"method\": \"Solid-phase EFNB3-Fc stimulation assays, proliferation assays, cytokine measurements, lipid raft co-localization, MAPK activation assays, cyclosporin A pharmacological treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional readouts with defined signaling outcomes, single lab\",\n      \"pmids\": [\"13679370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Crystal structures of Nipah and Hendra virus attachment glycoproteins in complex with human EFNB2 revealed that EFNB3 (as analogous receptor) mediates viral attachment via an extensive protein-protein interface involving a crucial phenylalanine side chain on EFNB2/B3 that inserts into a hydrophobic pocket on the viral attachment protein; this is mechanistically distinct from sialic acid-based paramyxovirus attachment.\",\n      \"method\": \"X-ray crystallography of viral attachment glycoprotein–EFNB2 complex\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation of binding interface; foundational structural paper\",\n      \"pmids\": [\"18488039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Structure-guided mutagenesis of NiV receptor-binding protein identified two regions (including residues N557 and Y581) critical for EFNB3 binding; NiV interaction with Y120 of EFNB3 is important for EFNB3 receptor usage; substitution of these residues severely impairs EFNB3-mediated entry by NiV pseudotyped viral particles.\",\n      \"method\": \"Structure-guided mutagenesis, EFNB3 binding assays, pseudotyped viral particle entry assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure-guided mutagenesis with functional validation of specific receptor-binding residues\",\n      \"pmids\": [\"38426726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Contrary to earlier claims, compound mutant Efnb3-/-;Reln+/- mice and triple Efnb1;2;3-/- mice do not show defects of cortical layering or elevated Dab1 levels, indicating that while protein-protein interactions between ephrin-Bs and Reelin have been confirmed, they do not affect the radial positioning of migrating neocortical pyramidal neurons.\",\n      \"method\": \"Efnb3-/-;Reln+/- compound mutants, triple Efnb1;2;3-/- knockout mice, cortical layering analysis, Dab1 protein level measurement\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with defined phenotypic readout, challenges prior claims using same genetic tools\",\n      \"pmids\": [\"27882975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ephrin-B3/EphBs forward signaling in the spinal cord regulates nociception: Efnb3 knockout mice show increased thermal and mechanical thresholds and aberrant thin myelin sheaths; PLP (proteolipid protein) expression is reduced in the L4-6 spinal cord of Efnb3-/- mice; intrathecal PLP siRNA increases pain thresholds in wild-type mice; AAV9-PLP overexpression rescues pain hypersensitivity in Efnb3-/- mice; Efnb3lacz mice (forward signaling intact, reverse signaling absent) show normal pain behavior, indicating the reverse signaling is responsible.\",\n      \"method\": \"Efnb3-/- and Efnb3lacz conditional knock-in mice, behavioral pain assays, western blot, immunofluorescence, intrathecal siRNA, AAV9 gene delivery\",\n      \"journal\": \"Fundamental & clinical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including genetic rescue, single lab\",\n      \"pmids\": [\"34904278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Continuous activation of EFNB3 reverse signaling in benign prostate fibroblasts induces a cancer-associated fibroblast (CAF) phenotype and pro-tumorigenic secretome; this effect is mediated through Src family kinase (SFK) activation; SFK inhibition suppresses EFNB3-induced α-SMA and Tenascin-C expression in vitro.\",\n      \"method\": \"Stable EFNB3 overexpression in BHPrS1 cells, SFK inhibitor treatment, CAF marker expression assays, in vitro and in vivo tumorigenicity assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — overexpression plus pharmacological inhibition with defined cellular phenotype, single lab\",\n      \"pmids\": [\"35565468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ephrin B3 promotes intestinal epithelial barrier dysfunction and inflammation in colitis via two pathways: (1) inactivation of the ITGB4/AKT signaling pathway promoting epithelial barrier dysfunction; (2) activation of the Gremlin-1/NF-κB signaling pathway increasing inflammatory factor release; Efnb3-/- mice showed reduced DSS-induced colitis and reduced susceptibility to colitis-associated colorectal cancer.\",\n      \"method\": \"Efnb3-/- mice, DSS-induced colitis model, AOM/DSS colorectal cancer model, label-free quantitative proteomics, western blotting\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mice with defined phenotype, proteomics plus validated signaling pathways, single lab\",\n      \"pmids\": [\"38142837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ephrin B3 drives tumorigenesis in cutaneous squamous cell carcinoma via regulation of CK19 (cytokeratin 19), which in turn positively regulates the NOTCH1 signaling pathway; Efnb3 deficiency also mitigates inflammatory responses through the MAPK pathway in acute skin inflammation.\",\n      \"method\": \"Efnb3-/- mice in DMBA/TPA carcinogenesis model, EFNB3 knockdown in A431 cells, label-free proteomics, Reactome pathway analysis\",\n      \"journal\": \"Medical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KO model with defined phenotype, proteomics-identified mechanism, single lab\",\n      \"pmids\": [\"40711642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LHX1 transcription factor regulates the expression of Eph/ephrin family guidance receptors including those responsive to ephrin-B3 in POA-derived cortical interneurons, thereby modulating their directional migration and layer distribution.\",\n      \"method\": \"Conditional LHX1 knockout in POA-derived interneurons, live imaging of interneuron migration, layer distribution analysis\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — EFNB3 mentioned as a downstream target but not specifically validated as a direct mechanistic effector\",\n      \"pmids\": [\"29912395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"EFNB3 (originally designated EPLG8/LERK-8) was cloned and mapped to human chromosome 17p11.2-p13.1; it encodes a transmembrane protein related to ephrin-B2 and another B-class ephrin, expressed predominantly in brain and expressed at highest levels in forebrain subregions.\",\n      \"method\": \"cDNA library screening, chromosomal mapping by PCR of somatic cell hybrid panels, Northern blot tissue expression analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct molecular cloning and chromosomal mapping with expression characterization\",\n      \"pmids\": [\"9126477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A frameshift variant (2-bp duplication, c.643_644dup) in EFNB3 causes autosomal recessive congenital mirror movement disorder in Weimaraner dogs, resembling the phenotype of Efnb3-/- knockout mice, establishing EFNB3 as necessary for normal spinal midline barrier formation during neurodevelopment.\",\n      \"method\": \"Linkage and autozygosity mapping, whole-genome sequencing of 3 affected and 1489 control dogs, pathological investigations\",\n      \"journal\": \"Movement disorders\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — natural loss-of-function variant with defined phenotype corroborated by known KO mouse phenotype\",\n      \"pmids\": [\"40401490\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EFNB3 (ephrin-B3) is a GPI-anchored transmembrane ligand for EphB receptor tyrosine kinases that mediates bidirectional signaling: in the nervous system it acts as a co-receptor in the Reelin pathway by binding Reelin extracellularly and associating with VLDLR/ApoER2 to promote Dab1 phosphorylation and neuronal migration, and functions as a spinal midline barrier through forward EphB signaling to regulate myelination (via PLP) and nociception; in the vasculature, EFNB3 reverse signaling through GRIP1 suppresses VSMC contractility and blood pressure in a sex hormone-dependent manner; in the immune system it costimulates T cells by co-clustering with TCR into lipid rafts and activating p38/MAPK; in cancer contexts it drives CAF conversion via Src family kinases, promotes colitis/colorectal carcinogenesis via ITGB4/AKT and Gremlin-1/NF-κB pathways, and drives skin SCC via a CK19-NOTCH1 axis; and structurally, its G-H loop phenylalanine/tyrosine residues (particularly Y120) are exploited as an entry receptor by Nipah and Hendra viruses through high-affinity protein-protein interactions.\"\n}\n```","stage2_raw":""}