{"gene":"EFNB3","run_date":"2026-06-14T07:33:11","timeline":{"discoveries":[],"current_model":"Parse failed"},"narrative":{"mechanistic_narrative":"No mechanistic discoveries found in literature.","teleology":[],"mechanism_profile":null},"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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International Conference on Complex Networks and Their Applications","url":"https://pubmed.ncbi.nlm.nih.gov/42181748","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":28843,"output_tokens":1528,"usd":0.054725,"stage1_stop_reason":"refusal"},"stage2":{"model":"","input_tokens":0,"output_tokens":0,"usd":0.0},"total_usd":0.054725,"stage1_batch_id":"msgbatch_015cW3C55o5xm8EPaM1UvcZR","stage2_batch_id":"msgbatch_018NDJHPntdYJzBohpB6hHKo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"Ephrin-B3 (EFNB3) is an essential component of the Reelin signaling pathway for neuronal migration: Reelin binds to the extracellular domain of ephrin Bs, which associate at the membrane with VLDLR and ApoER2 in neurons. Clustering of ephrin Bs recruits and phosphorylates Dab1, which is necessary for Reelin signaling. Loss of ephrin B function severely impairs Reelin-induced Dab1 phosphorylation, and activation of ephrin Bs can rescue reeler neuronal migration defects in the absence of Reelin protein.\",\n      \"method\": \"Genetic epistasis (compound Reln+/-;Efnb3-/- and triple Efnb1/2/3 knockout mice), co-immunoprecipitation/binding assays showing Reelin-ephrin B extracellular domain interaction, VLDLR/ApoER2 membrane association, Dab1 phosphorylation assays, and rescue experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assay, genetic epistasis, phosphorylation readout, and functional rescue in multiple orthogonal experiments\",\n      \"pmids\": [\"21460838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Ephrin-B3 knockout in female (but not male) mice leads to increased blood pressure. Vascular smooth muscle cells (VSMCs) from female Efnb3-/- mice show augmented contractility compared to wild-type. EFNB3 deletion reduces myosin light chain kinase phosphorylation in VSMCs, enhancing sensitivity to Ca2+ flux. Estrogen augments VSMC contractility via a nongenomic GPER pathway while testosterone reduces it in the absence of EFNB3; ovariectomy renders female KO mice normotensive.\",\n      \"method\": \"Efnb3 gene knockout mouse model, in vitro VSMC contractility assays, GPER knockdown assays, ovariectomy experiments, myosin light chain kinase phosphorylation western blot\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined cellular phenotype, multiple orthogonal methods (contractility assay, signaling analysis, in vivo BP, ovariectomy rescue), single lab\",\n      \"pmids\": [\"26851246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GRIP1, which is in the EFNB3 reverse signaling pathway, regulates VSMC contractility: siRNA knockdown of GRIP1 in mouse VSMCs increases their contractility. Efnb3 knockout mice show enhanced constriction in carotid arteries by echocardiography.\",\n      \"method\": \"siRNA knockdown of GRIP1 in mouse VSMCs with contractility assay, echocardiography of Efnb3 KO mice\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, siRNA KD with cellular phenotype, echocardiography, but limited mechanistic depth on GRIP1-EFNB3 connection\",\n      \"pmids\": [\"27941904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EFNB3 and its receptors (EphBs) are expressed on peripheral T cells and monocytes/macrophages. Solid-phase EFNB3-Fc costimulation with suboptimal anti-CD3 enhances T-cell proliferation, activation marker expression, IFN-γ production, and cytotoxic T-cell activity. After crosslinking, TCR and EFNB3 receptors co-localize in aggregated lipid rafts. EFNB3 costimulation augments p38 and p44/42 MAPK activation downstream.\",\n      \"method\": \"Solid-phase EFNB3-Fc costimulation assays, T-cell proliferation, cytokine ELISA, flow cytometry, lipid raft fractionation/microscopy, MAPK western blot, cyclosporin A insensitivity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal assays (proliferation, cytokine, raft co-localization, MAPK activation), 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 reveal that the complexes are maintained by an extensive protein-protein interface, including a crucial phenylalanine side chain on EFNB2 that fits into a hydrophobic pocket on the viral protein. EFNB3 is identified as a cell-surface receptor for both Nipah and Hendra viruses by analogy.\",\n      \"method\": \"X-ray crystallography of NiV/HeV attachment glycoprotein–EFNB2 complexes\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with defined interface residues, replicated for two related viruses\",\n      \"pmids\": [\"18488039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Structure-informed mutagenesis identified two NiV RBP regions and two point mutations (N","stage2_raw":"","audit_flag":{"gene":"EFNB3","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"recall_miss","uniprot_band":"medium","rules_fired":"R5","issue":"R5: no narrative despite experimental UniProt FUNCTION (820 chars) and on-target evidence in corpus (7 on-target corpus titles)"},"evaluation":null}