{"gene":"EFNA5","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1997,"finding":"LERK-7 (EFNA5) encodes a 228-amino acid GPI-anchored membrane protein that binds soluble forms of Eph-family receptors hek and elk when transfected into CV1/EBNA cells, and a soluble form of LERK-7 induces phosphorylation of the eck receptor expressed in a human duodenum adenocarcinoma cell line. LERK-7 is developmentally regulated in the brain, with highest expression in adult brain, heart, spleen, and ovary and fetal brain, lung, and kidney.","method":"Receptor-binding assay (soluble receptor-Fc fusion proteins binding to transfected cells), phosphorylation assay (soluble LERK-7 stimulating eck phosphorylation in cell line), Northern blot for tissue distribution","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and phosphorylation assays in cells, single lab, two orthogonal methods (binding + phosphorylation)","pmids":["9245480"],"is_preprint":false},{"year":1996,"finding":"The gene encoding LERK-7 (EPLG7/EFNA5) maps to human chromosome 5q21 and mouse chromosome 17, established by PCR-based somatic cell hybrid screening and fluorescence in situ hybridization.","method":"PCR-based somatic cell hybrid panel screening; fluorescence in situ hybridization (FISH); Southern blot of interspecific backcross mice","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal mapping methods (somatic cell hybrids, FISH, backcross Southern blot) establishing chromosomal localization","pmids":["8661153"],"is_preprint":false},{"year":2018,"finding":"EFNA5 (and its receptor EPHA2) participate in lens fiber cell pattern formation. Mice lacking EFNA5 (Efna5-null) develop lenses with misaligned elongating fiber cells at the lens equator, loss of Y-suture pattern formation, and disrupted radial column patterning of hexagonal fiber cells throughout the cortex. In situ hybridization localized Efna5 transcripts to lens epithelial cells and nascent fiber cells at the lens equator.","method":"Efna5-null mouse model; in situ hybridization; in vivo thymidine analog labeling; ex vivo imaging with membrane-targeted red fluorescent protein; immunofluorescent labeling of AQP0/MIP","journal":"Differentiation; research in biological diversity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function (null mouse) with multiple orthogonal morphological readouts and transcript localization","pmids":["29800803"],"is_preprint":false},{"year":2014,"finding":"Three single nucleotide polymorphisms in EFNA5 (c.668C>T, c.102C>T, c.-27C>G) were identified in Chinese age-related cataract patients and were absent in normal controls; c.668C>T was predicted to be possibly damaging by PolyPhen2, linking EFNA5 sequence variation to lens pathology.","method":"Sequencing of all EFNA5 exons in 140 ARC patients and 142 controls; PolyPhen2 computational analysis","journal":"Ophthalmic research","confidence":"Low","confidence_rationale":"Tier 4 / Weak — sequencing plus computational prediction only, no functional validation of variant effect","pmids":["25300504"],"is_preprint":false},{"year":2018,"finding":"A de novo balanced chromosomal translocation disrupting EFNA5 was identified in a symptomatic patient by shallow whole-genome mate-pair sequencing and Sanger sequencing; EFNA5 displayed high pLI and DOMINO scores indicating likely intolerance to haploinsufficiency, nominating it as a candidate gene for a human Mendelian disorder.","method":"Shallow whole-genome mate-pair sequencing (SGMPS); long-range PCR; Sanger sequencing; bioinformatic pLI/DOMINO scoring","journal":"Journal of medical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genomic breakpoint mapping in a single patient, no functional validation of EFNA5 loss-of-function consequence","pmids":["30352868"],"is_preprint":false},{"year":2021,"finding":"piR-017061 cooperates with PIWIL1 to directly bind EFNA5 mRNA and facilitate its degradation in pancreatic cancer cells; loss of piR-017061 results in accumulation of EFNA5 protein, which facilitates pancreatic cancer cell growth in vitro and in vivo.","method":"RNA pulldown (direct binding between piR-017061 and EFNA5 mRNA mediated by PIWIL1); in vitro cell proliferation assays; in vivo xenograft assays; qRT-PCR and Western blot for EFNA5 protein levels","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown establishing direct interaction, functional rescue/loss-of-function experiments in vitro and in vivo, single lab","pmids":["33389678"],"is_preprint":false},{"year":2020,"finding":"miR-645 directly targets the 3'-UTR of EFNA5 mRNA and represses its expression; EFNA5 knockdown attenuates the suppressive effects of miR-645 knockdown on colorectal cancer cell migration and invasion, placing EFNA5 downstream of miR-645 as a tumor-suppressive target in colorectal cancer.","method":"Luciferase reporter assay with EFNA5 3'-UTR; miR-645 overexpression/knockdown; EFNA5 siRNA knockdown; cell migration/invasion assays; in vivo tumor growth and metastasis assays; qRT-PCR correlation in patient tumors","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'-UTR targeting validated by luciferase assay, epistasis established by rescue experiment, single lab","pmids":["32036212"],"is_preprint":false},{"year":2023,"finding":"LINC00607 binds miR-1289 (validated by luciferase reporter, RNA pulldown, and RNA immunoprecipitation assays) and EFNA5 is a direct downstream target of miR-1289 (validated by luciferase reporter); EFNA5 overexpression inhibits NSCLC cell viability, proliferation, migration, and invasion, and EFNA5 knockdown antagonizes the tumor-suppressive effect of LINC00607 overexpression, placing EFNA5 as the functional effector of this lncRNA/miRNA axis.","method":"Luciferase reporter assay; RNA pulldown assay; RNA immunoprecipitation (RIP); EFNA5 overexpression and knockdown; cell viability (MTT), colony formation, wound healing, and Transwell invasion assays","journal":"Open medicine (Warsaw, Poland)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal binding assays plus genetic epistasis with functional readouts, single lab","pmids":["37333453"],"is_preprint":false},{"year":2023,"finding":"EGR1 binds the miR-182-5p promoter to inhibit miR-182-5p transcription (validated by ChIP and dual-luciferase assay), which in turn de-represses EFNA5 expression; EFNA5 overexpression promotes retinal neovascularization in a mouse ROP model and EGR1 knockdown-mediated suppression of neovascularization is reversed by miR-182-5p downregulation or EFNA5 overexpression.","method":"Chromatin immunoprecipitation (ChIP) of EGR1 at miR-182-5p promoter; dual-luciferase promoter assay; ROP mouse model; in vitro tube formation assay; RT-qPCR and Western blot; gain- and loss-of-function experiments","journal":"Biochemical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase validate EGR1→miR-182-5p→EFNA5 pathway, in vivo ROP model, single lab","pmids":["37530910"],"is_preprint":false},{"year":2024,"finding":"Upregulation of EFNA5 in hepatoma cell lines (HepG2 and LM3) inhibits cell proliferation, invasion, and migration; mechanistically, EFNA5 overexpression downregulates EMT-related molecules and EGFR protein levels, suggesting EFNA5 suppresses hepatoma progression through inhibition of epithelial-to-mesenchymal transition.","method":"EFNA5 plasmid overexpression; CCK-8 cell proliferation assay; Transwell and Boyden invasion/migration assays; Western blot for EMT markers and EGFR; IHC of patient samples","journal":"Discover oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression with phenotypic readouts but no genetic rescue or mechanistic epistasis confirming pathway; single lab, no knockdown validation","pmids":["39424684"],"is_preprint":false},{"year":2025,"finding":"EFNA5 is an oocyte-derived membrane ligand that is stably enriched in mammalian oocytes but reduced after in vitro maturation. Supplementation with recombinant EFNA5 during ovine IVM improves blastocyst formation, reduces apoptosis, promotes cumulus-oocyte complex expansion, reduces ROS accumulation, activates NRF2-dependent antioxidant signaling, and suppresses NF-κB-driven inflammation, as confirmed by RNA-seq and functional validation.","method":"Cross-species transcriptomic analysis; recombinant EFNA5 supplementation in ovine IVM; blastocyst formation and total cell count assays; ROS measurement; Western blot for NRF2 and NF-κB pathway proteins; RNA-seq; DNA damage assays","journal":"Antioxidants (Basel, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — recombinant protein supplementation with multiple orthogonal functional readouts and pathway validation by RNA-seq, single lab","pmids":["41462676"],"is_preprint":false},{"year":2025,"finding":"Mef2c downregulates EphA6 expression in layer 2/3 callosal projection neurons, thereby desensitizing their axons to EphrinA5 (EFNA5)-mediated repulsion at contralateral cortical targets; Mef2c deletion causes EphA6 upregulation and increased sensitivity to EFNA5 repulsion, resulting in mistargeting of S1-L2/3 CPN axons.","method":"Conditional Mef2c knockout mice; EphA-EphrinA functional manipulation; axon tracing; genetic epistasis (Mef2c deletion + EphA6 modulation)","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in vivo with conditional KO and functional manipulation, preprint not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"EFNA5 (ephrin-A5/LERK-7) is a GPI-anchored membrane ligand that binds and activates Eph-family receptor tyrosine kinases (including hek, elk, eck, and EphA2), is developmentally regulated in the brain and lens, participates in lens fiber cell patterning and Y-suture formation through EphA2 signaling, acts as an oocyte-derived factor that promotes oocyte developmental competence by activating NRF2 antioxidant signaling and suppressing NF-κB inflammation, mediates axonal repulsion in callosal projection neurons via EphA receptors, and functions as a tumor suppressor in colorectal cancer and hepatoma by suppressing EMT and cell invasion; its mRNA is subject to post-transcriptional regulation by miRNAs (miR-645, miR-182-5p, miR-1289) and piRNA/PIWIL1-mediated degradation."},"narrative":{"mechanistic_narrative":"EFNA5 (ephrin-A5/LERK-7) is a GPI-anchored membrane ligand for Eph-family receptor tyrosine kinases that drives contact-dependent cell patterning and repulsive signaling across neural, lens, and reproductive tissues [PMID:9245480]. It binds the Eph receptors hek and elk and, in soluble form, stimulates phosphorylation of the eck receptor, establishing its activity as a receptor-activating ligand [PMID:9245480]. In the developing lens, EFNA5 acts through EphA2 to align elongating fiber cells at the equator and organize Y-suture and radial column patterning, with loss of EFNA5 disrupting these morphologies [PMID:29800803]. In the nervous system, EFNA5 mediates axonal repulsion of layer 2/3 callosal projection neurons through EphA receptors, with target sensitivity set by receptor (EphA6) abundance. EFNA5 also functions as a tumor suppressor, inhibiting proliferation, migration, and invasion in colorectal, lung, and hepatoma cells, the last associated with downregulation of EMT markers and EGFR [PMID:32036212, PMID:37333453, PMID:39424684], and its expression is constrained post-transcriptionally by miRNAs (miR-645, miR-1289, miR-182-5p) and by PIWIL1/piRNA-mediated mRNA degradation [PMID:33389678, PMID:32036212, PMID:37333453, PMID:37530910]. As an oocyte-derived factor, recombinant EFNA5 improves oocyte developmental competence by activating NRF2 antioxidant signaling and suppressing NF-κB-driven inflammation during in vitro maturation [PMID:41462676]. The structural and biochemical details of EFNA5-Eph receptor engagement beyond ligand binding and receptor phosphorylation have not been characterized in the available corpus.","teleology":[{"year":1996,"claim":"Establishing the genomic location of EFNA5 anchored the gene for subsequent functional and disease studies.","evidence":"PCR somatic cell hybrid screening, FISH, and interspecific backcross Southern blot","pmids":["8661153"],"confidence":"High","gaps":["Mapping alone establishes no function","No protein or expression data"]},{"year":1997,"claim":"Identifying EFNA5/LERK-7 as a GPI-anchored ligand that binds Eph receptors and triggers receptor phosphorylation defined its core molecular activity as an Eph receptor agonist.","evidence":"Receptor-Fc binding to transfected cells, soluble ligand phosphorylation assay, and Northern blot tissue survey","pmids":["9245480"],"confidence":"Medium","gaps":["Which Eph receptors EFNA5 engages in each tissue not resolved","No structural model of the ligand-receptor interface","Downstream signaling not traced"]},{"year":2018,"claim":"Genetic loss-of-function in mice showed EFNA5 is required for lens fiber cell alignment and suture formation, assigning it a developmental patterning role through EphA2.","evidence":"Efna5-null mice with in situ hybridization, fiber cell imaging, and AQP0 immunofluorescence","pmids":["29800803"],"confidence":"High","gaps":["Whether EphA2 is the sole receptor partner in lens not established","Signaling effectors downstream of EFNA5-EphA2 in fiber cells unknown"]},{"year":2018,"claim":"Human sequence variants and a translocation disrupting EFNA5 nominated it as a candidate for lens pathology and a Mendelian disorder, but without functional validation.","evidence":"Exon sequencing in cataract patients with PolyPhen2 prediction; whole-genome mate-pair sequencing of a single translocation patient with pLI/DOMINO scoring","pmids":["25300504","30352868"],"confidence":"Low","gaps":["No functional validation of variant or breakpoint consequence","Single-patient breakpoint evidence","Causality for disease not demonstrated"]},{"year":2021,"claim":"Demonstrating piRNA/PIWIL1-mediated degradation of EFNA5 mRNA revealed a post-transcriptional control axis whose loss elevates EFNA5 and drives pancreatic cancer growth.","evidence":"RNA pulldown, in vitro proliferation, and xenograft assays in pancreatic cancer cells","pmids":["33389678"],"confidence":"Medium","gaps":["Mechanism linking EFNA5 protein level to proliferation not defined","Single lab","Receptor dependence of the growth effect untested"]},{"year":2023,"claim":"Identification of multiple miRNA and lncRNA regulatory axes (miR-645, miR-1289/LINC00607, EGR1→miR-182-5p) placing EFNA5 as a functional effector clarified how its expression is tuned in cancer and neovascularization.","evidence":"Luciferase reporter, RNA pulldown, RIP, ChIP, and gain/loss-of-function with migration/invasion and ROP mouse readouts","pmids":["32036212","37333453","37530910"],"confidence":"Medium","gaps":["Context-dependent direction of EFNA5 effect (suppressive in cancer, pro-angiogenic in ROP) not mechanistically reconciled","Receptor partners in each context unresolved","Single lab per axis"]},{"year":2024,"claim":"EFNA5 overexpression suppressing hepatoma EMT and EGFR levels extended its tumor-suppressor role to liver cancer.","evidence":"Plasmid overexpression with proliferation/invasion assays, EMT/EGFR Western blot, and patient IHC","pmids":["39424684"],"confidence":"Low","gaps":["No knockdown or rescue to confirm pathway","Mechanism connecting EFNA5 to EGFR downregulation unknown","Single lab"]},{"year":2025,"claim":"Showing recombinant EFNA5 improves oocyte competence via NRF2 and NF-κB modulation expanded its role to reproductive biology and redox/inflammatory signaling.","evidence":"Cross-species transcriptomics, recombinant EFNA5 supplementation in ovine IVM, ROS and apoptosis assays, RNA-seq, and NRF2/NF-κB Western blot","pmids":["41462676"],"confidence":"Medium","gaps":["Receptor mediating the oocyte effect not identified","Whether NRF2/NF-κB regulation is direct or downstream of Eph signaling unknown"]},{"year":2025,"claim":"Genetic epistasis showed Mef2c sets EphA6 levels to control axonal sensitivity to EFNA5 repulsion, defining EFNA5 as a repulsive cue in callosal axon targeting.","evidence":"Conditional Mef2c knockout mice with EphA-ephrinA manipulation and axon tracing (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Direct EFNA5-EphA6 binding not shown in this system","Signaling mechanism of repulsion not detailed"]},{"year":null,"claim":"How EFNA5-Eph receptor engagement is transduced into the divergent outcomes of repulsion, EMT suppression, and antioxidant signaling across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying downstream signaling mechanism identified","Receptor identity in cancer and oocyte contexts unknown","No structural data on the ligand-receptor complex"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6,7,9]}],"complexes":[],"partners":["EPHA2","EPHA6","PIWIL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P52803","full_name":"Ephrin-A5","aliases":["AL-1","EPH-related receptor tyrosine kinase ligand 7","LERK-7"],"length_aa":228,"mass_kda":26.3,"function":"Cell surface GPI-bound 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. Induces compartmentalized signaling within a caveolae-like membrane microdomain when bound to the extracellular domain of its cognate receptor. This signaling event requires the activity of the Fyn tyrosine kinase. Activates the EPHA3 receptor to regulate cell-cell adhesion and cytoskeletal organization. With the receptor EPHA2 may regulate lens fiber cells shape and interactions and be important for lens transparency maintenance. May function actively to stimulate axon fasciculation. The interaction of EFNA5 with EPHA5 also mediates communication between pancreatic islet cells to regulate glucose-stimulated insulin secretion. Cognate/functional ligand for EPHA7, their interaction regulates brain development modulating cell-cell adhesion and repulsion","subcellular_location":"Cell membrane; Membrane, caveola","url":"https://www.uniprot.org/uniprotkb/P52803/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EFNA5","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EFNA5","total_profiled":1310},"omim":[{"mim_id":"611123","title":"EPHRIN RECEPTOR EphA10; EPHA10","url":"https://www.omim.org/entry/611123"},{"mim_id":"602756","title":"EPHRIN A2; EFNA2","url":"https://www.omim.org/entry/602756"},{"mim_id":"601535","title":"EPHRIN A5; EFNA5","url":"https://www.omim.org/entry/601535"},{"mim_id":"601381","title":"EPHRIN A3; EFNA3","url":"https://www.omim.org/entry/601381"},{"mim_id":"600004","title":"EPHRIN RECEPTOR EphA5; EPHA5","url":"https://www.omim.org/entry/600004"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EFNA5"},"hgnc":{"alias_symbol":["AF1","LERK7"],"prev_symbol":["EPLG7"]},"alphafold":{"accession":"P52803","domains":[{"cath_id":"2.60.40.420","chopping":"28-165","consensus_level":"medium","plddt":92.4552,"start":28,"end":165}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P52803","model_url":"https://alphafold.ebi.ac.uk/files/AF-P52803-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P52803-F1-predicted_aligned_error_v6.png","plddt_mean":78.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EFNA5","jax_strain_url":"https://www.jax.org/strain/search?query=EFNA5"},"sequence":{"accession":"P52803","fasta_url":"https://rest.uniprot.org/uniprotkb/P52803.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P52803/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P52803"}},"corpus_meta":[{"pmid":"10230404","id":"PMC_10230404","title":"Ligand-independent 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Competence by Modulating Oxidative Stress, Inflammation, and Apoptosis During In Vitro Maturation.","date":"2025","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/41462676","citation_count":1,"is_preprint":false},{"pmid":"26461309","id":"PMC_26461309","title":"AF-1 a novel regulator of the redox equilibrium during aging.","date":"2014","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26461309","citation_count":1,"is_preprint":false},{"pmid":"30310730","id":"PMC_30310730","title":"The Transactivating Function 2 (AF-2) of Estrogen Receptor (ER) α is Indispensable for ERα-mediated Physiological Responses and AF-1 Activity.","date":"2013","source":"Open journal of endocrine and metabolic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/30310730","citation_count":1,"is_preprint":false},{"pmid":"19293991","id":"PMC_19293991","title":"Finding Alu in primate genomes with AF-1.","date":"2009","source":"Bioinformation","url":"https://pubmed.ncbi.nlm.nih.gov/19293991","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.23.684277","title":"Methylation mimic mutations of progesterone receptor AF1 impair gene-specific regulation through stabilized chromatin interactions","date":"2025-10-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.23.684277","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.22.634300","title":"Mef2c Controls Postnatal Callosal Axon Targeting by Regulating Sensitivity to Ephrin Repulsion","date":"2025-01-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.22.634300","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48632,"output_tokens":3975,"usd":0.102761,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11009,"output_tokens":3210,"usd":0.067647,"stage2_stop_reason":"end_turn"},"total_usd":0.170408,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers that are actually about EFNA5 (ephrin-A5, also known as LERK-7/EPLG7) — the GPI-anchored membrane ligand for Eph receptor tyrosine kinases. The vast majority of papers in this corpus are about completely different proteins that happen to share the \"AF-1\" alias (activation function-1 domains of nuclear receptors, nematode neuropeptides, bacterial strains, etc.). These are symbol/alias collisions and must be excluded.\n\nPapers genuinely about EFNA5:\n- [65] LERK-7 isolation and characterization (PMID 9245480)\n- [80] LERK-7/EPLG7 chromosomal mapping (PMID 8661153)\n- [43] Epha2 and Efna5 in lens patterning (PMID 29800803)\n- [70] EFNA5 mutations in cataract (PMID 25300504)\n- [69] Chromosomal translocations disrupting EFNA5 (PMID 30352868)\n- [40] piR-017061/PIWIL1 regulates EFNA5 mRNA degradation (PMID 33389678)\n- [41] miR-645 targets EFNA5 in colorectal cancer (PMID 32036212)\n- [77] LINC00607/miR-1289/EFNA5 axis (PMID 37333453)\n- [88] EGR1/miR-182-5p/EFNA5 in ROP (PMID 37530910)\n- [91] EFNA5 in hepatoma EMT (PMID 39424684)\n- [95] EFNA5 as oocyte-derived factor in IVM (PMID 41462676)\n- [100] Mef2c/EphA6/EfnA5 repulsion in callosal axons (preprint bio_10.1101_2025.01.22.634300)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"LERK-7 (EFNA5) encodes a 228-amino acid GPI-anchored membrane protein that binds soluble forms of Eph-family receptors hek and elk when transfected into CV1/EBNA cells, and a soluble form of LERK-7 induces phosphorylation of the eck receptor expressed in a human duodenum adenocarcinoma cell line. LERK-7 is developmentally regulated in the brain, with highest expression in adult brain, heart, spleen, and ovary and fetal brain, lung, and kidney.\",\n      \"method\": \"Receptor-binding assay (soluble receptor-Fc fusion proteins binding to transfected cells), phosphorylation assay (soluble LERK-7 stimulating eck phosphorylation in cell line), Northern blot for tissue distribution\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and phosphorylation assays in cells, single lab, two orthogonal methods (binding + phosphorylation)\",\n      \"pmids\": [\"9245480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The gene encoding LERK-7 (EPLG7/EFNA5) maps to human chromosome 5q21 and mouse chromosome 17, established by PCR-based somatic cell hybrid screening and fluorescence in situ hybridization.\",\n      \"method\": \"PCR-based somatic cell hybrid panel screening; fluorescence in situ hybridization (FISH); Southern blot of interspecific backcross mice\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal mapping methods (somatic cell hybrids, FISH, backcross Southern blot) establishing chromosomal localization\",\n      \"pmids\": [\"8661153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EFNA5 (and its receptor EPHA2) participate in lens fiber cell pattern formation. Mice lacking EFNA5 (Efna5-null) develop lenses with misaligned elongating fiber cells at the lens equator, loss of Y-suture pattern formation, and disrupted radial column patterning of hexagonal fiber cells throughout the cortex. In situ hybridization localized Efna5 transcripts to lens epithelial cells and nascent fiber cells at the lens equator.\",\n      \"method\": \"Efna5-null mouse model; in situ hybridization; in vivo thymidine analog labeling; ex vivo imaging with membrane-targeted red fluorescent protein; immunofluorescent labeling of AQP0/MIP\",\n      \"journal\": \"Differentiation; research in biological diversity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function (null mouse) with multiple orthogonal morphological readouts and transcript localization\",\n      \"pmids\": [\"29800803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Three single nucleotide polymorphisms in EFNA5 (c.668C>T, c.102C>T, c.-27C>G) were identified in Chinese age-related cataract patients and were absent in normal controls; c.668C>T was predicted to be possibly damaging by PolyPhen2, linking EFNA5 sequence variation to lens pathology.\",\n      \"method\": \"Sequencing of all EFNA5 exons in 140 ARC patients and 142 controls; PolyPhen2 computational analysis\",\n      \"journal\": \"Ophthalmic research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — sequencing plus computational prediction only, no functional validation of variant effect\",\n      \"pmids\": [\"25300504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A de novo balanced chromosomal translocation disrupting EFNA5 was identified in a symptomatic patient by shallow whole-genome mate-pair sequencing and Sanger sequencing; EFNA5 displayed high pLI and DOMINO scores indicating likely intolerance to haploinsufficiency, nominating it as a candidate gene for a human Mendelian disorder.\",\n      \"method\": \"Shallow whole-genome mate-pair sequencing (SGMPS); long-range PCR; Sanger sequencing; bioinformatic pLI/DOMINO scoring\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genomic breakpoint mapping in a single patient, no functional validation of EFNA5 loss-of-function consequence\",\n      \"pmids\": [\"30352868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"piR-017061 cooperates with PIWIL1 to directly bind EFNA5 mRNA and facilitate its degradation in pancreatic cancer cells; loss of piR-017061 results in accumulation of EFNA5 protein, which facilitates pancreatic cancer cell growth in vitro and in vivo.\",\n      \"method\": \"RNA pulldown (direct binding between piR-017061 and EFNA5 mRNA mediated by PIWIL1); in vitro cell proliferation assays; in vivo xenograft assays; qRT-PCR and Western blot for EFNA5 protein levels\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown establishing direct interaction, functional rescue/loss-of-function experiments in vitro and in vivo, single lab\",\n      \"pmids\": [\"33389678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-645 directly targets the 3'-UTR of EFNA5 mRNA and represses its expression; EFNA5 knockdown attenuates the suppressive effects of miR-645 knockdown on colorectal cancer cell migration and invasion, placing EFNA5 downstream of miR-645 as a tumor-suppressive target in colorectal cancer.\",\n      \"method\": \"Luciferase reporter assay with EFNA5 3'-UTR; miR-645 overexpression/knockdown; EFNA5 siRNA knockdown; cell migration/invasion assays; in vivo tumor growth and metastasis assays; qRT-PCR correlation in patient tumors\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'-UTR targeting validated by luciferase assay, epistasis established by rescue experiment, single lab\",\n      \"pmids\": [\"32036212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LINC00607 binds miR-1289 (validated by luciferase reporter, RNA pulldown, and RNA immunoprecipitation assays) and EFNA5 is a direct downstream target of miR-1289 (validated by luciferase reporter); EFNA5 overexpression inhibits NSCLC cell viability, proliferation, migration, and invasion, and EFNA5 knockdown antagonizes the tumor-suppressive effect of LINC00607 overexpression, placing EFNA5 as the functional effector of this lncRNA/miRNA axis.\",\n      \"method\": \"Luciferase reporter assay; RNA pulldown assay; RNA immunoprecipitation (RIP); EFNA5 overexpression and knockdown; cell viability (MTT), colony formation, wound healing, and Transwell invasion assays\",\n      \"journal\": \"Open medicine (Warsaw, Poland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal binding assays plus genetic epistasis with functional readouts, single lab\",\n      \"pmids\": [\"37333453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EGR1 binds the miR-182-5p promoter to inhibit miR-182-5p transcription (validated by ChIP and dual-luciferase assay), which in turn de-represses EFNA5 expression; EFNA5 overexpression promotes retinal neovascularization in a mouse ROP model and EGR1 knockdown-mediated suppression of neovascularization is reversed by miR-182-5p downregulation or EFNA5 overexpression.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) of EGR1 at miR-182-5p promoter; dual-luciferase promoter assay; ROP mouse model; in vitro tube formation assay; RT-qPCR and Western blot; gain- and loss-of-function experiments\",\n      \"journal\": \"Biochemical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase validate EGR1→miR-182-5p→EFNA5 pathway, in vivo ROP model, single lab\",\n      \"pmids\": [\"37530910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Upregulation of EFNA5 in hepatoma cell lines (HepG2 and LM3) inhibits cell proliferation, invasion, and migration; mechanistically, EFNA5 overexpression downregulates EMT-related molecules and EGFR protein levels, suggesting EFNA5 suppresses hepatoma progression through inhibition of epithelial-to-mesenchymal transition.\",\n      \"method\": \"EFNA5 plasmid overexpression; CCK-8 cell proliferation assay; Transwell and Boyden invasion/migration assays; Western blot for EMT markers and EGFR; IHC of patient samples\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression with phenotypic readouts but no genetic rescue or mechanistic epistasis confirming pathway; single lab, no knockdown validation\",\n      \"pmids\": [\"39424684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EFNA5 is an oocyte-derived membrane ligand that is stably enriched in mammalian oocytes but reduced after in vitro maturation. Supplementation with recombinant EFNA5 during ovine IVM improves blastocyst formation, reduces apoptosis, promotes cumulus-oocyte complex expansion, reduces ROS accumulation, activates NRF2-dependent antioxidant signaling, and suppresses NF-κB-driven inflammation, as confirmed by RNA-seq and functional validation.\",\n      \"method\": \"Cross-species transcriptomic analysis; recombinant EFNA5 supplementation in ovine IVM; blastocyst formation and total cell count assays; ROS measurement; Western blot for NRF2 and NF-κB pathway proteins; RNA-seq; DNA damage assays\",\n      \"journal\": \"Antioxidants (Basel, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant protein supplementation with multiple orthogonal functional readouts and pathway validation by RNA-seq, single lab\",\n      \"pmids\": [\"41462676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mef2c downregulates EphA6 expression in layer 2/3 callosal projection neurons, thereby desensitizing their axons to EphrinA5 (EFNA5)-mediated repulsion at contralateral cortical targets; Mef2c deletion causes EphA6 upregulation and increased sensitivity to EFNA5 repulsion, resulting in mistargeting of S1-L2/3 CPN axons.\",\n      \"method\": \"Conditional Mef2c knockout mice; EphA-EphrinA functional manipulation; axon tracing; genetic epistasis (Mef2c deletion + EphA6 modulation)\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in vivo with conditional KO and functional manipulation, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"EFNA5 (ephrin-A5/LERK-7) is a GPI-anchored membrane ligand that binds and activates Eph-family receptor tyrosine kinases (including hek, elk, eck, and EphA2), is developmentally regulated in the brain and lens, participates in lens fiber cell patterning and Y-suture formation through EphA2 signaling, acts as an oocyte-derived factor that promotes oocyte developmental competence by activating NRF2 antioxidant signaling and suppressing NF-κB inflammation, mediates axonal repulsion in callosal projection neurons via EphA receptors, and functions as a tumor suppressor in colorectal cancer and hepatoma by suppressing EMT and cell invasion; its mRNA is subject to post-transcriptional regulation by miRNAs (miR-645, miR-182-5p, miR-1289) and piRNA/PIWIL1-mediated degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EFNA5 (ephrin-A5/LERK-7) is a GPI-anchored membrane ligand for Eph-family receptor tyrosine kinases that drives contact-dependent cell patterning and repulsive signaling across neural, lens, and reproductive tissues [#0]. It binds the Eph receptors hek and elk and, in soluble form, stimulates phosphorylation of the eck receptor, establishing its activity as a receptor-activating ligand [#0]. In the developing lens, EFNA5 acts through EphA2 to align elongating fiber cells at the equator and organize Y-suture and radial column patterning, with loss of EFNA5 disrupting these morphologies [#2]. In the nervous system, EFNA5 mediates axonal repulsion of layer 2/3 callosal projection neurons through EphA receptors, with target sensitivity set by receptor (EphA6) abundance [#11]. EFNA5 also functions as a tumor suppressor, inhibiting proliferation, migration, and invasion in colorectal, lung, and hepatoma cells, the last associated with downregulation of EMT markers and EGFR [#6, #7, #9], and its expression is constrained post-transcriptionally by miRNAs (miR-645, miR-1289, miR-182-5p) and by PIWIL1/piRNA-mediated mRNA degradation [#5, #6, #7, #8]. As an oocyte-derived factor, recombinant EFNA5 improves oocyte developmental competence by activating NRF2 antioxidant signaling and suppressing NF-\\u03baB-driven inflammation during in vitro maturation [#10]. The structural and biochemical details of EFNA5-Eph receptor engagement beyond ligand binding and receptor phosphorylation have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing the genomic location of EFNA5 anchored the gene for subsequent functional and disease studies.\",\n      \"evidence\": \"PCR somatic cell hybrid screening, FISH, and interspecific backcross Southern blot\",\n      \"pmids\": [\"8661153\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mapping alone establishes no function\", \"No protein or expression data\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identifying EFNA5/LERK-7 as a GPI-anchored ligand that binds Eph receptors and triggers receptor phosphorylation defined its core molecular activity as an Eph receptor agonist.\",\n      \"evidence\": \"Receptor-Fc binding to transfected cells, soluble ligand phosphorylation assay, and Northern blot tissue survey\",\n      \"pmids\": [\"9245480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which Eph receptors EFNA5 engages in each tissue not resolved\", \"No structural model of the ligand-receptor interface\", \"Downstream signaling not traced\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Genetic loss-of-function in mice showed EFNA5 is required for lens fiber cell alignment and suture formation, assigning it a developmental patterning role through EphA2.\",\n      \"evidence\": \"Efna5-null mice with in situ hybridization, fiber cell imaging, and AQP0 immunofluorescence\",\n      \"pmids\": [\"29800803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EphA2 is the sole receptor partner in lens not established\", \"Signaling effectors downstream of EFNA5-EphA2 in fiber cells unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Human sequence variants and a translocation disrupting EFNA5 nominated it as a candidate for lens pathology and a Mendelian disorder, but without functional validation.\",\n      \"evidence\": \"Exon sequencing in cataract patients with PolyPhen2 prediction; whole-genome mate-pair sequencing of a single translocation patient with pLI/DOMINO scoring\",\n      \"pmids\": [\"25300504\", \"30352868\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional validation of variant or breakpoint consequence\", \"Single-patient breakpoint evidence\", \"Causality for disease not demonstrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating piRNA/PIWIL1-mediated degradation of EFNA5 mRNA revealed a post-transcriptional control axis whose loss elevates EFNA5 and drives pancreatic cancer growth.\",\n      \"evidence\": \"RNA pulldown, in vitro proliferation, and xenograft assays in pancreatic cancer cells\",\n      \"pmids\": [\"33389678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking EFNA5 protein level to proliferation not defined\", \"Single lab\", \"Receptor dependence of the growth effect untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of multiple miRNA and lncRNA regulatory axes (miR-645, miR-1289/LINC00607, EGR1\\u2192miR-182-5p) placing EFNA5 as a functional effector clarified how its expression is tuned in cancer and neovascularization.\",\n      \"evidence\": \"Luciferase reporter, RNA pulldown, RIP, ChIP, and gain/loss-of-function with migration/invasion and ROP mouse readouts\",\n      \"pmids\": [\"32036212\", \"37333453\", \"37530910\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependent direction of EFNA5 effect (suppressive in cancer, pro-angiogenic in ROP) not mechanistically reconciled\", \"Receptor partners in each context unresolved\", \"Single lab per axis\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"EFNA5 overexpression suppressing hepatoma EMT and EGFR levels extended its tumor-suppressor role to liver cancer.\",\n      \"evidence\": \"Plasmid overexpression with proliferation/invasion assays, EMT/EGFR Western blot, and patient IHC\",\n      \"pmids\": [\"39424684\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No knockdown or rescue to confirm pathway\", \"Mechanism connecting EFNA5 to EGFR downregulation unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showing recombinant EFNA5 improves oocyte competence via NRF2 and NF-\\u03baB modulation expanded its role to reproductive biology and redox/inflammatory signaling.\",\n      \"evidence\": \"Cross-species transcriptomics, recombinant EFNA5 supplementation in ovine IVM, ROS and apoptosis assays, RNA-seq, and NRF2/NF-\\u03baB Western blot\",\n      \"pmids\": [\"41462676\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating the oocyte effect not identified\", \"Whether NRF2/NF-\\u03baB regulation is direct or downstream of Eph signaling unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Genetic epistasis showed Mef2c sets EphA6 levels to control axonal sensitivity to EFNA5 repulsion, defining EFNA5 as a repulsive cue in callosal axon targeting.\",\n      \"evidence\": \"Conditional Mef2c knockout mice with EphA-ephrinA manipulation and axon tracing (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Direct EFNA5-EphA6 binding not shown in this system\", \"Signaling mechanism of repulsion not detailed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EFNA5-Eph receptor engagement is transduced into the divergent outcomes of repulsion, EMT suppression, and antioxidant signaling across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying downstream signaling mechanism identified\", \"Receptor identity in cancer and oocyte contexts unknown\", \"No structural data on the ligand-receptor complex\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6, 7, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EPHA2\", \"EphA6\", \"PIWIL1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}