{"gene":"EFNA1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2002,"finding":"EFNA1 (ephrinA1) is a GPI-anchored ligand that preferentially binds to the receptor tyrosine kinase EphA2; activation of EphA2 by EFNA1 in HT29 colon carcinoma cells leads to tyrosine hyperphosphorylation of EphA2, E-cadherin, and beta-catenin, and reduced EFNA1 expression slows three-dimensional spheroid growth but not monolayer growth, implicating autocrine EFNA1-EphA2 signaling in overcoming contact inhibition.","method":"Antisense transfection to reduce EFNA1 expression, EFNA1-Fc stimulation, western blot for phosphorylation of EphA2/E-cadherin/beta-catenin, 3D spheroid vs monolayer growth assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD with defined phenotypic readout and biochemical phosphorylation assay in single lab with two orthogonal methods","pmids":["11741747"],"is_preprint":false},{"year":2005,"finding":"Stimulation of EPHA2-expressing gastric cancer cell lines with soluble ephrinA1-Fc (EFNA1) leads to decreased EphA2 protein expression, increased EphA2 phosphorylation, and inhibition of cell growth upon repetitive stimulation, demonstrating that EFNA1 engagement of EphA2 triggers receptor downregulation and growth suppression.","method":"Stimulation with soluble ephrinA1-Fc, western blotting, northern blotting, RT-PCR, cell growth assay","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ligand stimulation with multiple orthogonal readouts (protein level, phosphorylation, growth) in single lab","pmids":["15649254"],"is_preprint":false},{"year":2006,"finding":"Efna1 (ephrinA1) is expressed in overlapping and complementary domains with its receptor Epha1 and paralog Efna3 in the primitive streak and posterior paraxial mesoderm during early mouse development, consistent with bidirectional Eph-ephrin signaling regulating cell migratory and adhesive behavior in this context.","method":"Whole-mount in situ hybridization in early mouse embryos","journal":"Gene expression patterns : GEP","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization by in situ hybridization without functional consequence directly demonstrated for EFNA1 specifically","pmids":["16466970"],"is_preprint":false},{"year":2018,"finding":"The lncRNA GMAN promotes translation of EFNA1 mRNA into protein by competitively binding GMAN-AS (an antisense RNA complementary to EFNA1 mRNA), thereby preventing GMAN-AS from suppressing EFNA1 translation; elevated EFNA1 protein in turn promotes gastric cancer cell invasion and metastasis, as demonstrated by rescue of GMAN-knockdown invasive phenotype by ectopic EFNA1 expression.","method":"RNA pulldown and mapping assays, polysome profiling, siRNA/shRNA knockdown, CRISPR/Cas9 knockout, overexpression, Transwell invasion assay, mouse xenograft metastasis model, immunoblot","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNA pulldown, polysome profiling, genetic rescue, in vivo) in single rigorous study establishing the GMAN-GMAN-AS-EFNA1 translational regulatory mechanism","pmids":["30445010"],"is_preprint":false},{"year":2012,"finding":"A SNP (rs12904, G>A) in the 3'UTR of EFNA1 alters the binding site for hsa-miR-200c; luciferase assays confirmed EFNA1 as a direct target of miR-200c and showed that the G allele reduces miR-200c-mediated suppression of EFNA1 expression, while the A allele permits stronger miR-200c-mediated repression.","method":"Luciferase reporter assay, case-control genotyping, qRT-PCR on patient tumor tissues","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter with allele-specific constructs plus patient tissue expression data in single lab","pmids":["23065816"],"is_preprint":false},{"year":2025,"finding":"EFNA1 cis-interacts with its receptor EphA2 on the same cell surface in cervical cancer cells, leading to decreased EphA2 tyrosine phosphorylation and subsequent activation of the Src/AKT/STAT3 forward signaling pathway; inhibition of this pathway with specific inhibitors attenuated tumorigenic capacity, and EFNA1 expression is driven by a tumor-specific super-enhancer containing FOSL2 binding sites whose knockdown suppresses both H3K27ac enrichment and luciferase activity at the SE region.","method":"Integrated epigenomic/transcriptomic profiling, FOSL2 knockdown with luciferase and ChIP assays, EFNA1 knockdown, specific pathway inhibitors, in vitro and in vivo tumor models","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional methods (ChIP, luciferase, KD, inhibitors, in vivo) in single study; cis-interaction mechanism is novel but single lab","pmids":["39964764"],"is_preprint":false},{"year":2025,"finding":"Flagellin-induced TLR5 signaling causes ADAM9 metalloproteinase-dependent cleavage/shedding of EFNA1 from airway epithelial cells, disrupting EPHA2-EFNA1 trans-binding and activating ligand-independent EPHA2 signaling; EPHA2 ablation reduced inflammatory responses to flagellin and Pseudomonas aeruginosa, and forced EFNA1 shedding alone (without PAMPs) was sufficient to stimulate inflammatory responses, establishing EFNA1 shedding as a pathogen-sensing mechanism.","method":"EFNA1 cleavage assay, ADAM9 inhibition/knockdown, EPHA2 knockout, in vitro and in vivo (mouse) flagellin/P. aeruginosa challenge, inflammatory cytokine readout","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic KO, metalloproteinase inhibition, forced shedding, in vivo model) in single study with mechanistic pathway dissection","pmids":["39991543"],"is_preprint":false},{"year":2025,"finding":"In HNSCC cells, EFNA1 knockdown reduces activity of the AKT/ERK1/2 signaling pathway, and EFNA1 overexpression increases cell proliferation that is reversible by EFNA1 antibody treatment, establishing that EFNA1 promotes survival signaling through AKT/ERK1/2.","method":"EFNA1 knockdown and overexpression, western blotting for EphA2pS898/EphA2/EFNA1/AKT/ERK1/2, cell proliferation and apoptosis assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD/OE with defined pathway readout but single lab, single publication, abstract-level detail","pmids":["40578286"],"is_preprint":false},{"year":2025,"finding":"In diabetic retinopathy, IL-15 secreted by monocytes/macrophages activates STAT5 in endothelial cells, which binds the EFNA1 promoter in an NCOA2-dependent manner to induce EFNA1 expression and promote angiogenesis; EFNA1 and NCOA2 form a positive feedback loop where knockdown of either gene reduces expression of the other.","method":"STAT5 inhibition, NCOA2 knockdown, EFNA1 knockdown, ChIP-implied STAT5 promoter binding assay, co-culture with THP-1 under high-glucose conditions, angiogenesis assays","journal":"Molecular vision","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic perturbation of multiple pathway components with defined angiogenesis phenotype and transcription factor binding evidence, single lab","pmids":["41867368"],"is_preprint":false},{"year":2026,"finding":"Diclofenac reduces EFNA1 expression in breast cancer cells by impairing EPAS1 (HIF-2α) binding to the EFNA1 promoter region (-1353 to -782); EFNA1 overexpression rescues the anti-tumor effects of diclofenac, establishing EFNA1 as the critical mediator of diclofenac's COX-independent anti-cancer activity.","method":"RNA-seq, luciferase reporter assay for EFNA1 promoter, EFNA1 overexpression rescue, qRT-PCR, western blot, xenograft model","journal":"Current medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase promoter assay plus genetic rescue plus in vivo validation in single lab, multiple orthogonal methods","pmids":["41941163"],"is_preprint":false},{"year":2025,"finding":"In esophageal squamous cell carcinoma, EFNA1 knockdown suppresses cMYC expression and its downstream cell cycle genes and activates autophagy; similar effects are seen with knockdown of its receptor EPHA2, placing EFNA1 upstream of the EPHA2-cMYC-cell cycle/autophagy axis.","method":"EFNA1 and EPHA2 knockdown, CCK-8 and colony formation assays, wound healing, flow cytometry (cell cycle), transmission electron microscopy (autophagolysosome), western blot","journal":"Discover oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — parallel KD of ligand and receptor with multiple orthogonal phenotypic readouts establishing epistatic relationship, single lab","pmids":["37160815"],"is_preprint":false},{"year":1996,"finding":"EFNA1 (LERK-1/EPLG1) encodes a GPI-anchored membrane protein belonging to the LERK family of Eph receptor ligands and is located on human chromosome 1q21-q22; its GPI anchor distinguishes it from transmembrane LERKs and is consistent with bidirectional signaling via Eph receptors.","method":"Southern hybridization of somatic cell hybrid DNAs, fluorescence in situ hybridization, interspecific backcross mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromosomal mapping with Southern/FISH and structural classification by GPI-anchor, replicated in two species","pmids":["8660976"],"is_preprint":false}],"current_model":"EFNA1 (ephrinA1) is a GPI-anchored ligand that binds Eph receptor tyrosine kinases (primarily EphA2, also EphA1 and EphA4) to initiate bidirectional signaling; in cis it can reduce EphA2 tyrosine phosphorylation and activate Src/AKT/STAT3 forward signaling, while trans engagement of EphA2 triggers receptor phosphorylation followed by downregulation; EFNA1 expression is transcriptionally driven by FOSL2 and EPAS1 via super-enhancers/promoter binding and post-transcriptionally regulated by miR-200c and by the lncRNA GMAN (which sequesters the inhibitory antisense GMAN-AS to promote EFNA1 translation); EFNA1 shedding by ADAM9 metalloproteinase upon TLR5/flagellin stimulation disrupts EPHA2-EFNA1 trans-binding and activates ligand-independent inflammatory EPHA2 signaling; downstream, EFNA1 promotes cell proliferation and invasion through AKT/ERK1/2 and cMYC-cell cycle pathways while suppressing autophagy, and in endothelial cells IL-15/STAT5/NCOA2 drives an EFNA1 positive-feedback loop that promotes angiogenesis."},"narrative":{"mechanistic_narrative":"EFNA1 (ephrinA1) is a GPI-anchored ligand for Eph receptor tyrosine kinases, primarily EphA2, and functions as a context-dependent regulator of cell proliferation, invasion, angiogenesis, and inflammatory signaling [PMID:11741747, PMID:8660976]. In trans, engagement of EphA2 by soluble or surface EFNA1 drives receptor tyrosine hyperphosphorylation followed by EphA2 downregulation, and concurrently phosphorylates E-cadherin and beta-catenin, an autocrine circuit that overcomes contact inhibition in carcinoma cells [PMID:11741747, PMID:15649254]. In cis on the same cell surface, EFNA1 instead lowers EphA2 tyrosine phosphorylation and activates Src/AKT/STAT3 forward signaling to promote tumorigenesis [PMID:39964764], and across multiple tumor types EFNA1 sustains pro-survival and proliferative signaling through AKT/ERK1/2 and through an EphA2–cMYC–cell cycle axis whose disruption activates autophagy [PMID:40578286, PMID:37160815]. EFNA1 expression is multiply controlled: transcriptionally by FOSL2-bound super-enhancers [PMID:39964764], by EPAS1/HIF-2α promoter binding [PMID:41941163], and by STAT5/NCOA2 in an angiogenic positive-feedback loop in endothelial cells [PMID:41867368]; and post-transcriptionally by miR-200c acting on a 3'UTR SNP site [PMID:23065816] and by the lncRNA GMAN, which sequesters the inhibitory antisense GMAN-AS to license EFNA1 translation and drive invasion and metastasis [PMID:30445010]. Beyond ligand–receptor engagement, EFNA1 is shed from epithelial cells by ADAM9 upon TLR5/flagellin stimulation, disrupting EPHA2–EFNA1 trans-binding and triggering ligand-independent inflammatory EPHA2 signaling, defining a pathogen-sensing role [PMID:39991543].","teleology":[{"year":1996,"claim":"Established the molecular identity of EFNA1 as a GPI-anchored Eph receptor ligand, defining the structural class that enables bidirectional Eph signaling.","evidence":"Chromosomal mapping by Southern/FISH and structural classification in human and mouse","pmids":["8660976"],"confidence":"Medium","gaps":["No functional signaling consequence tested","Receptor binding partners not yet defined in this study"]},{"year":2002,"claim":"Showed that autocrine EFNA1-EphA2 signaling drives EphA2/E-cadherin/beta-catenin phosphorylation and supports 3D growth, linking the ligand to overcoming contact inhibition.","evidence":"Antisense knockdown, EFNA1-Fc stimulation, phospho-western, and 3D spheroid vs monolayer assays in HT29 colon carcinoma cells","pmids":["11741747"],"confidence":"Medium","gaps":["Mechanism connecting EphA2 to beta-catenin phosphorylation not resolved","Single cell line"]},{"year":2005,"claim":"Demonstrated that trans EFNA1 engagement triggers EphA2 phosphorylation followed by receptor downregulation and growth suppression, establishing a ligand-induced negative-feedback outcome.","evidence":"Soluble ephrinA1-Fc stimulation with protein/phosphorylation/growth readouts in gastric cancer lines","pmids":["15649254"],"confidence":"Medium","gaps":["Growth-suppressive trans effect contrasts with proliferative roles elsewhere; context determinants unresolved","No in vivo confirmation"]},{"year":2006,"claim":"Mapped Efna1 expression alongside Epha1 and Efna3 in early mouse mesoderm, suggesting a developmental migratory/adhesive role.","evidence":"Whole-mount in situ hybridization in early mouse embryos","pmids":["16466970"],"confidence":"Low","gaps":["Localization only; no functional consequence demonstrated for EFNA1","No loss-of-function phenotype"]},{"year":2012,"claim":"Identified EFNA1 as a direct miR-200c target whose suppression is modulated by a 3'UTR SNP, adding allele-dependent post-transcriptional control.","evidence":"Allele-specific luciferase reporter assays, genotyping, and tumor qRT-PCR","pmids":["23065816"],"confidence":"Medium","gaps":["Functional downstream consequence of altered EFNA1 not tested","Effect on EphA2 signaling not measured"]},{"year":2018,"claim":"Defined a lncRNA-based translational control mechanism where GMAN sequesters GMAN-AS to permit EFNA1 translation, with EFNA1 mediating invasion and metastasis.","evidence":"RNA pulldown/mapping, polysome profiling, CRISPR/RNAi, genetic rescue, and xenograft metastasis in gastric cancer","pmids":["30445010"],"confidence":"High","gaps":["Receptor signaling pathway downstream of EFNA1 in this context not dissected","How GMAN-AS blocks translation mechanistically not fully resolved"]},{"year":2025,"claim":"Revealed a cis EFNA1-EphA2 interaction that lowers EphA2 phosphorylation and activates Src/AKT/STAT3, plus super-enhancer/FOSL2 transcriptional control, distinguishing cis from trans signaling outcomes.","evidence":"Epigenomic profiling, FOSL2 knockdown with ChIP/luciferase, EFNA1 knockdown, pathway inhibitors, in vivo cervical cancer models","pmids":["39964764"],"confidence":"Medium","gaps":["Molecular basis of cis vs trans switch unresolved","Single lab"]},{"year":2025,"claim":"Established ADAM9-mediated EFNA1 shedding downstream of TLR5/flagellin as a pathogen-sensing trigger of ligand-independent inflammatory EPHA2 signaling.","evidence":"EFNA1 cleavage assay, ADAM9 and EPHA2 perturbation, forced shedding, and in vivo flagellin/P. aeruginosa challenge","pmids":["39991543"],"confidence":"High","gaps":["How loss of trans-binding mechanistically activates EPHA2 not fully defined","Cleavage site not mapped"]},{"year":2025,"claim":"Showed EFNA1 promotes pro-survival AKT/ERK1/2 signaling and proliferation in HNSCC reversible by EFNA1 antibody, and placed EFNA1 upstream of an EPHA2-cMYC-cell cycle/autophagy axis in ESCC.","evidence":"EFNA1/EPHA2 knockdown and overexpression, proliferation/colony/cell-cycle assays, autophagy imaging, and western blot","pmids":["40578286","37160815"],"confidence":"Medium","gaps":["Direct link from EFNA1 to cMYC regulation not mechanistically traced","Single lab per tumor type"]},{"year":2025,"claim":"Identified an IL-15/STAT5/NCOA2-driven EFNA1 positive-feedback loop promoting endothelial angiogenesis in diabetic retinopathy.","evidence":"STAT5 inhibition, NCOA2/EFNA1 knockdown, promoter binding assay, high-glucose co-culture, and angiogenesis assays","pmids":["41867368"],"confidence":"Medium","gaps":["Mechanism of EFNA1 feedback onto NCOA2 not defined","Eph receptor involvement in angiogenic effect not tested"]},{"year":2026,"claim":"Defined EFNA1 as the critical EPAS1/HIF-2α-driven mediator of diclofenac's COX-independent anti-tumor activity in breast cancer.","evidence":"RNA-seq, EFNA1 promoter luciferase assay, overexpression rescue, and xenograft validation","pmids":["41941163"],"confidence":"Medium","gaps":["Downstream signaling through which EFNA1 mediates the effect not specified","Single lab"]},{"year":null,"claim":"The determinants that switch EFNA1 between growth-suppressive trans signaling and proliferative cis/forward signaling, and the signaling output of EFNA1 in non-tumor developmental and vascular contexts, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of cis vs trans signaling control","No structural model of cis EFNA1-EphA2 engagement","Developmental loss-of-function phenotype uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,6,11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,5,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6]}],"complexes":[],"partners":["EPHA2","ADAM9","EPHA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P20827","full_name":"Ephrin-A1","aliases":["EPH-related receptor tyrosine kinase ligand 1","LERK-1","Immediate early response protein B61","Tumor necrosis factor alpha-induced protein 4","TNF alpha-induced protein 4"],"length_aa":205,"mass_kda":23.8,"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 (PubMed:17332925, PubMed:18794797). Involved in angiogenesis, regulating vascular endothelial cell differentiation and migration through activation of EPHA2. Acts as a ligand for EPHA3, inhibiting epithelial-to-mesenchymal transition of cardiac cells and playing a role in heart development (PubMed:12794130). May also contribute to dendritic spine morphogenesis (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P20827/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EFNA1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EFNA1","total_profiled":1310},"omim":[{"mim_id":"605991","title":"NEURONAL GUANINE NUCLEOTIDE EXCHANGE FACTOR; NGEF","url":"https://www.omim.org/entry/605991"},{"mim_id":"602188","title":"EPHRIN RECEPTOR EphA4; EPHA4","url":"https://www.omim.org/entry/602188"},{"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":"601380","title":"EPHRIN A4; EFNA4","url":"https://www.omim.org/entry/601380"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":476.5}],"url":"https://www.proteinatlas.org/search/EFNA1"},"hgnc":{"alias_symbol":["LERK1","ECKLG","GMAN"],"prev_symbol":["TNFAIP4","EPLG1"]},"alphafold":{"accession":"P20827","domains":[{"cath_id":"2.60.40.420","chopping":"18-151","consensus_level":"medium","plddt":93.5216,"start":18,"end":151}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P20827","model_url":"https://alphafold.ebi.ac.uk/files/AF-P20827-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P20827-F1-predicted_aligned_error_v6.png","plddt_mean":79.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EFNA1","jax_strain_url":"https://www.jax.org/strain/search?query=EFNA1"},"sequence":{"accession":"P20827","fasta_url":"https://rest.uniprot.org/uniprotkb/P20827.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P20827/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P20827"}},"corpus_meta":[{"pmid":"30445010","id":"PMC_30445010","title":"Long Noncoding RNA GMAN, Up-regulated in Gastric Cancer Tissues, Is Associated With Metastasis in Patients and Promotes Translation of Ephrin A1 by Competitively Binding GMAN-AS.","date":"2018","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/30445010","citation_count":217,"is_preprint":false},{"pmid":"15649254","id":"PMC_15649254","title":"EPHA2/EFNA1 expression in human gastric cancer.","date":"2005","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/15649254","citation_count":126,"is_preprint":false},{"pmid":"19642143","id":"PMC_19642143","title":"EFNA1 ligand and its receptor EphA2: potential biomarkers for hepatocellular carcinoma.","date":"2010","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19642143","citation_count":73,"is_preprint":false},{"pmid":"11741747","id":"PMC_11741747","title":"Reduced expression of EphrinA1 (EFNA1) inhibits three-dimensional growth of HT29 colon carcinoma 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pain","date":"2025-03-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.24.645122","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.05.636641","title":"microRNA-Mediated Effects of Caloric Restriction on Trophoblast Invasion and Angiogenic Signaling in a Mouse Model of Fetal Growth Restriction","date":"2025-02-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.05.636641","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17427,"output_tokens":3519,"usd":0.052533,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11079,"output_tokens":3673,"usd":0.07361,"stage2_stop_reason":"end_turn"},"total_usd":0.126143,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"EFNA1 (ephrinA1) is a GPI-anchored ligand that preferentially binds to the receptor tyrosine kinase EphA2; activation of EphA2 by EFNA1 in HT29 colon carcinoma cells leads to tyrosine hyperphosphorylation of EphA2, E-cadherin, and beta-catenin, and reduced EFNA1 expression slows three-dimensional spheroid growth but not monolayer growth, implicating autocrine EFNA1-EphA2 signaling in overcoming contact inhibition.\",\n      \"method\": \"Antisense transfection to reduce EFNA1 expression, EFNA1-Fc stimulation, western blot for phosphorylation of EphA2/E-cadherin/beta-catenin, 3D spheroid vs monolayer growth assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD with defined phenotypic readout and biochemical phosphorylation assay in single lab with two orthogonal methods\",\n      \"pmids\": [\"11741747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Stimulation of EPHA2-expressing gastric cancer cell lines with soluble ephrinA1-Fc (EFNA1) leads to decreased EphA2 protein expression, increased EphA2 phosphorylation, and inhibition of cell growth upon repetitive stimulation, demonstrating that EFNA1 engagement of EphA2 triggers receptor downregulation and growth suppression.\",\n      \"method\": \"Stimulation with soluble ephrinA1-Fc, western blotting, northern blotting, RT-PCR, cell growth assay\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ligand stimulation with multiple orthogonal readouts (protein level, phosphorylation, growth) in single lab\",\n      \"pmids\": [\"15649254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Efna1 (ephrinA1) is expressed in overlapping and complementary domains with its receptor Epha1 and paralog Efna3 in the primitive streak and posterior paraxial mesoderm during early mouse development, consistent with bidirectional Eph-ephrin signaling regulating cell migratory and adhesive behavior in this context.\",\n      \"method\": \"Whole-mount in situ hybridization in early mouse embryos\",\n      \"journal\": \"Gene expression patterns : GEP\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization by in situ hybridization without functional consequence directly demonstrated for EFNA1 specifically\",\n      \"pmids\": [\"16466970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The lncRNA GMAN promotes translation of EFNA1 mRNA into protein by competitively binding GMAN-AS (an antisense RNA complementary to EFNA1 mRNA), thereby preventing GMAN-AS from suppressing EFNA1 translation; elevated EFNA1 protein in turn promotes gastric cancer cell invasion and metastasis, as demonstrated by rescue of GMAN-knockdown invasive phenotype by ectopic EFNA1 expression.\",\n      \"method\": \"RNA pulldown and mapping assays, polysome profiling, siRNA/shRNA knockdown, CRISPR/Cas9 knockout, overexpression, Transwell invasion assay, mouse xenograft metastasis model, immunoblot\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNA pulldown, polysome profiling, genetic rescue, in vivo) in single rigorous study establishing the GMAN-GMAN-AS-EFNA1 translational regulatory mechanism\",\n      \"pmids\": [\"30445010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A SNP (rs12904, G>A) in the 3'UTR of EFNA1 alters the binding site for hsa-miR-200c; luciferase assays confirmed EFNA1 as a direct target of miR-200c and showed that the G allele reduces miR-200c-mediated suppression of EFNA1 expression, while the A allele permits stronger miR-200c-mediated repression.\",\n      \"method\": \"Luciferase reporter assay, case-control genotyping, qRT-PCR on patient tumor tissues\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter with allele-specific constructs plus patient tissue expression data in single lab\",\n      \"pmids\": [\"23065816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EFNA1 cis-interacts with its receptor EphA2 on the same cell surface in cervical cancer cells, leading to decreased EphA2 tyrosine phosphorylation and subsequent activation of the Src/AKT/STAT3 forward signaling pathway; inhibition of this pathway with specific inhibitors attenuated tumorigenic capacity, and EFNA1 expression is driven by a tumor-specific super-enhancer containing FOSL2 binding sites whose knockdown suppresses both H3K27ac enrichment and luciferase activity at the SE region.\",\n      \"method\": \"Integrated epigenomic/transcriptomic profiling, FOSL2 knockdown with luciferase and ChIP assays, EFNA1 knockdown, specific pathway inhibitors, in vitro and in vivo tumor models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional methods (ChIP, luciferase, KD, inhibitors, in vivo) in single study; cis-interaction mechanism is novel but single lab\",\n      \"pmids\": [\"39964764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Flagellin-induced TLR5 signaling causes ADAM9 metalloproteinase-dependent cleavage/shedding of EFNA1 from airway epithelial cells, disrupting EPHA2-EFNA1 trans-binding and activating ligand-independent EPHA2 signaling; EPHA2 ablation reduced inflammatory responses to flagellin and Pseudomonas aeruginosa, and forced EFNA1 shedding alone (without PAMPs) was sufficient to stimulate inflammatory responses, establishing EFNA1 shedding as a pathogen-sensing mechanism.\",\n      \"method\": \"EFNA1 cleavage assay, ADAM9 inhibition/knockdown, EPHA2 knockout, in vitro and in vivo (mouse) flagellin/P. aeruginosa challenge, inflammatory cytokine readout\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic KO, metalloproteinase inhibition, forced shedding, in vivo model) in single study with mechanistic pathway dissection\",\n      \"pmids\": [\"39991543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In HNSCC cells, EFNA1 knockdown reduces activity of the AKT/ERK1/2 signaling pathway, and EFNA1 overexpression increases cell proliferation that is reversible by EFNA1 antibody treatment, establishing that EFNA1 promotes survival signaling through AKT/ERK1/2.\",\n      \"method\": \"EFNA1 knockdown and overexpression, western blotting for EphA2pS898/EphA2/EFNA1/AKT/ERK1/2, cell proliferation and apoptosis assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD/OE with defined pathway readout but single lab, single publication, abstract-level detail\",\n      \"pmids\": [\"40578286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In diabetic retinopathy, IL-15 secreted by monocytes/macrophages activates STAT5 in endothelial cells, which binds the EFNA1 promoter in an NCOA2-dependent manner to induce EFNA1 expression and promote angiogenesis; EFNA1 and NCOA2 form a positive feedback loop where knockdown of either gene reduces expression of the other.\",\n      \"method\": \"STAT5 inhibition, NCOA2 knockdown, EFNA1 knockdown, ChIP-implied STAT5 promoter binding assay, co-culture with THP-1 under high-glucose conditions, angiogenesis assays\",\n      \"journal\": \"Molecular vision\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic perturbation of multiple pathway components with defined angiogenesis phenotype and transcription factor binding evidence, single lab\",\n      \"pmids\": [\"41867368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Diclofenac reduces EFNA1 expression in breast cancer cells by impairing EPAS1 (HIF-2α) binding to the EFNA1 promoter region (-1353 to -782); EFNA1 overexpression rescues the anti-tumor effects of diclofenac, establishing EFNA1 as the critical mediator of diclofenac's COX-independent anti-cancer activity.\",\n      \"method\": \"RNA-seq, luciferase reporter assay for EFNA1 promoter, EFNA1 overexpression rescue, qRT-PCR, western blot, xenograft model\",\n      \"journal\": \"Current medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase promoter assay plus genetic rescue plus in vivo validation in single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41941163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In esophageal squamous cell carcinoma, EFNA1 knockdown suppresses cMYC expression and its downstream cell cycle genes and activates autophagy; similar effects are seen with knockdown of its receptor EPHA2, placing EFNA1 upstream of the EPHA2-cMYC-cell cycle/autophagy axis.\",\n      \"method\": \"EFNA1 and EPHA2 knockdown, CCK-8 and colony formation assays, wound healing, flow cytometry (cell cycle), transmission electron microscopy (autophagolysosome), western blot\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — parallel KD of ligand and receptor with multiple orthogonal phenotypic readouts establishing epistatic relationship, single lab\",\n      \"pmids\": [\"37160815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"EFNA1 (LERK-1/EPLG1) encodes a GPI-anchored membrane protein belonging to the LERK family of Eph receptor ligands and is located on human chromosome 1q21-q22; its GPI anchor distinguishes it from transmembrane LERKs and is consistent with bidirectional signaling via Eph receptors.\",\n      \"method\": \"Southern hybridization of somatic cell hybrid DNAs, fluorescence in situ hybridization, interspecific backcross mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromosomal mapping with Southern/FISH and structural classification by GPI-anchor, replicated in two species\",\n      \"pmids\": [\"8660976\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EFNA1 (ephrinA1) is a GPI-anchored ligand that binds Eph receptor tyrosine kinases (primarily EphA2, also EphA1 and EphA4) to initiate bidirectional signaling; in cis it can reduce EphA2 tyrosine phosphorylation and activate Src/AKT/STAT3 forward signaling, while trans engagement of EphA2 triggers receptor phosphorylation followed by downregulation; EFNA1 expression is transcriptionally driven by FOSL2 and EPAS1 via super-enhancers/promoter binding and post-transcriptionally regulated by miR-200c and by the lncRNA GMAN (which sequesters the inhibitory antisense GMAN-AS to promote EFNA1 translation); EFNA1 shedding by ADAM9 metalloproteinase upon TLR5/flagellin stimulation disrupts EPHA2-EFNA1 trans-binding and activates ligand-independent inflammatory EPHA2 signaling; downstream, EFNA1 promotes cell proliferation and invasion through AKT/ERK1/2 and cMYC-cell cycle pathways while suppressing autophagy, and in endothelial cells IL-15/STAT5/NCOA2 drives an EFNA1 positive-feedback loop that promotes angiogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EFNA1 (ephrinA1) is a GPI-anchored ligand for Eph receptor tyrosine kinases, primarily EphA2, and functions as a context-dependent regulator of cell proliferation, invasion, angiogenesis, and inflammatory signaling [#0, #11]. In trans, engagement of EphA2 by soluble or surface EFNA1 drives receptor tyrosine hyperphosphorylation followed by EphA2 downregulation, and concurrently phosphorylates E-cadherin and beta-catenin, an autocrine circuit that overcomes contact inhibition in carcinoma cells [#0, #1]. In cis on the same cell surface, EFNA1 instead lowers EphA2 tyrosine phosphorylation and activates Src/AKT/STAT3 forward signaling to promote tumorigenesis [#5], and across multiple tumor types EFNA1 sustains pro-survival and proliferative signaling through AKT/ERK1/2 and through an EphA2–cMYC–cell cycle axis whose disruption activates autophagy [#7, #10]. EFNA1 expression is multiply controlled: transcriptionally by FOSL2-bound super-enhancers [#5], by EPAS1/HIF-2α promoter binding [#9], and by STAT5/NCOA2 in an angiogenic positive-feedback loop in endothelial cells [#8]; and post-transcriptionally by miR-200c acting on a 3'UTR SNP site [#4] and by the lncRNA GMAN, which sequesters the inhibitory antisense GMAN-AS to license EFNA1 translation and drive invasion and metastasis [#3]. Beyond ligand–receptor engagement, EFNA1 is shed from epithelial cells by ADAM9 upon TLR5/flagellin stimulation, disrupting EPHA2–EFNA1 trans-binding and triggering ligand-independent inflammatory EPHA2 signaling, defining a pathogen-sensing role [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the molecular identity of EFNA1 as a GPI-anchored Eph receptor ligand, defining the structural class that enables bidirectional Eph signaling.\",\n      \"evidence\": \"Chromosomal mapping by Southern/FISH and structural classification in human and mouse\",\n      \"pmids\": [\"8660976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional signaling consequence tested\", \"Receptor binding partners not yet defined in this study\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed that autocrine EFNA1-EphA2 signaling drives EphA2/E-cadherin/beta-catenin phosphorylation and supports 3D growth, linking the ligand to overcoming contact inhibition.\",\n      \"evidence\": \"Antisense knockdown, EFNA1-Fc stimulation, phospho-western, and 3D spheroid vs monolayer assays in HT29 colon carcinoma cells\",\n      \"pmids\": [\"11741747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting EphA2 to beta-catenin phosphorylation not resolved\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated that trans EFNA1 engagement triggers EphA2 phosphorylation followed by receptor downregulation and growth suppression, establishing a ligand-induced negative-feedback outcome.\",\n      \"evidence\": \"Soluble ephrinA1-Fc stimulation with protein/phosphorylation/growth readouts in gastric cancer lines\",\n      \"pmids\": [\"15649254\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Growth-suppressive trans effect contrasts with proliferative roles elsewhere; context determinants unresolved\", \"No in vivo confirmation\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Mapped Efna1 expression alongside Epha1 and Efna3 in early mouse mesoderm, suggesting a developmental migratory/adhesive role.\",\n      \"evidence\": \"Whole-mount in situ hybridization in early mouse embryos\",\n      \"pmids\": [\"16466970\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Localization only; no functional consequence demonstrated for EFNA1\", \"No loss-of-function phenotype\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified EFNA1 as a direct miR-200c target whose suppression is modulated by a 3'UTR SNP, adding allele-dependent post-transcriptional control.\",\n      \"evidence\": \"Allele-specific luciferase reporter assays, genotyping, and tumor qRT-PCR\",\n      \"pmids\": [\"23065816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional downstream consequence of altered EFNA1 not tested\", \"Effect on EphA2 signaling not measured\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a lncRNA-based translational control mechanism where GMAN sequesters GMAN-AS to permit EFNA1 translation, with EFNA1 mediating invasion and metastasis.\",\n      \"evidence\": \"RNA pulldown/mapping, polysome profiling, CRISPR/RNAi, genetic rescue, and xenograft metastasis in gastric cancer\",\n      \"pmids\": [\"30445010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor signaling pathway downstream of EFNA1 in this context not dissected\", \"How GMAN-AS blocks translation mechanistically not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a cis EFNA1-EphA2 interaction that lowers EphA2 phosphorylation and activates Src/AKT/STAT3, plus super-enhancer/FOSL2 transcriptional control, distinguishing cis from trans signaling outcomes.\",\n      \"evidence\": \"Epigenomic profiling, FOSL2 knockdown with ChIP/luciferase, EFNA1 knockdown, pathway inhibitors, in vivo cervical cancer models\",\n      \"pmids\": [\"39964764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of cis vs trans switch unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established ADAM9-mediated EFNA1 shedding downstream of TLR5/flagellin as a pathogen-sensing trigger of ligand-independent inflammatory EPHA2 signaling.\",\n      \"evidence\": \"EFNA1 cleavage assay, ADAM9 and EPHA2 perturbation, forced shedding, and in vivo flagellin/P. aeruginosa challenge\",\n      \"pmids\": [\"39991543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How loss of trans-binding mechanistically activates EPHA2 not fully defined\", \"Cleavage site not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed EFNA1 promotes pro-survival AKT/ERK1/2 signaling and proliferation in HNSCC reversible by EFNA1 antibody, and placed EFNA1 upstream of an EPHA2-cMYC-cell cycle/autophagy axis in ESCC.\",\n      \"evidence\": \"EFNA1/EPHA2 knockdown and overexpression, proliferation/colony/cell-cycle assays, autophagy imaging, and western blot\",\n      \"pmids\": [\"40578286\", \"37160815\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link from EFNA1 to cMYC regulation not mechanistically traced\", \"Single lab per tumor type\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified an IL-15/STAT5/NCOA2-driven EFNA1 positive-feedback loop promoting endothelial angiogenesis in diabetic retinopathy.\",\n      \"evidence\": \"STAT5 inhibition, NCOA2/EFNA1 knockdown, promoter binding assay, high-glucose co-culture, and angiogenesis assays\",\n      \"pmids\": [\"41867368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of EFNA1 feedback onto NCOA2 not defined\", \"Eph receptor involvement in angiogenic effect not tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined EFNA1 as the critical EPAS1/HIF-2α-driven mediator of diclofenac's COX-independent anti-tumor activity in breast cancer.\",\n      \"evidence\": \"RNA-seq, EFNA1 promoter luciferase assay, overexpression rescue, and xenograft validation\",\n      \"pmids\": [\"41941163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling through which EFNA1 mediates the effect not specified\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The determinants that switch EFNA1 between growth-suppressive trans signaling and proliferative cis/forward signaling, and the signaling output of EFNA1 in non-tumor developmental and vascular contexts, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of cis vs trans signaling control\", \"No structural model of cis EFNA1-EphA2 engagement\", \"Developmental loss-of-function phenotype uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 6, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 5, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EPHA2\", \"ADAM9\", \"EPHA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}