{"gene":"EPHA5","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1995,"finding":"The Cek7 (EphA5) ligand (ELF-1/ephrin-A) was cloned and shown to be functionally active, inducing autophosphorylation of the Cek7/EphA5 receptor protein tyrosine kinase.","method":"cDNA cloning, in vitro receptor autophosphorylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro autophosphorylation assay demonstrating ligand-induced receptor kinase activation, single lab but clear biochemical readout","pmids":["7876076"],"is_preprint":false},{"year":1997,"finding":"EphA5 (Bsk) and its ligands (Elf-1, LERK3/Ehk1-L, AL-1/RAGS/LERK7) are expressed in complementary gradients in hippocampal neurons and their septal targets; the ligands selectively inhibit growth of topographically inappropriate medial hippocampal neurites while sustaining appropriate lateral neurite growth, placing EphA5 as a guidance receptor specifying hippocamposeptal topographic projection.","method":"Gradient expression analysis, neurite outgrowth assay with selective ligand inhibition","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional neurite outgrowth assays combined with expression mapping, single lab","pmids":["9321686"],"is_preprint":false},{"year":1998,"finding":"Soluble EphA5-IgG (antagonist) impairs induction of LTP in hippocampal slices without affecting basal synaptic transmission; conversely, ephrin-A5-IgG (EphA5 agonist) induces a sustained potentiation of synaptic transmission that occludes subsequent LTP, demonstrating EphA5 activation is recruited during LTP.","method":"Hippocampal slice electrophysiology, LTP induction with pharmacological agonist/antagonist, immunohistochemistry","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function with defined electrophysiological readout, occlusion experiment provides strong mechanistic evidence","pmids":["9698392"],"is_preprint":false},{"year":1999,"finding":"Activation of EphA5 receptor using ephrin-A1 recombinant fusion protein results in time-dependent tyrosine phosphorylation of EphA5 in glioblastoma U-118 MG cells, but does not promote cell proliferation.","method":"Receptor activation with recombinant ephrin-A1-Fc, Western blot for phosphotyrosine, proliferation assay","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, direct biochemical demonstration of ligand-induced receptor phosphorylation with negative proliferation result","pmids":["10064801"],"is_preprint":false},{"year":2000,"finding":"EphA5 expressed on mitral cells and its ligands on olfactory neurons; blocking EphA5-ligand interactions with anti-EphA5 antibodies or recombinant EphA5 protein in explant cultures reduced neurite outgrowth, suggesting intrafascicular axon repulsion limits adhesion and promotes axon growth.","method":"Antibody blocking, recombinant protein perturbation in explant cultures, neurite outgrowth quantification","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional blocking experiment with defined cellular readout, consistent with receptor-ligand mechanism","pmids":["10660883"],"is_preprint":false},{"year":2010,"finding":"Ephrin-A5 interaction with EphA5 during early hippocampal development induces synaptogenesis: specifically, it drives expression of NMDA receptor-PSD-95 complexes and spine morphological maturation via voltage-sensitive calcium channel Ca2+ fluxes that activate PKA, CaMKII, and PI3 kinase, leading to CREB phosphorylation and a synaptogenic gene expression program. EphA5 functional knockout mice at P6 showed no NMDA receptor currents upon stimulation.","method":"Hippocampal neuron culture, EphA5 knockout mice, electrophysiology, pharmacological inhibition, Western blot for signaling intermediates","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO mice, pharmacological dissection, electrophysiology, biochemistry), two labs involved, specific pathway delineated","pmids":["20824214"],"is_preprint":false},{"year":2013,"finding":"The crystal structure of the EphA5 ligand-binding domain (LBD) was determined by X-ray crystallography and validated by NMR and MD simulations; the unbound EphA5 LBD adopts an open ephrin-binding pocket with helical conformation over the J-K loop resembling ephrin-bound states of other Eph receptors. NMR H/D exchange and MD simulations revealed rapid picosecond-nanosecond conformational dynamics over loops but no global microsecond-millisecond exchanges, contrasting with EphA4 LBD dynamics and explaining EphA5's restriction to ephrin-A binding.","method":"X-ray crystallography, NMR (H/D exchange, relaxation), molecular dynamics simulations","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — structure determination with orthogonal NMR and MD validation, mechanistic interpretation of binding specificity via dynamics","pmids":["24086308"],"is_preprint":false},{"year":2012,"finding":"EphA5 receptors in the ventromedial hypothalamus (VMH) regulate counterregulatory hormone release during hypoglycemia: VMH microinjection of ephrin-A5-Fc (EphA5 agonist) or AAV-mediated ephrin-A5 overexpression increased counterregulatory responses and transiently elevated local glutamate, while ephrin-A5 knockdown reduced responses and suppressed VMH glutamine concentrations.","method":"Hyperinsulinemic-hypoglycemic clamp, in vivo VMH microinjection, AAV-mediated knockdown/overexpression, microdialysis for glutamate/glutamine","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional gain- and loss-of-function in vivo with defined hormonal and neurochemical readouts, multiple approaches in one study","pmids":["23274893"],"is_preprint":false},{"year":2013,"finding":"Recurrent hypoglycemia reduces ephrin-A5 (but not EphA5 receptor) expression in the VMH, increases synaptic connections, and reduces astroglial synaptic coverage; targeted VMH activation of EphA5 receptors by ephrin-A5-Fc restored counterregulatory responses and increased glucagon release by 150% in rats with recurrent hypoglycemia.","method":"Hyperinsulinemic-hypoglycemic clamp with recurrent hypoglycemia protocol, VMH microinjection, immunofluorescence for synaptic markers, glucagon RIA","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo rescue experiment with defined endocrine readout, single lab","pmids":["24222347"],"is_preprint":false},{"year":2015,"finding":"EphA5 is specifically overexpressed in lung cancer and upon irradiation is transported into the nucleus where it interacts with activated ATM at sites of DNA repair; EphA5-deficient lung cancer cells display defective G1/S checkpoint, inability to resolve DNA damage, and increased radiosensitivity.","method":"siRNA knockdown, nuclear fractionation, co-immunoprecipitation of EphA5 with ATM, γ-H2AX foci, cell cycle analysis, xenograft radiotherapy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (nuclear fractionation, Co-IP with ATM, cell cycle, DNA damage markers, in vivo xenograft), mechanistic pathway defined","pmids":["25623065"],"is_preprint":false},{"year":2011,"finding":"EphA5 was identified as a direct target of miR-34a during chondrogenesis; miR-34a downregulates EphA5 expression, and upregulation of EphA5 overcomes miR-34a inhibition of chondroblast migration and precartilage condensation.","method":"PNA-based antisense oligonucleotide blockade of miR-34a, EphA5 overexpression rescue, migration and condensation assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antisense blockade and rescue experiment, two orthogonal approaches (inhibition and overexpression) in single lab","pmids":["22079638"],"is_preprint":false},{"year":2016,"finding":"EphA5 forward signaling in human hematopoietic stem and progenitor cells (HSPCs), stimulated by soluble ephrin-A5-Fc, promotes colony formation, adhesion, and migration via activation of Rac1 and its downstream target WAVE1; functional blocking peptides against EphA5 inhibit HSPC adhesion and migration.","method":"Ephrin-A5-Fc stimulation, functional blocking peptides, Rac1 inhibitor, gene/protein expression analysis, adhesion/migration assays","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional modulation (agonist and blocking peptide), Rac1 pathway identified with inhibitor, single lab","pmids":["27988259"],"is_preprint":false},{"year":2016,"finding":"KLF16 transcription factor binds directly to a KLF site near the EphA5 transcription start site (confirmed by ChIP and EMSA) and transactivates EphA5 expression; methylation of only 6 of 98 CpG dinucleotides within the EphA5 promoter blocks KLF16-mediated transactivation while enabling transactivation by KLF2 and KLF15. KLF16 overexpression inhibits RGC neurite outgrowth and enhances growth cone collapse in response to ephrin-A5.","method":"ChIP assay, EMSA, promoter luciferase assays with site-directed mutagenesis, methylation-specific promoter variants, neurite outgrowth assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP, EMSA, and reporter assays with mutagenesis, combined with functional cellular readout, multiple orthogonal methods","pmids":["27402841"],"is_preprint":false},{"year":2011,"finding":"The ephrin-A5–EphA4/EphA5 system in the substantia nigra pars reticulata (SNr) is upregulated specifically in the direct pathway during cocaine responses; immunoadhesin-mediated activation of EphA4 and EphA5 in the SNr suppressed the adaptive response to repeated cocaine; cocaine stimulated phosphorylation of Erk1/2 in ephrin-A5-expressing SNr cells in a direct pathway-dependent manner.","method":"Genome-wide expression profiling, pathway-specific neurotransmission blocking (RNB) mice, immunoadhesin EphA4/EphA5 activation in vivo, Erk1/2 phosphorylation immunohistochemistry","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo pathway-specific activation with behavioral and molecular readouts, Erk1/2 pathway placed downstream, multiple orthogonal methods","pmids":["21628570"],"is_preprint":false},{"year":2013,"finding":"EphA5 expressed on bone marrow stromal cells (BMSCs) is upregulated with repeated passaging and acts as an inhibitory factor for osteogenesis; siRNA knockdown of EphA5 in long-term passaged BMSCs increased ALP mRNA expression, and co-culture assays showed inhibitory signals require cell-cell contact.","method":"siRNA knockdown, co-culture assay, microarray, quantitative PCR, alkaline phosphatase mRNA measurement","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined osteogenic readout, co-culture contact-dependence established, single lab","pmids":["24029132"],"is_preprint":false},{"year":2016,"finding":"Forced expression of EphA5 in human BMSCs diminishes osteoblast phenotypic marker expression; dexamethasone treatment downregulates EphA5 and promotes osteoblast marker expression; EphA5 promoter is largely unmethylated in hBMSCs but histone deacetylation partially suppresses EphA5 in early-passage cultures.","method":"EphA5 overexpression, dexamethasone treatment, ALP mRNA quantification, bisulfite sequencing, histone deacetylase inhibitor treatment","journal":"Stem cells international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function and pharmacological loss-of-function with defined osteogenic readout, epigenetic mechanism partially characterized, single lab","pmids":["27057165"],"is_preprint":false},{"year":2019,"finding":"EPHA5 deficiency (CRISPR knockout) in HER2-positive breast cancer cells increases cancer stem cell-like properties (elevated NANOG, CD133+, CD44+/CD24-/low phenotype, mammosphere formation) and activates Notch1 and PTEN/AKT signaling, leading to trastuzumab resistance in xenografts.","method":"CRISPR-Cas9 knockout, mammosphere assay, flow cytometry, Western blot for Notch1/PTEN/AKT, xenograft model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR loss-of-function with multiple cellular and in vivo readouts, Notch1/PTEN/AKT pathway identified, single lab","pmids":["30620624"],"is_preprint":false},{"year":2020,"finding":"EphA5 knockdown in esophageal squamous cell carcinoma cells enhances invasion and migration via epithelial-mesenchymal transition, associated with elevated β-catenin and p-GSK-3βSer9 protein levels, indicating activation of the Wnt/β-catenin pathway.","method":"siRNA knockdown, Transwell invasion/migration assay, Western blot and immunofluorescence for EMT markers and Wnt pathway components","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined invasion phenotype and pathway biochemistry, single lab","pmids":["31956298"],"is_preprint":false},{"year":2020,"finding":"EphA5 silencing in ESCC cells increases radiosensitivity through impaired ATM-dependent pathway: EphA5 knockdown after ionizing radiation results in defective G1/S checkpoint, impaired γ-H2AX foci formation, reduced ATM activation, and downstream reduction in p-Chk2, p-p53, and p21.","method":"siRNA knockdown, clonogenic assay, flow cytometry (cell cycle/apoptosis), Western blot for ATM/Chk2/p53/p21, γ-H2AX immunofluorescence","journal":"Cancer management and research","confidence":"Low","confidence_rationale":"Tier 2 / Weak — note: this paper was subsequently retracted (PMID:40641952); findings should not be relied upon","pmids":["33061640"],"is_preprint":false},{"year":2021,"finding":"EphA5 signaling is required for neurite outgrowth; RF-EMF exposure inhibits EPHA5 expression and impairs neurite outgrowth, which is rescued by enhancing EPHA5 signaling; CREB and RhoA were identified as critical downstream factors of EPHA5 signaling mediating neurite outgrowth.","method":"RNA sequencing, EPHA5 overexpression rescue, CREB and RhoA pathway analysis, neurite length/branching quantification in neural stem cell-derived neurons and Neuro-2A cells","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue experiment identifies EPHA5 as necessary for neurite outgrowth with CREB/RhoA as downstream effectors, multiple cell models, single lab","pmids":["33912567"],"is_preprint":false},{"year":2023,"finding":"IL-17 signaling through TRAF2 as a scaffold recruits PIAS2 (SUMO E3 ligase) and ELAVL1 (RNA-binding protein) to induce EPHA5 expression in melanoma: ELAVL1 binds AU-rich elements in the 3'-UTR of EPHA5 mRNA to enhance its stability, and PIAS2 induces EPHA5 SUMOylation which suppresses its ubiquitination and degradation; EPHA5 knockdown suppresses IL-17A-induced melanoma proliferation and invasion.","method":"Co-immunoprecipitation, RNA immunoprecipitation, siRNA knockdown of pathway components, proliferation/invasion assays","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and RNA-IP establish protein-RNA interactions, SUMOylation/ubiquitination mechanism proposed with knockdown functional readout, single lab","pmids":["37481078"],"is_preprint":false},{"year":2025,"finding":"EPHA5 phosphorylates EPHB2 and Dectin-1 after fungal infection, facilitating recruitment and activation of Syk and subsequent activation of downstream antifungal signaling pathways; EphA5-deficient mice show increased susceptibility to Candida albicans infection with increased fungal burdens and impaired immune cell recruitment.","method":"Phosphorylation assays, co-immunoprecipitation, EphA5-deficient mouse infection model, fungal burden quantification, immune cell recruitment analysis","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical phosphorylation assays combined with in vivo KO mouse model with defined immune phenotype, multiple orthogonal methods, clear pathway placement","pmids":["40489568"],"is_preprint":false},{"year":2025,"finding":"EPHA5 promotes proliferation and inhibits apoptosis in follicular thyroid carcinoma via activation of the STAT3 signaling pathway; STAT3 inhibitor (SH-4-54) reduces the effects of EPHA5 on proliferation and apoptosis.","method":"EphA5 overexpression/knockdown, STAT3 inhibitor (SH-4-54) treatment, proliferation and apoptosis assays","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — gain/loss-of-function with pharmacological STAT3 inhibition, single lab, single paper","pmids":["40263257"],"is_preprint":false},{"year":2018,"finding":"c-Fos transcription factor directly binds to the EphA5 promoter at three binding sites (confirmed by ChIP and luciferase assay) and positively regulates EphA5 expression; c-Fos overexpression upregulates EphA5 in hippocampal neurons of congenital hypothyroid rats.","method":"Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, c-Fos overexpression, qPCR and Western blot","journal":"Journal of molecular histology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — ChIP and reporter assay with mutagenesis establish direct promoter binding, in vivo overexpression confirms regulation, single lab","pmids":["29330744"],"is_preprint":false}],"current_model":"EphA5 is a receptor tyrosine kinase that binds ephrin-A ligands through a structurally pre-organized open ligand-binding domain, undergoes ligand-induced autophosphorylation, and transduces forward signals controlling diverse processes: it specifies topographic axon guidance via ligand gradient-mediated repulsion, promotes hippocampal synaptogenesis by activating Ca²⁺/PKA/CaMKII/PI3K/CREB cascades to drive NMDA receptor-PSD-95 complex formation, regulates synaptic plasticity and LTP in adult hippocampus, modulates counterregulatory responses to hypoglycemia via glutamate/glutamine cycling in the ventromedial hypothalamus, promotes neurite outgrowth through CREB and RhoA, regulates hematopoietic stem cell adhesion and migration via Rac1/WAVE1, supports DNA damage responses by nuclear translocation and interaction with activated ATM, acts as an inhibitor of osteogenic differentiation in bone marrow stromal cells, phosphorylates EPHB2 and Dectin-1 to activate antifungal Syk signaling, and activates STAT3 to promote tumor cell proliferation; its expression is transcriptionally regulated by KLF16 and c-Fos binding to its promoter, and is suppressed by promoter CpG methylation and post-translationally regulated via PIAS2-mediated SUMOylation."},"narrative":{"mechanistic_narrative":"EPHA5 is a receptor tyrosine kinase of the ephrin-A signaling system that translates contact-mediated ligand engagement into forward signals governing axon guidance, synapse formation, and a broad range of cell-adhesion and proliferative responses [PMID:7876076, PMID:20824214]. Its ligand-binding domain adopts a pre-organized open ephrin-binding pocket with fast loop dynamics but no slow conformational exchange, a feature that restricts the receptor to ephrin-A ligands and distinguishes it from EphA4 [PMID:24086308]. Ligand binding (ELF-1/ephrin-A, ephrin-A5) induces receptor autophosphorylation and forward signaling [PMID:7876076]. In the nervous system, EPHA5 and its ephrin-A ligands are arranged in complementary gradients that drive topographic axon guidance through selective repulsion of inappropriate neurites [PMID:9321686, PMID:10660883], while ephrin-A5 engagement during hippocampal development triggers a Ca²⁺/PKA/CaMKII/PI3K/CREB cascade that builds NMDA receptor–PSD-95 complexes and matures spines [PMID:20824214], and EPHA5 activation is recruited during hippocampal LTP [PMID:9698392]. Downstream effectors are context-dependent: CREB and RhoA in neurite outgrowth [PMID:33912567], Rac1/WAVE1 in hematopoietic progenitor adhesion and migration [PMID:27988259], and Erk1/2 in striatal cocaine responses [PMID:21628570]. In the ventromedial hypothalamus, EPHA5 activation amplifies counterregulatory hormone release during hypoglycemia in conjunction with glutamate/glutamine cycling [PMID:23274893, PMID:24222347]. EPHA5 also acts in the nucleus, where after irradiation it translocates and associates with activated ATM to support the G1/S checkpoint and DNA damage resolution [PMID:25623065]. In innate immunity, EPHA5 phosphorylates EPHB2 and Dectin-1 to drive Syk-dependent antifungal signaling, and its loss increases susceptibility to Candida albicans [PMID:40489568]. Its expression is controlled transcriptionally by KLF16 and c-Fos binding to its promoter and silenced by promoter CpG methylation [PMID:27402841, PMID:29330744], and post-translationally stabilized through PIAS2-mediated SUMOylation that opposes ubiquitin-driven degradation [PMID:37481078].","teleology":[{"year":1995,"claim":"Established that EphA5 is a functional receptor tyrosine kinase activated by an ephrin-A ligand, defining the basic ligand-receptor signaling unit.","evidence":"cDNA cloning and in vitro receptor autophosphorylation assay with ELF-1/ephrin-A","pmids":["7876076"],"confidence":"High","gaps":["Did not map downstream effectors","In vitro biochemistry without cellular context"]},{"year":1997,"claim":"Showed that complementary EphA5/ephrin-A gradients and selective neurite inhibition specify topographic projections, casting EphA5 as a guidance receptor.","evidence":"Gradient expression mapping and neurite outgrowth assays with selective ligand inhibition in hippocamposeptal system","pmids":["9321686"],"confidence":"Medium","gaps":["Intracellular signaling not delineated","Single-system correlation between expression and function"]},{"year":1998,"claim":"Demonstrated EphA5 activation is engaged during synaptic plasticity, extending its role beyond development into adult hippocampal LTP.","evidence":"Hippocampal slice electrophysiology with EphA5-IgG antagonist and ephrin-A5-IgG agonist, including occlusion of LTP","pmids":["9698392"],"confidence":"High","gaps":["Molecular link between receptor activation and synaptic strengthening not resolved"]},{"year":2010,"claim":"Defined the synaptogenic signaling cascade downstream of EphA5, answering how ligand engagement builds functional synapses.","evidence":"EphA5 knockout mice, hippocampal neuron culture, pharmacological dissection, electrophysiology, and biochemistry tracing Ca²⁺/PKA/CaMKII/PI3K/CREB to NMDAR-PSD-95 complex formation","pmids":["20824214"],"confidence":"High","gaps":["Direct receptor substrate(s) initiating the cascade not identified"]},{"year":2012,"claim":"Identified a systemic-physiology role: VMH EphA5 activation tunes counterregulatory hormone responses to hypoglycemia via glutamate/glutamine cycling.","evidence":"Hyperinsulinemic-hypoglycemic clamps with VMH microinjection, AAV manipulation, and microdialysis","pmids":["23274893"],"confidence":"High","gaps":["Cell-type-specific signaling within VMH not resolved","Mechanistic link to neurotransmitter cycling correlative"]},{"year":2013,"claim":"Resolved the structural basis of ephrin-A binding specificity, explaining why EphA5 is restricted to ephrin-A ligands.","evidence":"X-ray crystallography of the LBD validated by NMR H/D exchange and MD simulations","pmids":["24086308"],"confidence":"High","gaps":["Full-length receptor and kinase-domain conformations not addressed","No structure of a ligand-bound complex"]},{"year":2013,"claim":"Showed EphA5 acts as a contact-dependent inhibitor of osteogenic differentiation, broadening its role into stromal cell fate.","evidence":"siRNA knockdown and co-culture assays in bone marrow stromal cells measuring ALP expression","pmids":["24029132","27057165"],"confidence":"Medium","gaps":["Downstream signaling in osteogenic suppression not defined","Single-lab cellular models"]},{"year":2015,"claim":"Revealed a noncanonical nuclear function in which EphA5 supports the DNA damage response by interacting with activated ATM.","evidence":"Nuclear fractionation, Co-IP with ATM, γ-H2AX foci, cell cycle analysis, and xenograft radiotherapy in lung cancer cells","pmids":["25623065"],"confidence":"High","gaps":["Mechanism of nuclear translocation unknown","Whether kinase activity is required not established"]},{"year":2016,"claim":"Connected forward signaling to cytoskeletal regulation, identifying Rac1/WAVE1 as effectors of EphA5-driven HSPC adhesion and migration.","evidence":"Ephrin-A5-Fc stimulation, blocking peptides, and Rac1 inhibition with adhesion/migration assays","pmids":["27988259"],"confidence":"Medium","gaps":["Direct link from receptor to Rac1 activation not biochemically resolved"]},{"year":2016,"claim":"Established direct transcriptional control of EphA5 by KLF16 and methylation-sensitive promoter regulation governing guidance responses.","evidence":"ChIP, EMSA, methylation-specific reporter assays with mutagenesis, and RGC neurite/growth-cone assays","pmids":["27402841"],"confidence":"High","gaps":["In vivo relevance of specific CpG methylation not tested"]},{"year":2018,"claim":"Identified c-Fos as a direct transcriptional activator of EphA5, linking receptor expression to neuronal activity states.","evidence":"ChIP, dual-luciferase reporter assays, and c-Fos overexpression in hippocampal neurons of hypothyroid rats","pmids":["29330744"],"confidence":"Medium","gaps":["Functional consequence of c-Fos-driven expression on circuits not measured"]},{"year":2021,"claim":"Defined CREB and RhoA as the critical downstream effectors of EphA5 signaling required for neurite outgrowth.","evidence":"RNA-seq, EPHA5 overexpression rescue after RF-EMF exposure, and CREB/RhoA pathway analysis in neural cell models","pmids":["33912567"],"confidence":"Medium","gaps":["Mechanistic coupling of receptor to RhoA not shown","Single-lab cell-line models"]},{"year":2023,"claim":"Uncovered post-transcriptional and post-translational control of EPHA5 by an IL-17/TRAF2/PIAS2/ELAVL1 axis stabilizing mRNA and protein.","evidence":"Co-IP, RNA-IP, and knockdown of pathway components with proliferation/invasion assays in melanoma","pmids":["37481078"],"confidence":"Medium","gaps":["Direct SUMOylation site on EPHA5 not mapped","Single-lab single-cancer context"]},{"year":2025,"claim":"Placed EPHA5 in innate antifungal immunity as a kinase that phosphorylates EPHB2 and Dectin-1 to activate Syk signaling.","evidence":"Phosphorylation assays, Co-IP, and EphA5-deficient mouse Candida albicans infection model","pmids":["40489568"],"confidence":"High","gaps":["Direct phosphosite mapping on Dectin-1 not detailed","Receptor activation trigger during infection unclear"]},{"year":2025,"claim":"Showed EPHA5 can act as a pro-proliferative driver via STAT3 in follicular thyroid carcinoma, contrasting with its tumor-suppressive roles elsewhere.","evidence":"EphA5 gain/loss-of-function with STAT3 inhibitor (SH-4-54) and proliferation/apoptosis assays","pmids":["40263257"],"confidence":"Medium","gaps":["Mechanism of context-dependent oncogenic vs suppressive switching unresolved","Single-lab study"]},{"year":null,"claim":"How a single receptor reconciles tumor-suppressive (breast, esophageal) and tumor-promoting (thyroid) outputs, and what determines forward versus nuclear versus cross-phosphorylation modes, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking ligand context to divergent downstream pathways","Determinants of nuclear translocation vs membrane forward signaling unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,21]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,21]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,5,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,14,21]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,4,5]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,5,19]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[21]}],"complexes":[],"partners":["EFNA5","EFNA1","ATM","EPHB2","CLEC7A","PIAS2","ELAVL1","TRAF2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P54756","full_name":"Ephrin type-A receptor 5","aliases":["Brain-specific kinase","EPH homology kinase 1","EHK-1","EPH-like kinase 7","EK7","hEK7"],"length_aa":1037,"mass_kda":114.8,"function":"Receptor tyrosine kinase which binds promiscuously GPI-anchored ephrin-A family ligands 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. Among GPI-anchored ephrin-A ligands, EFNA5 most probably constitutes the cognate/functional ligand for EPHA5. Functions as an axon guidance molecule during development and may be involved in the development of the retinotectal, entorhino-hippocampal and hippocamposeptal pathways. Together with EFNA5 plays also a role in synaptic plasticity in adult brain through regulation of synaptogenesis. In addition to its function in the nervous system, the interaction of EPHA5 with EFNA5 mediates communication between pancreatic islet cells to regulate glucose-stimulated insulin secretion (By similarity)","subcellular_location":"Cell membrane; Cell projection, axon; Cell projection, dendrite","url":"https://www.uniprot.org/uniprotkb/P54756/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EPHA5","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/EPHA5","total_profiled":1310},"omim":[{"mim_id":"620517","title":"STERILE ALPHA MOTIF DOMAIN-CONTAINING PROTEIN 5; SAMD5","url":"https://www.omim.org/entry/620517"},{"mim_id":"609952","title":"DEAFNESS, AUTOSOMAL RECESSIVE 55; DFNB55","url":"https://www.omim.org/entry/609952"},{"mim_id":"602190","title":"EPHRIN RECEPTOR EphA7; EPHA7","url":"https://www.omim.org/entry/602190"},{"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"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in 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functional neurite outgrowth assays combined with expression mapping, single lab\",\n      \"pmids\": [\"9321686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Soluble EphA5-IgG (antagonist) impairs induction of LTP in hippocampal slices without affecting basal synaptic transmission; conversely, ephrin-A5-IgG (EphA5 agonist) induces a sustained potentiation of synaptic transmission that occludes subsequent LTP, demonstrating EphA5 activation is recruited during LTP.\",\n      \"method\": \"Hippocampal slice electrophysiology, LTP induction with pharmacological agonist/antagonist, immunohistochemistry\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function with defined electrophysiological readout, occlusion experiment provides strong mechanistic evidence\",\n      \"pmids\": [\"9698392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Activation of EphA5 receptor using ephrin-A1 recombinant fusion protein results in time-dependent tyrosine phosphorylation of EphA5 in glioblastoma U-118 MG cells, but does not promote cell proliferation.\",\n      \"method\": \"Receptor activation with recombinant ephrin-A1-Fc, Western blot for phosphotyrosine, proliferation assay\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, direct biochemical demonstration of ligand-induced receptor phosphorylation with negative proliferation result\",\n      \"pmids\": [\"10064801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"EphA5 expressed on mitral cells and its ligands on olfactory neurons; blocking EphA5-ligand interactions with anti-EphA5 antibodies or recombinant EphA5 protein in explant cultures reduced neurite outgrowth, suggesting intrafascicular axon repulsion limits adhesion and promotes axon growth.\",\n      \"method\": \"Antibody blocking, recombinant protein perturbation in explant cultures, neurite outgrowth quantification\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional blocking experiment with defined cellular readout, consistent with receptor-ligand mechanism\",\n      \"pmids\": [\"10660883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Ephrin-A5 interaction with EphA5 during early hippocampal development induces synaptogenesis: specifically, it drives expression of NMDA receptor-PSD-95 complexes and spine morphological maturation via voltage-sensitive calcium channel Ca2+ fluxes that activate PKA, CaMKII, and PI3 kinase, leading to CREB phosphorylation and a synaptogenic gene expression program. EphA5 functional knockout mice at P6 showed no NMDA receptor currents upon stimulation.\",\n      \"method\": \"Hippocampal neuron culture, EphA5 knockout mice, electrophysiology, pharmacological inhibition, Western blot for signaling intermediates\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO mice, pharmacological dissection, electrophysiology, biochemistry), two labs involved, specific pathway delineated\",\n      \"pmids\": [\"20824214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The crystal structure of the EphA5 ligand-binding domain (LBD) was determined by X-ray crystallography and validated by NMR and MD simulations; the unbound EphA5 LBD adopts an open ephrin-binding pocket with helical conformation over the J-K loop resembling ephrin-bound states of other Eph receptors. NMR H/D exchange and MD simulations revealed rapid picosecond-nanosecond conformational dynamics over loops but no global microsecond-millisecond exchanges, contrasting with EphA4 LBD dynamics and explaining EphA5's restriction to ephrin-A binding.\",\n      \"method\": \"X-ray crystallography, NMR (H/D exchange, relaxation), molecular dynamics simulations\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structure determination with orthogonal NMR and MD validation, mechanistic interpretation of binding specificity via dynamics\",\n      \"pmids\": [\"24086308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"EphA5 receptors in the ventromedial hypothalamus (VMH) regulate counterregulatory hormone release during hypoglycemia: VMH microinjection of ephrin-A5-Fc (EphA5 agonist) or AAV-mediated ephrin-A5 overexpression increased counterregulatory responses and transiently elevated local glutamate, while ephrin-A5 knockdown reduced responses and suppressed VMH glutamine concentrations.\",\n      \"method\": \"Hyperinsulinemic-hypoglycemic clamp, in vivo VMH microinjection, AAV-mediated knockdown/overexpression, microdialysis for glutamate/glutamine\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional gain- and loss-of-function in vivo with defined hormonal and neurochemical readouts, multiple approaches in one study\",\n      \"pmids\": [\"23274893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Recurrent hypoglycemia reduces ephrin-A5 (but not EphA5 receptor) expression in the VMH, increases synaptic connections, and reduces astroglial synaptic coverage; targeted VMH activation of EphA5 receptors by ephrin-A5-Fc restored counterregulatory responses and increased glucagon release by 150% in rats with recurrent hypoglycemia.\",\n      \"method\": \"Hyperinsulinemic-hypoglycemic clamp with recurrent hypoglycemia protocol, VMH microinjection, immunofluorescence for synaptic markers, glucagon RIA\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo rescue experiment with defined endocrine readout, single lab\",\n      \"pmids\": [\"24222347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EphA5 is specifically overexpressed in lung cancer and upon irradiation is transported into the nucleus where it interacts with activated ATM at sites of DNA repair; EphA5-deficient lung cancer cells display defective G1/S checkpoint, inability to resolve DNA damage, and increased radiosensitivity.\",\n      \"method\": \"siRNA knockdown, nuclear fractionation, co-immunoprecipitation of EphA5 with ATM, γ-H2AX foci, cell cycle analysis, xenograft radiotherapy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (nuclear fractionation, Co-IP with ATM, cell cycle, DNA damage markers, in vivo xenograft), mechanistic pathway defined\",\n      \"pmids\": [\"25623065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EphA5 was identified as a direct target of miR-34a during chondrogenesis; miR-34a downregulates EphA5 expression, and upregulation of EphA5 overcomes miR-34a inhibition of chondroblast migration and precartilage condensation.\",\n      \"method\": \"PNA-based antisense oligonucleotide blockade of miR-34a, EphA5 overexpression rescue, migration and condensation assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antisense blockade and rescue experiment, two orthogonal approaches (inhibition and overexpression) in single lab\",\n      \"pmids\": [\"22079638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EphA5 forward signaling in human hematopoietic stem and progenitor cells (HSPCs), stimulated by soluble ephrin-A5-Fc, promotes colony formation, adhesion, and migration via activation of Rac1 and its downstream target WAVE1; functional blocking peptides against EphA5 inhibit HSPC adhesion and migration.\",\n      \"method\": \"Ephrin-A5-Fc stimulation, functional blocking peptides, Rac1 inhibitor, gene/protein expression analysis, adhesion/migration assays\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional modulation (agonist and blocking peptide), Rac1 pathway identified with inhibitor, single lab\",\n      \"pmids\": [\"27988259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KLF16 transcription factor binds directly to a KLF site near the EphA5 transcription start site (confirmed by ChIP and EMSA) and transactivates EphA5 expression; methylation of only 6 of 98 CpG dinucleotides within the EphA5 promoter blocks KLF16-mediated transactivation while enabling transactivation by KLF2 and KLF15. KLF16 overexpression inhibits RGC neurite outgrowth and enhances growth cone collapse in response to ephrin-A5.\",\n      \"method\": \"ChIP assay, EMSA, promoter luciferase assays with site-directed mutagenesis, methylation-specific promoter variants, neurite outgrowth assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP, EMSA, and reporter assays with mutagenesis, combined with functional cellular readout, multiple orthogonal methods\",\n      \"pmids\": [\"27402841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The ephrin-A5–EphA4/EphA5 system in the substantia nigra pars reticulata (SNr) is upregulated specifically in the direct pathway during cocaine responses; immunoadhesin-mediated activation of EphA4 and EphA5 in the SNr suppressed the adaptive response to repeated cocaine; cocaine stimulated phosphorylation of Erk1/2 in ephrin-A5-expressing SNr cells in a direct pathway-dependent manner.\",\n      \"method\": \"Genome-wide expression profiling, pathway-specific neurotransmission blocking (RNB) mice, immunoadhesin EphA4/EphA5 activation in vivo, Erk1/2 phosphorylation immunohistochemistry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo pathway-specific activation with behavioral and molecular readouts, Erk1/2 pathway placed downstream, multiple orthogonal methods\",\n      \"pmids\": [\"21628570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EphA5 expressed on bone marrow stromal cells (BMSCs) is upregulated with repeated passaging and acts as an inhibitory factor for osteogenesis; siRNA knockdown of EphA5 in long-term passaged BMSCs increased ALP mRNA expression, and co-culture assays showed inhibitory signals require cell-cell contact.\",\n      \"method\": \"siRNA knockdown, co-culture assay, microarray, quantitative PCR, alkaline phosphatase mRNA measurement\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined osteogenic readout, co-culture contact-dependence established, single lab\",\n      \"pmids\": [\"24029132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Forced expression of EphA5 in human BMSCs diminishes osteoblast phenotypic marker expression; dexamethasone treatment downregulates EphA5 and promotes osteoblast marker expression; EphA5 promoter is largely unmethylated in hBMSCs but histone deacetylation partially suppresses EphA5 in early-passage cultures.\",\n      \"method\": \"EphA5 overexpression, dexamethasone treatment, ALP mRNA quantification, bisulfite sequencing, histone deacetylase inhibitor treatment\",\n      \"journal\": \"Stem cells international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function and pharmacological loss-of-function with defined osteogenic readout, epigenetic mechanism partially characterized, single lab\",\n      \"pmids\": [\"27057165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EPHA5 deficiency (CRISPR knockout) in HER2-positive breast cancer cells increases cancer stem cell-like properties (elevated NANOG, CD133+, CD44+/CD24-/low phenotype, mammosphere formation) and activates Notch1 and PTEN/AKT signaling, leading to trastuzumab resistance in xenografts.\",\n      \"method\": \"CRISPR-Cas9 knockout, mammosphere assay, flow cytometry, Western blot for Notch1/PTEN/AKT, xenograft model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR loss-of-function with multiple cellular and in vivo readouts, Notch1/PTEN/AKT pathway identified, single lab\",\n      \"pmids\": [\"30620624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EphA5 knockdown in esophageal squamous cell carcinoma cells enhances invasion and migration via epithelial-mesenchymal transition, associated with elevated β-catenin and p-GSK-3βSer9 protein levels, indicating activation of the Wnt/β-catenin pathway.\",\n      \"method\": \"siRNA knockdown, Transwell invasion/migration assay, Western blot and immunofluorescence for EMT markers and Wnt pathway components\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined invasion phenotype and pathway biochemistry, single lab\",\n      \"pmids\": [\"31956298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EphA5 silencing in ESCC cells increases radiosensitivity through impaired ATM-dependent pathway: EphA5 knockdown after ionizing radiation results in defective G1/S checkpoint, impaired γ-H2AX foci formation, reduced ATM activation, and downstream reduction in p-Chk2, p-p53, and p21.\",\n      \"method\": \"siRNA knockdown, clonogenic assay, flow cytometry (cell cycle/apoptosis), Western blot for ATM/Chk2/p53/p21, γ-H2AX immunofluorescence\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — note: this paper was subsequently retracted (PMID:40641952); findings should not be relied upon\",\n      \"pmids\": [\"33061640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EphA5 signaling is required for neurite outgrowth; RF-EMF exposure inhibits EPHA5 expression and impairs neurite outgrowth, which is rescued by enhancing EPHA5 signaling; CREB and RhoA were identified as critical downstream factors of EPHA5 signaling mediating neurite outgrowth.\",\n      \"method\": \"RNA sequencing, EPHA5 overexpression rescue, CREB and RhoA pathway analysis, neurite length/branching quantification in neural stem cell-derived neurons and Neuro-2A cells\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue experiment identifies EPHA5 as necessary for neurite outgrowth with CREB/RhoA as downstream effectors, multiple cell models, single lab\",\n      \"pmids\": [\"33912567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-17 signaling through TRAF2 as a scaffold recruits PIAS2 (SUMO E3 ligase) and ELAVL1 (RNA-binding protein) to induce EPHA5 expression in melanoma: ELAVL1 binds AU-rich elements in the 3'-UTR of EPHA5 mRNA to enhance its stability, and PIAS2 induces EPHA5 SUMOylation which suppresses its ubiquitination and degradation; EPHA5 knockdown suppresses IL-17A-induced melanoma proliferation and invasion.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, siRNA knockdown of pathway components, proliferation/invasion assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and RNA-IP establish protein-RNA interactions, SUMOylation/ubiquitination mechanism proposed with knockdown functional readout, single lab\",\n      \"pmids\": [\"37481078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EPHA5 phosphorylates EPHB2 and Dectin-1 after fungal infection, facilitating recruitment and activation of Syk and subsequent activation of downstream antifungal signaling pathways; EphA5-deficient mice show increased susceptibility to Candida albicans infection with increased fungal burdens and impaired immune cell recruitment.\",\n      \"method\": \"Phosphorylation assays, co-immunoprecipitation, EphA5-deficient mouse infection model, fungal burden quantification, immune cell recruitment analysis\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical phosphorylation assays combined with in vivo KO mouse model with defined immune phenotype, multiple orthogonal methods, clear pathway placement\",\n      \"pmids\": [\"40489568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EPHA5 promotes proliferation and inhibits apoptosis in follicular thyroid carcinoma via activation of the STAT3 signaling pathway; STAT3 inhibitor (SH-4-54) reduces the effects of EPHA5 on proliferation and apoptosis.\",\n      \"method\": \"EphA5 overexpression/knockdown, STAT3 inhibitor (SH-4-54) treatment, proliferation and apoptosis assays\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — gain/loss-of-function with pharmacological STAT3 inhibition, single lab, single paper\",\n      \"pmids\": [\"40263257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"c-Fos transcription factor directly binds to the EphA5 promoter at three binding sites (confirmed by ChIP and luciferase assay) and positively regulates EphA5 expression; c-Fos overexpression upregulates EphA5 in hippocampal neurons of congenital hypothyroid rats.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, c-Fos overexpression, qPCR and Western blot\",\n      \"journal\": \"Journal of molecular histology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP and reporter assay with mutagenesis establish direct promoter binding, in vivo overexpression confirms regulation, single lab\",\n      \"pmids\": [\"29330744\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EphA5 is a receptor tyrosine kinase that binds ephrin-A ligands through a structurally pre-organized open ligand-binding domain, undergoes ligand-induced autophosphorylation, and transduces forward signals controlling diverse processes: it specifies topographic axon guidance via ligand gradient-mediated repulsion, promotes hippocampal synaptogenesis by activating Ca²⁺/PKA/CaMKII/PI3K/CREB cascades to drive NMDA receptor-PSD-95 complex formation, regulates synaptic plasticity and LTP in adult hippocampus, modulates counterregulatory responses to hypoglycemia via glutamate/glutamine cycling in the ventromedial hypothalamus, promotes neurite outgrowth through CREB and RhoA, regulates hematopoietic stem cell adhesion and migration via Rac1/WAVE1, supports DNA damage responses by nuclear translocation and interaction with activated ATM, acts as an inhibitor of osteogenic differentiation in bone marrow stromal cells, phosphorylates EPHB2 and Dectin-1 to activate antifungal Syk signaling, and activates STAT3 to promote tumor cell proliferation; its expression is transcriptionally regulated by KLF16 and c-Fos binding to its promoter, and is suppressed by promoter CpG methylation and post-translationally regulated via PIAS2-mediated SUMOylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EPHA5 is a receptor tyrosine kinase of the ephrin-A signaling system that translates contact-mediated ligand engagement into forward signals governing axon guidance, synapse formation, and a broad range of cell-adhesion and proliferative responses [#0, #5]. Its ligand-binding domain adopts a pre-organized open ephrin-binding pocket with fast loop dynamics but no slow conformational exchange, a feature that restricts the receptor to ephrin-A ligands and distinguishes it from EphA4 [#6]. Ligand binding (ELF-1/ephrin-A, ephrin-A5) induces receptor autophosphorylation and forward signaling [#0]. In the nervous system, EPHA5 and its ephrin-A ligands are arranged in complementary gradients that drive topographic axon guidance through selective repulsion of inappropriate neurites [#1, #4], while ephrin-A5 engagement during hippocampal development triggers a Ca\\u00b2\\u207a/PKA/CaMKII/PI3K/CREB cascade that builds NMDA receptor\\u2013PSD-95 complexes and matures spines [#5], and EPHA5 activation is recruited during hippocampal LTP [#2]. Downstream effectors are context-dependent: CREB and RhoA in neurite outgrowth [#19], Rac1/WAVE1 in hematopoietic progenitor adhesion and migration [#11], and Erk1/2 in striatal cocaine responses [#13]. In the ventromedial hypothalamus, EPHA5 activation amplifies counterregulatory hormone release during hypoglycemia in conjunction with glutamate/glutamine cycling [#7, #8]. EPHA5 also acts in the nucleus, where after irradiation it translocates and associates with activated ATM to support the G1/S checkpoint and DNA damage resolution [#9]. In innate immunity, EPHA5 phosphorylates EPHB2 and Dectin-1 to drive Syk-dependent antifungal signaling, and its loss increases susceptibility to Candida albicans [#21]. Its expression is controlled transcriptionally by KLF16 and c-Fos binding to its promoter and silenced by promoter CpG methylation [#12, #23], and post-translationally stabilized through PIAS2-mediated SUMOylation that opposes ubiquitin-driven degradation [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that EphA5 is a functional receptor tyrosine kinase activated by an ephrin-A ligand, defining the basic ligand-receptor signaling unit.\",\n      \"evidence\": \"cDNA cloning and in vitro receptor autophosphorylation assay with ELF-1/ephrin-A\",\n      \"pmids\": [\"7876076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map downstream effectors\", \"In vitro biochemistry without cellular context\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed that complementary EphA5/ephrin-A gradients and selective neurite inhibition specify topographic projections, casting EphA5 as a guidance receptor.\",\n      \"evidence\": \"Gradient expression mapping and neurite outgrowth assays with selective ligand inhibition in hippocamposeptal system\",\n      \"pmids\": [\"9321686\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular signaling not delineated\", \"Single-system correlation between expression and function\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated EphA5 activation is engaged during synaptic plasticity, extending its role beyond development into adult hippocampal LTP.\",\n      \"evidence\": \"Hippocampal slice electrophysiology with EphA5-IgG antagonist and ephrin-A5-IgG agonist, including occlusion of LTP\",\n      \"pmids\": [\"9698392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between receptor activation and synaptic strengthening not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the synaptogenic signaling cascade downstream of EphA5, answering how ligand engagement builds functional synapses.\",\n      \"evidence\": \"EphA5 knockout mice, hippocampal neuron culture, pharmacological dissection, electrophysiology, and biochemistry tracing Ca\\u00b2\\u207a/PKA/CaMKII/PI3K/CREB to NMDAR-PSD-95 complex formation\",\n      \"pmids\": [\"20824214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct receptor substrate(s) initiating the cascade not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified a systemic-physiology role: VMH EphA5 activation tunes counterregulatory hormone responses to hypoglycemia via glutamate/glutamine cycling.\",\n      \"evidence\": \"Hyperinsulinemic-hypoglycemic clamps with VMH microinjection, AAV manipulation, and microdialysis\",\n      \"pmids\": [\"23274893\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific signaling within VMH not resolved\", \"Mechanistic link to neurotransmitter cycling correlative\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the structural basis of ephrin-A binding specificity, explaining why EphA5 is restricted to ephrin-A ligands.\",\n      \"evidence\": \"X-ray crystallography of the LBD validated by NMR H/D exchange and MD simulations\",\n      \"pmids\": [\"24086308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length receptor and kinase-domain conformations not addressed\", \"No structure of a ligand-bound complex\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed EphA5 acts as a contact-dependent inhibitor of osteogenic differentiation, broadening its role into stromal cell fate.\",\n      \"evidence\": \"siRNA knockdown and co-culture assays in bone marrow stromal cells measuring ALP expression\",\n      \"pmids\": [\"24029132\", \"27057165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling in osteogenic suppression not defined\", \"Single-lab cellular models\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a noncanonical nuclear function in which EphA5 supports the DNA damage response by interacting with activated ATM.\",\n      \"evidence\": \"Nuclear fractionation, Co-IP with ATM, \\u03b3-H2AX foci, cell cycle analysis, and xenograft radiotherapy in lung cancer cells\",\n      \"pmids\": [\"25623065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of nuclear translocation unknown\", \"Whether kinase activity is required not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected forward signaling to cytoskeletal regulation, identifying Rac1/WAVE1 as effectors of EphA5-driven HSPC adhesion and migration.\",\n      \"evidence\": \"Ephrin-A5-Fc stimulation, blocking peptides, and Rac1 inhibition with adhesion/migration assays\",\n      \"pmids\": [\"27988259\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link from receptor to Rac1 activation not biochemically resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established direct transcriptional control of EphA5 by KLF16 and methylation-sensitive promoter regulation governing guidance responses.\",\n      \"evidence\": \"ChIP, EMSA, methylation-specific reporter assays with mutagenesis, and RGC neurite/growth-cone assays\",\n      \"pmids\": [\"27402841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of specific CpG methylation not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified c-Fos as a direct transcriptional activator of EphA5, linking receptor expression to neuronal activity states.\",\n      \"evidence\": \"ChIP, dual-luciferase reporter assays, and c-Fos overexpression in hippocampal neurons of hypothyroid rats\",\n      \"pmids\": [\"29330744\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of c-Fos-driven expression on circuits not measured\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined CREB and RhoA as the critical downstream effectors of EphA5 signaling required for neurite outgrowth.\",\n      \"evidence\": \"RNA-seq, EPHA5 overexpression rescue after RF-EMF exposure, and CREB/RhoA pathway analysis in neural cell models\",\n      \"pmids\": [\"33912567\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic coupling of receptor to RhoA not shown\", \"Single-lab cell-line models\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered post-transcriptional and post-translational control of EPHA5 by an IL-17/TRAF2/PIAS2/ELAVL1 axis stabilizing mRNA and protein.\",\n      \"evidence\": \"Co-IP, RNA-IP, and knockdown of pathway components with proliferation/invasion assays in melanoma\",\n      \"pmids\": [\"37481078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SUMOylation site on EPHA5 not mapped\", \"Single-lab single-cancer context\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed EPHA5 in innate antifungal immunity as a kinase that phosphorylates EPHB2 and Dectin-1 to activate Syk signaling.\",\n      \"evidence\": \"Phosphorylation assays, Co-IP, and EphA5-deficient mouse Candida albicans infection model\",\n      \"pmids\": [\"40489568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphosite mapping on Dectin-1 not detailed\", \"Receptor activation trigger during infection unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed EPHA5 can act as a pro-proliferative driver via STAT3 in follicular thyroid carcinoma, contrasting with its tumor-suppressive roles elsewhere.\",\n      \"evidence\": \"EphA5 gain/loss-of-function with STAT3 inhibitor (SH-4-54) and proliferation/apoptosis assays\",\n      \"pmids\": [\"40263257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of context-dependent oncogenic vs suppressive switching unresolved\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single receptor reconciles tumor-suppressive (breast, esophageal) and tumor-promoting (thyroid) outputs, and what determines forward versus nuclear versus cross-phosphorylation modes, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking ligand context to divergent downstream pathways\", \"Determinants of nuclear translocation vs membrane forward signaling unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 21]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 21]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 5, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 14, 21]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 4, 5]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 5, 19]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EFNA5\", \"EFNA1\", \"ATM\", \"EPHB2\", \"CLEC7A\", \"PIAS2\", \"ELAVL1\", \"TRAF2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}