{"gene":"EPHA2","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1994,"finding":"B61 (ephrin-A1) was identified as the ligand for the ECK (EphA2) receptor protein-tyrosine kinase; recombinant B61 induces autophosphorylation of ECK in intact cells, establishing a functional ligand-receptor pair.","method":"Receptor affinity chromatography, surface plasmon resonance, autophosphorylation assay in intact cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical reconstitution (affinity purification + autophosphorylation assay), foundational ligand-receptor identification replicated by subsequent work","pmids":["8139691"],"is_preprint":false},{"year":1994,"finding":"Activation of the ECK (EphA2) receptor stimulates phosphatidylinositol 3-kinase (PI3K) activity; the p85 subunit of PI3K binds the cytoplasmic domain of ECK via its C-terminal SH2 domain, and this interaction is confirmed by co-immunoprecipitation in ligand-activated cells.","method":"Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, PI3K activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods (Y2H, GST fusion, co-IP, enzymatic assay) in a single rigorous study","pmids":["7982920"],"is_preprint":false},{"year":1994,"finding":"B61/ephrin-A1 can exist as a GPI-linked cell-surface protein capable of activating the ECK (EphA2) receptor, representing the first GPI-linked ligand for a receptor protein-tyrosine kinase.","method":"Biochemical characterization, in situ hybridization, receptor activation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical characterization with functional validation, single lab","pmids":["7890684"],"is_preprint":false},{"year":1995,"finding":"SLAP (Src-like adapter protein), a novel protein with SH3 and SH2 adapter modules but no kinase domain, was identified as an interactor of activated ECK (EphA2) receptor via GST fusion protein binding.","method":"Yeast two-hybrid screen, GST pulldown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — two complementary binding methods (Y2H + GST pulldown), single lab, no functional follow-up in same paper","pmids":["7543898"],"is_preprint":false},{"year":2000,"finding":"Activation of endogenous EphA2 kinase by ephrin-A1 induces an inactive conformation of integrins and inhibits cell spreading, migration and integrin-mediated adhesion. EphA2 is constitutively associated with FAK in resting cells; within one minute of ephrin-A1 stimulation, SHP2 is recruited to EphA2, followed by dephosphorylation of FAK and paxillin, and dissociation of the FAK-EphA2 complex.","method":"Co-immunoprecipitation, phosphorylation assays, cell spreading/migration assays, integrin conformation assay","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, kinase assay, functional cellular assays), mechanistically detailed, widely replicated in subsequent literature","pmids":["10655584"],"is_preprint":false},{"year":2001,"finding":"EphA2 is a transcriptional target of the p53 family (p53, p73, p63); a p53 response element in the EphA2 promoter is responsive to wild-type p53, p73, and p63 but not mutant p53. EphA2 induction correlates with p53 activation after DNA damage, and forced EphA2 expression increases apoptosis.","method":"Promoter analysis, reporter assay, Western blot, stable inducible cell lines, apoptosis assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter/reporter assay identifies p53 response element, inducible expression system links EphA2 to apoptosis, single lab","pmids":["11641774"],"is_preprint":false},{"year":2002,"finding":"Ligand stimulation of EphA2 promotes ERK kinase nuclear translocation and phosphorylation, and activation of the Elk-1 transcription factor. EphA2 forms a molecular complex with SHC (via PTB and SH2 domains) and GRB2 (indirectly via SHC), and this complex is required for EphA2-mediated ERK activation.","method":"Co-immunoprecipitation, Western blot for nuclear translocation, Elk-1 reporter assay, domain mapping with SHC mutants","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping and functional readout (ERK activation/Elk-1), single lab","pmids":["12400011"],"is_preprint":false},{"year":2002,"finding":"EphA2 is negatively regulated by the ubiquitin ligase Cbl; kinase-active EphA2 recruits Cbl via Cbl's TKB domain and the RING finger domain of Cbl is required for its negative regulatory function. Kinase-inactive EphA2 cannot be regulated by Cbl.","method":"Co-immunoprecipitation, mutagenesis (G306E-Cbl, 70Z-Cbl dominant negative, kinase-inactive EphA2), Western blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of both receptor and E3 ligase with domain requirements established, single lab","pmids":["12147253"],"is_preprint":false},{"year":2005,"finding":"EphA2 receptor kinase activity and phosphorylation are required for its tumor-promoting functions; kinase-dead or cytoplasmic-domain-deleted EphA2 mutants reduce tumor volume, increase apoptosis, reduce lung metastases, and abolish RhoA GTPase activation and cell migration in breast cancer models.","method":"Site-directed mutagenesis, in vivo xenograft and metastasis models, RhoA activation assay, cell migration assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis with multiple in vivo and in vitro functional readouts, identifies RhoA as downstream effector","pmids":["16103880"],"is_preprint":false},{"year":2009,"finding":"EphA2 engages Git1 via Nck1 to suppress Arf6 activity and regulate E-cadherin-based cell-cell adhesion. Ligand-activated EphA2 phosphorylated on Tyr594 binds the SH2 domain of Nck1, which via its SH3 domain recruits Git1 to suppress Arf6 activity, inducing cell compaction and polarization.","method":"Co-immunoprecipitation, Arf6 activity assay, domain mapping, phospho-mutant analysis, MDCK cell density/calcium experiments","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, domain mapping with phospho-site identification, functional Arf6 activity assay, multiple orthogonal methods","pmids":["19193766"],"is_preprint":false},{"year":2009,"finding":"Trastuzumab resistance in breast cancer cells is mediated by elevated EphA2; trastuzumab treatment promotes EphA2 phosphorylation by activating Src kinase, which amplifies PI3K/Akt and MAPK signaling in resistant cells.","method":"Western blot, Src kinase assay, siRNA knockdown, in vivo xenograft with trastuzumab treatment","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling assays and in vivo validation, identifies Src as writer of EphA2 phosphorylation in resistance context, single lab","pmids":["20028874"],"is_preprint":false},{"year":2010,"finding":"Ephexin4 is a guanine nucleotide exchange factor for RhoG that interacts with EphA2 in breast cancer cells and acts downstream of EphA2 to promote ligand-independent cell migration and invasion via RhoG activation. RhoG recruits effector ELMO2 and Rac GEF Dock4 to form a complex with EphA2, and Dock4-mediated Rac activation is required for migration.","method":"Co-immunoprecipitation, GEF activity assay, knockdown-rescue experiments, cell migration/invasion assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockdown-rescue with GEF activity assay and complex characterization by co-IP, multiple orthogonal methods, clearly defines pathway","pmids":["20679435"],"is_preprint":false},{"year":2011,"finding":"Ephexin4 mediates resistance to anoikis downstream of EphA2 through activation of RhoG and PI3K/Akt; Ephexin4 knockdown promotes anoikis with decreased RhoG activity and Akt phosphorylation in suspended cells.","method":"RhoG activity assay, Akt phosphorylation assay, siRNA knockdown, anoikis assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with functional readout and signaling pathway placed, single lab","pmids":["21621533"],"is_preprint":false},{"year":2013,"finding":"EphA2 and Src cooperate in equatorial lens cell morphogenesis; EphA2 regulates Src/cortactin/F-actin complexes at cell vertices of hexagonal epithelial cells. Loss of EphA2 abolishes phosphorylated Src-Y424 and cortactin-Y466 at cell vertices, disrupts F-actin distribution, and leads to mislocalized E-cadherin junctions.","method":"Epha2-/- mouse model, immunofluorescence, phospho-specific antibodies, confocal microscopy","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined cellular and molecular phenotype, multiple readouts, single lab","pmids":["24026120"],"is_preprint":false},{"year":2014,"finding":"Spatial organization of EphA2 at the cell-cell interface modulates trans-endocytosis of ephrinA1; EphA2-ephrinA1 trans-endocytosis is sensitive to lateral reorganization and is not efficiently internalized when spatial reorganization at contact sites is physically hindered.","method":"Supported lipid bilayer reconstitution, 3D fluorescence microscopy trans-endocytosis assay, receptor clustering analysis","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — biophysical reconstitution with quantitative assay, single lab but rigorous methodology","pmids":["24853748"],"is_preprint":false},{"year":2015,"finding":"EphA2 is a cell-surface receptor and intracellular signaling receptor for Chlamydia trachomatis; C. trachomatis activates EphA2, inducing PI3K/Akt signaling via the p85 subunit, promoting chlamydial replication. EphA2 lacking the intracellular cytoplasmic domain does not enhance PI3K activation or infection.","method":"siRNA knockdown, overexpression of wild-type vs. cytoplasmic-domain-deleted mutant, PI3K/Akt assays, infection quantification","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain deletion mutant distinguishes extracellular from intracellular functions, multiple infection and signaling assays, single lab","pmids":["25906164"],"is_preprint":false},{"year":2015,"finding":"Unliganded EphA2 forms dimers in the plasma membrane; a dimerization-deficient EphA2 mutant shows enhanced cell migration with increased Ser897 phosphorylation and decreased tyrosine phosphorylation, indicating that EphA2 pro-tumorigenic activity is mediated by the EphA2 monomer.","method":"FRET-based dimerization assay in HEK293T cells, mutagenesis, Western blot for phosphorylation, cell migration assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative FRET with mutagenesis and functional readout, single lab","pmids":["26363067"],"is_preprint":false},{"year":2016,"finding":"The EphA2 SAM domain inhibits receptor dimerization and decreases tyrosine phosphorylation; SAM domain deletion increases EphA2 oligomerization and constitutive kinase activation, as shown by FRET and phosphorylation assays.","method":"FRET-based dimerization measurement, SAM domain deletion mutant, Western blot for tyrosine phosphorylation","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative FRET with mutant analysis, single lab, two orthogonal readouts","pmids":["27776928"],"is_preprint":false},{"year":2016,"finding":"EphA2 SAM domain deletion induces constitutive kinase activation (elevated tyrosine autophosphorylation) and increases receptor oligomerization; ephrinA1 stimulation further increases oligomerization of SAM-deleted EphA2 to larger oligomers than wild-type.","method":"Fluorescence correlation spectroscopy in live cells, Western blot for tyrosine phosphorylation, multiple cell lines","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative live-cell spectroscopy with multiple cell lines and phosphorylation assays, single lab","pmids":["28338017"],"is_preprint":false},{"year":2016,"finding":"Protein kinase A (PKA), activated via the β2-adrenoceptor/cAMP axis, phosphorylates EphA2 at Ser897 (and nearby Ser/Thr residues), and this S897 phosphorylation can coexist with EphA2 tyrosine phosphorylation and block ephrin-A1-induced cell retraction mediated by EphA2 kinase activity.","method":"High-content screening, phospho-specific Western blot, cAMP elevation, pharmacological PKA activation/inhibition, cell retraction assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection with phospho-site specific assays and functional cell readout, single lab","pmids":["27385333"],"is_preprint":false},{"year":2016,"finding":"EphA2 is a functional signaling receptor for the growth factor progranulin; progranulin binds EphA2 with high affinity, causes prolonged receptor activation, stimulates MAPK and Akt downstream, and promotes capillary morphogenesis in an EphA2-dependent manner.","method":"Solid-phase and solution binding assays, Western blot for MAPK/Akt phosphorylation, capillary morphogenesis assay, EphA2 knockdown","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple binding assay formats, functional downstream signaling, loss-of-function confirmation, single lab with orthogonal methods","pmids":["27903606"],"is_preprint":false},{"year":2016,"finding":"Crystal structures of 24 clinical kinase inhibitors bound to the EPHA2 kinase domain were determined; key, scaffold, potency, and selectivity residues in the ATP-binding site were defined, providing a structural classification system for EPHA2 inhibitor interactions.","method":"Chemical proteomics (kinase selectivity profiling), X-ray crystallography (9 co-crystal structures), NMR conformational dynamics","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple co-crystal structures with chemical proteomics validation and NMR, multiple orthogonal methods","pmids":["27768280"],"is_preprint":false},{"year":2017,"finding":"EphA2 functions as a pattern recognition receptor (PRR) for fungal β-glucans on Candida albicans in oral epithelial cells; β-glucan binding to EphA2 activates STAT3 and MAPK signaling in an inoculum-dependent manner, and EphA2-/- mice show impaired inflammatory response and reduced IL-17 signaling during oropharyngeal candidiasis.","method":"EphA2-/- mouse model, β-glucan binding assay, STAT3/MAPK signaling assays, in vivo infection model","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mouse in vivo model combined with direct binding and signaling assays, replicated across in vitro and in vivo systems","pmids":["29133884"],"is_preprint":false},{"year":2018,"finding":"C. neoformans promotes EphA2 activity via CD44-dependent phosphorylation of EphA2 at the blood-brain barrier, inducing receptor clustering and internalization that creates a permeable barrier facilitating fungal transmigration.","method":"EphA2 silencing, chemical inhibition, EphA2 agonist treatment, HEK293T overexpression, in vitro BBB transmigration assay","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple perturbation approaches (siRNA, inhibitor, agonist, overexpression) with functional transmigration readout, single lab","pmids":["29197141"],"is_preprint":false},{"year":2018,"finding":"Molecular dynamics simulations and biochemical studies reveal that PIP lipids interact with the EphA2 transmembrane, juxtamembrane, and kinase domains; positively charged patches on the kinase domain and juxtamembrane region induce nanoclusters of PIP molecules, and the kinase domain orientation relative to the membrane is modulated by the juxtamembrane region.","method":"Molecular dynamics simulation, biochemical membrane interaction studies","journal":"Structure","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — MD simulation with biochemical validation but limited experimental depth reported in abstract","pmids":["29887500"],"is_preprint":false},{"year":2019,"finding":"Crystal structures of the YSA peptide and derivatives in complex with EphA2 LBD show YSA targets the ephrin-binding pocket of EphA2 mimicking ephrin-A ligand contacts. C-terminal modifications convert YSA from antagonist to agonist by promoting bivalent EphA2 oligomerization and autophosphorylation, confirmed by quantitative FRET in live cells.","method":"X-ray crystallography (1.53–2.20 Å resolution), quantitative FRET in live cells, receptor autophosphorylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structures plus live-cell FRET and phosphorylation assays, multiple orthogonal methods in single study","pmids":["31015204"],"is_preprint":false},{"year":2019,"finding":"EphA2 regulates PTGS2 (COX-2) expression downstream through TGFβ signaling; EPHA2 deletion in pancreatic tumors reversed T cell exclusion and sensitized tumors to immunotherapy, and PTGS2 deletion recapitulated this phenotype.","method":"EPHA2 and PTGS2 genetic deletion in mouse tumor models, T cell infiltration analysis, immunotherapy combination experiments","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via parallel KO of EPHA2 and PTGS2 with defined immune phenotype readout, single lab","pmids":["31162144"],"is_preprint":false},{"year":2019,"finding":"Crystal structures of KSHV gHgL and EBV gHgL in complex with the EphA2 ligand-binding domain (LBD) show both viral glycoproteins bind the channel and peripheral regions of the LBD primarily using gL; binding was verified by cell-based fusion assays with mutations in key EphA2 residues.","method":"X-ray crystallography, surface plasmon resonance/affinity measurements, cell-based fusion assay with site-directed mutagenesis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with functional validation by mutagenesis in cell-based assay, multiple orthogonal methods","pmids":["33235207"],"is_preprint":false},{"year":2020,"finding":"ANXA1 competes with Cbl for binding to EphA2, inhibiting Cbl-mediated EphA2 ubiquitination and proteasomal degradation, thereby stabilizing EphA2 and increasing its oncogenic S897 phosphorylation in nasopharyngeal carcinoma.","method":"Co-immunoprecipitation, ubiquitination assay, protein stability assay, ANXA1 peptide competition, in vivo xenograft","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, and domain-mapping peptide competition, single lab","pmids":["32737118"],"is_preprint":false},{"year":2020,"finding":"RSK1/2 phosphorylates EphA2 at Ser897 in response to chemotherapy (cisplatin/carboplatin), driving an oncogenic ERK1/2-RSK1/2-EphA2-GPRC5A signaling switch; pharmacological RSK inhibition prevents EphA2-S897 phosphorylation and shifts signaling to canonical tumor-suppressive tyrosine phosphorylation with EphA2 downregulation.","method":"Patient tumor analysis, pharmacological RSK inhibition, siRNA knockdown, phospho-specific Western blot","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic inhibition with phospho-site readout in patient material and cell lines, single lab","pmids":["32115889"],"is_preprint":false},{"year":2020,"finding":"PIP2 promotes EphA2 transmembrane domain dimerization specifically in the small crossing-angle (ligand-independent) conformation, likely by alleviating electrostatic repulsion from juxtamembrane positively charged segments; this suggests PIP2 directly regulates EphA2 activation in the ligand-independent state.","method":"Hydrophobic matching peptide system, styrene maleic acid lipid particles single-molecule dimerization assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — novel biophysical assay with conformational specificity, single lab","pmids":["33277361"],"is_preprint":false},{"year":2020,"finding":"EphA2 forms a protein complex with pendrin (SLC26A4), controlling pendrin localization. Ephrin-B2 binding to EphA2 triggers EphA2 autophosphorylation and co-internalization with pendrin. EphA2 mutants found in Pendred syndrome patients attenuate ephrin-B2-induced but not ephrin-A1-induced EphA2 internalization with pendrin.","method":"Co-immunoprecipitation, internalization assay, autophosphorylation assay, patient mutation characterization","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of complex plus functional internalization assay and patient mutation validation, single lab","pmids":["32165640"],"is_preprint":false},{"year":2020,"finding":"EphA2 directly binds NLRP3 and phosphorylates it at Tyr132, interfering with ASC speck formation and blocking NLRP3-inflammasome activation in airway epithelial cells during reovirus infection.","method":"Co-immunoprecipitation, phospho-specific Western blot, inflammasome activation assay, EphA2-/- mouse model, ASC speck formation assay","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP of EphA2-NLRP3 complex with site-specific phosphorylation mapping and in vivo genetic KO validation, multiple orthogonal methods","pmids":["32352641"],"is_preprint":false},{"year":2021,"finding":"EphA2 phosphorylates YES1 kinase, which in turn phosphorylates ANXA2 at Tyr24, increasing ANXA2 nuclear distribution and driving gastric cancer invasion/migration; reexpression of ANXA2-Tyr24F mutant fails to rescue YES1-induced invasion, establishing the phosphorylation site's requirement.","method":"Co-immunoprecipitation, phospho-specific Western blot, knockdown-rescue with wild-type vs. Tyr24F ANXA2 mutant, in vitro migration/invasion assays, mouse xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis-based epistasis with co-IP and in vivo validation, single lab","pmids":["33941853"],"is_preprint":false},{"year":2021,"finding":"Accumulation of multiple negative charges in the EphA2 kinase-SAM linker (mimicking phosphorylation) induces cooperative conformational changes from closed to extended in the intracellular region, perturbs the juxtamembrane and kinase domains, and promotes EphA2 oligomerization in cells. Multiple kinases catalyze linker phosphorylation.","method":"Integrative structural biology (NMR, SAXS, crystallography), phosphomimetic mutagenesis, FRET-based oligomerization assay in cells, kinase identification assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — integrative structural biology with multiple biophysical methods plus cell-based functional validation, multiple orthogonal approaches in single study","pmids":["34857764"],"is_preprint":false},{"year":2021,"finding":"EphA2 interacts with and phosphorylates YAP, leading to YAP stabilization, nuclear translocation, and activation in gastric cancer cells; EphA2-induced YAP activity drives chemotherapy resistance and tumor growth.","method":"Co-immunoprecipitation, nuclear fractionation, YAP phosphorylation assay, YAP knockdown in EphA2-overexpressing xenograft models","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, fractionation, and in vivo rescue, single lab","pmids":["31376289"],"is_preprint":false},{"year":2023,"finding":"Ligand-free EphA2 assembles into multimers through two types of ectodomain interactions: (1) extended symmetric interactions required for ligand-induced clustering and tumor-suppressive signaling (inhibiting ERK/AKT, suppressing migration), and (2) asymmetric interactions between the amino terminus and membrane-proximal domain of neighboring receptors supporting oncogenic signaling and promoting migration and tumor invasiveness.","method":"Time-resolved live-cell fluorescence spectroscopy, mutagenesis of ectodomain interactions, cell migration assays, in vivo tumor invasiveness model","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — novel quantitative live-cell spectroscopy with domain-specific mutagenesis and both in vitro and in vivo functional validation","pmids":["37972196"],"is_preprint":false},{"year":2024,"finding":"USP3 deubiquitinase binds EPHA2 (via its F2 domain, with amino acid 203 critical) and reduces EphA2 protein degradation, leading to activation of the PI3K/AKT signaling pathway in osteosarcoma; EphA2 knockdown reverses the pro-tumor effects of USP3 overexpression.","method":"Co-immunoprecipitation, USP3 truncation mutant mapping, Western blot for ubiquitination and AKT signaling, knockdown-rescue experiments, in vivo tumor model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping and functional rescue, single lab","pmids":["38531846"],"is_preprint":false},{"year":2006,"finding":"Loss of EphA2 in mouse skin increases susceptibility to chemical carcinogenesis with enhanced tumor frequency, shortened latency, and faster growth; ephrin-A1 stimulation suppresses keratinocyte proliferation and inhibits ERK1/2 activities in wild-type but not EphA2-null keratinocytes, indicating ERK inhibition is one mechanism of EphA2 tumor suppression.","method":"EphA2 knockout mouse in two-stage skin carcinogenesis model (DMBA/TPA), primary keratinocyte ephrin-A1 stimulation, ERK1/2 activity assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in vivo with primary cell mechanistic follow-up, single lab","pmids":["16849550"],"is_preprint":false},{"year":2022,"finding":"EGF stimulation induces binding of the RR domain of EGFR to the kinase domain of EphA2, and this interaction is promoted by Ephexin1 and by AKT-mediated Ser897 phosphorylation of EphA2; EGFR mutations L858R and T790M also promote EphA2 binding in an Ephexin1-dependent manner.","method":"Co-immunoprecipitation with domain mapping, phospho-mutant analysis, patient tissue analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP with domain and mutant analysis, but limited functional follow-up in abstract, single lab","pmids":["35668076"],"is_preprint":false},{"year":2023,"finding":"CLDN1 directly interacts with EphA2 via its PDZ-binding motif, increases EphA2 protein expression by inhibiting its degradation, and enhances downstream AKT signaling and CD44 expression to promote cancer stemness and chemoresistance in colorectal cancer.","method":"Co-immunoprecipitation, biophysical binding assays, proteomics, mutagenesis of PDZ-binding motif, patient-derived organoids","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding and functional methods including patient organoids, single lab","pmids":["37924938"],"is_preprint":false}],"current_model":"EphA2 is a receptor tyrosine kinase that signals through two opposing pathways: a canonical ligand-dependent pathway (ephrin-A binding triggers autophosphorylation, SHP2/FAK dephosphorylation, integrin inactivation, ERK/PI3K activation via SHC-GRB2, Arf6 suppression via Nck1-Git1, and tumor suppression) and a noncanonical ligand-independent pathway driven by Ser897 phosphorylation (by AKT, RSK, and PKA) that promotes migration via Ephexin4-RhoG-Rac and EGFR/Ephexin1 complexes; receptor oligomeric state—determined by ectodomain symmetric vs. asymmetric interactions, SAM domain inhibition, TM domain conformation regulated by PIP2, and linker phosphorylation—dictates which pathway predominates, while protein stability is regulated by Cbl-mediated ubiquitination (opposed by ANXA1 and USP3), and the receptor additionally functions as a PRR for fungal β-glucans and an entry receptor for multiple pathogens."},"narrative":{"mechanistic_narrative":"EphA2 is a receptor tyrosine kinase that operates as a bidirectional signaling hub controlling cell adhesion, migration, and proliferation, with opposing outputs determined by its activation mode [PMID:8139691, PMID:37972196]. In the canonical ligand-dependent pathway, binding of GPI-anchored ephrin-A1 (B61) induces receptor autophosphorylation [PMID:8139691, PMID:7890684] and engages downstream effectors: the p85 subunit of PI3K binds the cytoplasmic domain via its SH2 module [PMID:7982920], an SHC-GRB2 complex drives ERK nuclear translocation and Elk-1 activation [PMID:12400011], and rapid recruitment of SHP2 dephosphorylates FAK and paxillin to inactivate integrins and suppress spreading and migration [PMID:10655584]. Ligand engagement also drives Nck1-mediated recruitment of Git1 to suppress Arf6 and promote E-cadherin-based cell compaction [PMID:19193766], and inhibits ERK to restrain proliferation, accounting for its tumor-suppressive role in skin carcinogenesis [PMID:16849550]. A noncanonical, ligand-independent pathway is driven by Ser897 phosphorylation, catalyzed by PKA via the β2-adrenoceptor/cAMP axis [PMID:27385333], by RSK1/2 in response to chemotherapy [PMID:32115889], and downstream of AKT [PMID:35668076]; Ser897-phosphorylated EphA2 acts through the RhoG GEF Ephexin4, which assembles ELMO2 and the Rac GEF Dock4 to drive migration, invasion, and anoikis resistance [PMID:20679435, PMID:21621533], and forms EGFR-Ephexin1 complexes [PMID:35668076]. These opposing outputs are dictated by receptor oligomeric state: unliganded monomers favor pro-tumorigenic signaling [PMID:26363067], symmetric ectodomain interactions support tumor-suppressive clustering whereas asymmetric interactions drive oncogenic migration [PMID:37972196], the SAM domain restrains dimerization and kinase activation [PMID:27776928, PMID:28338017], PIP2 promotes transmembrane dimerization in the ligand-independent conformation [PMID:33277361], and negative charge in the kinase-SAM linker triggers a closed-to-extended conformational switch promoting oligomerization [PMID:34857764]. Receptor abundance is set by Cbl-mediated ubiquitination and degradation, which requires kinase activity [PMID:12147253] and is antagonized by ANXA1 [PMID:32737118], USP3 [PMID:38531846], and CLDN1 [PMID:37924938] to stabilize EphA2 and amplify oncogenic AKT signaling. EphA2 additionally functions as a pattern recognition receptor for fungal β-glucans, activating STAT3/MAPK and IL-17 immunity [PMID:29133884], phosphorylates NLRP3 at Tyr132 to block inflammasome activation [PMID:32352641], and serves as an entry/signaling receptor co-opted by Chlamydia trachomatis [PMID:25906164], Cryptococcus neoformans [PMID:29197141], and herpesviruses KSHV and EBV [PMID:33235207].","teleology":[{"year":1994,"claim":"Establishing the ligand for EphA2 (then ECK) defined it as a functional receptor tyrosine kinase and opened mechanistic study of its signaling.","evidence":"Receptor affinity chromatography, SPR, and autophosphorylation assays identifying B61/ephrin-A1, including its GPI-anchored cell-surface form","pmids":["8139691","7890684"],"confidence":"High","gaps":["Did not resolve downstream effectors","Did not address oligomeric requirements for activation"]},{"year":1994,"claim":"Identifying p85/PI3K and the adapter SLAP as binders of the activated cytoplasmic domain began mapping the proximal signaling complex.","evidence":"Yeast two-hybrid, GST pulldown, co-IP, and PI3K activity assays in ligand-activated cells","pmids":["7982920","7543898"],"confidence":"Medium","gaps":["SLAP function downstream of EphA2 not established","Phosphosites mediating these interactions not defined here"]},{"year":2000,"claim":"Defining the SHP2-FAK axis showed how ligand-activated EphA2 inactivates integrins and suppresses adhesion and migration, the basis of its anti-migratory output.","evidence":"Co-IP, kinase/phosphorylation assays, and integrin conformation and migration assays with endogenous EphA2","pmids":["10655584"],"confidence":"High","gaps":["Direct phosphatase substrate specificity not dissected","Link to oligomeric state not addressed"]},{"year":2001,"claim":"Placing EphA2 as a p53-family transcriptional target connected its expression to DNA-damage responses and apoptosis.","evidence":"Promoter/reporter assays with a p53 response element and inducible expression with apoptosis readout","pmids":["11641774"],"confidence":"Medium","gaps":["In vivo relevance of p53-EphA2 axis untested","Mechanism linking EphA2 to apoptosis not resolved"]},{"year":2002,"claim":"Identifying the SHC-GRB2-ERK and Cbl-ubiquitination modules established both a positive transcriptional effector arm and a negative stability control on EphA2.","evidence":"Co-IP with domain mapping, Elk-1 reporter assays, and Cbl/EphA2 mutagenesis","pmids":["12400011","12147253"],"confidence":"Medium","gaps":["Kinetics of ERK activation versus degradation not integrated","Cbl ubiquitination sites on EphA2 not mapped"]},{"year":2005,"claim":"Demonstrating that kinase activity is required for tumor promotion and RhoA activation linked EphA2 catalytic function to invasive phenotypes in vivo.","evidence":"Kinase-dead and domain-deletion mutants in xenograft/metastasis models with RhoA and migration assays","pmids":["16103880"],"confidence":"High","gaps":["Did not distinguish tyrosine versus serine phosphorylation contributions","RhoA GEF not identified"]},{"year":2006,"claim":"Genetic loss-of-function in mouse skin revealed a tumor-suppressive role for EphA2 via ERK inhibition, contrasting with its pro-tumor kinase functions.","evidence":"EphA2 knockout in DMBA/TPA carcinogenesis with keratinocyte ERK1/2 assays","pmids":["16849550"],"confidence":"Medium","gaps":["Reconciliation of suppressor versus oncogenic outputs left unresolved","Tissue-context dependence not explained mechanistically"]},{"year":2009,"claim":"The Nck1-Git1-Arf6 module showed how phospho-Tyr594 EphA2 controls E-cadherin junctions and epithelial compaction.","evidence":"Reciprocal co-IP, domain mapping, phospho-mutants, and Arf6 activity assays in MDCK cells","pmids":["19193766"],"confidence":"High","gaps":["In vivo relevance of Arf6 suppression not tested","Crosstalk with SHP2/FAK arm not addressed"]},{"year":2010,"claim":"Linking elevated EphA2 and Src-driven phosphorylation to trastuzumab resistance gave a therapeutic context to EphA2 signaling amplification.","evidence":"Western blot, Src kinase assays, siRNA, and trastuzumab xenografts","pmids":["20028874"],"confidence":"Medium","gaps":["Specific Src-targeted EphA2 sites not mapped","Single resistance context"]},{"year":2011,"claim":"Defining Ephexin4-RhoG signaling established the ligand-independent migratory and anoikis-resistance arm of EphA2.","evidence":"Co-IP, GEF activity assays, knockdown-rescue, and migration/invasion/anoikis assays defining the RhoG-ELMO2-Dock4-Rac axis","pmids":["20679435","21621533"],"confidence":"High","gaps":["Trigger for ligand-independent Ephexin4 recruitment not defined here","Relationship to Ser897 not yet established"]},{"year":2013,"claim":"An Epha2-null lens phenotype connected EphA2 to Src/cortactin/F-actin organization and junctional E-cadherin in epithelial morphogenesis in vivo.","evidence":"Knockout mouse with phospho-specific immunofluorescence and confocal imaging","pmids":["24026120"],"confidence":"Medium","gaps":["Direct versus indirect control of Src at vertices unresolved","Kinase dependence not tested"]},{"year":2014,"claim":"Reconstitution showed that spatial reorganization at cell-cell contacts governs trans-endocytosis of ephrinA1, linking receptor clustering geometry to internalization.","evidence":"Supported lipid bilayer reconstitution with 3D fluorescence trans-endocytosis assays","pmids":["24853748"],"confidence":"Medium","gaps":["Cellular machinery of internalization not identified","Signaling consequences of endocytosis not measured"]},{"year":2015,"claim":"Quantitative biophysics and pathogen studies established that unliganded EphA2 dimerizes and that the monomer favors pro-tumorigenic Ser897 signaling, while its cytoplasmic domain is exploited by Chlamydia for PI3K/Akt-driven replication.","evidence":"FRET dimerization with mutagenesis and migration assays; domain-deletion mutants in Chlamydia infection and PI3K/Akt assays","pmids":["26363067","25906164"],"confidence":"Medium","gaps":["Structural basis of monomer-biased signaling not resolved","Pathogen ligand on EphA2 not defined"]},{"year":2016,"claim":"Multiple studies converged on oligomeric-state control: the SAM domain restrains dimerization/kinase activity, while PKA Ser897 phosphorylation and progranulin binding diversify EphA2 inputs.","evidence":"FRET and fluorescence correlation spectroscopy with SAM deletion; pharmacological PKA dissection with phospho-specific assays; progranulin binding and capillary morphogenesis assays; plus EphA2 kinase-domain inhibitor co-crystal structures","pmids":["27776928","28338017","27385333","27903606","27768280"],"confidence":"High","gaps":["How SAM and Ser897 inputs are integrated not resolved","Progranulin binding site on EphA2 not mapped"]},{"year":2017,"claim":"Identifying EphA2 as a β-glucan pattern recognition receptor extended its role beyond development and cancer into innate antifungal immunity.","evidence":"EphA2-/- mice, β-glucan binding, STAT3/MAPK assays, and oropharyngeal candidiasis model","pmids":["29133884"],"confidence":"High","gaps":["β-glucan binding interface on EphA2 not structurally defined","Coreceptor requirements not established"]},{"year":2018,"claim":"BBB transmigration and membrane-simulation studies tied EphA2 phosphorylation and PIP lipid interactions to barrier permeability and kinase-domain orientation.","evidence":"CD44-dependent transmigration assays with EphA2 perturbation; molecular dynamics and biochemical membrane interaction studies","pmids":["29197141","29887500"],"confidence":"Medium","gaps":["MD predictions on PIP nanoclusters await direct structural confirmation","Mechanism of CD44-EphA2 coupling not defined"]},{"year":2019,"claim":"Structural and genetic work defined the ephrin-binding pocket as a drug target, established viral glycoprotein recognition, and linked EphA2 to immune evasion via PTGS2.","evidence":"YSA peptide co-crystal structures with FRET/autophosphorylation; KSHV/EBV gHgL-LBD structures with fusion assays; EPHA2/PTGS2 epistasis in tumor immunotherapy models","pmids":["31015204","33235207","31162144"],"confidence":"High","gaps":["TGFβ-PTGS2 mechanistic link downstream of EphA2 not fully resolved","Generalizability of viral binding mode across herpesviruses untested"]},{"year":2020,"claim":"Multiple studies resolved stability and conformational control (ANXA1 versus Cbl, PIP2-driven TM dimerization), the EphA2-pendrin complex underlying Pendred syndrome, RSK-driven Ser897 signaling, and NLRP3 inflammasome suppression, broadening EphA2's mechanistic and disease roles.","evidence":"Co-IP/ubiquitination/stability assays; single-molecule TM dimerization assays; pendrin co-internalization with patient mutations; RSK pharmacology with phospho-readout; EphA2-NLRP3 phosphosite mapping with KO mouse","pmids":["32737118","33277361","32165640","32115889","32352641"],"confidence":"High","gaps":["Integration of stability control with oligomeric-state switching incomplete","Direct NLRP3 phosphorylation effect in vivo across diseases not generalized"]},{"year":2021,"claim":"Substrate identification (YES1-ANXA2, YAP) and integrative structural analysis of the kinase-SAM linker connected EphA2 catalytic output to invasion/chemoresistance and defined a conformational switch driving oligomerization.","evidence":"Co-IP with phosphosite mutagenesis and rescue, nuclear fractionation, xenografts; NMR/SAXS/crystallography with phosphomimetics and FRET","pmids":["33941853","31376289","34857764"],"confidence":"High","gaps":["Direct versus indirect YAP phosphorylation not fully resolved","Identity of all linker-phosphorylating kinases not enumerated"]},{"year":2022,"claim":"Defining the EGFR-EphA2 interaction promoted by Ephexin1 and Ser897 phosphorylation linked receptor crosstalk to oncogenic EGFR mutations.","evidence":"Co-IP with domain mapping, phospho-mutant analysis, and patient tissue analysis","pmids":["35668076"],"confidence":"Medium","gaps":["Functional output of the EGFR-EphA2 complex not quantified","Single co-IP-based study with limited functional follow-up"]},{"year":2023,"claim":"Distinguishing symmetric versus asymmetric ectodomain interactions provided a unifying structural basis for the switch between tumor-suppressive and oncogenic EphA2 signaling.","evidence":"Time-resolved live-cell fluorescence spectroscopy with ectodomain mutagenesis, migration assays, and in vivo invasiveness; plus CLDN1 PDZ-motif binding stabilizing EphA2","pmids":["37972196","37924938"],"confidence":"High","gaps":["How specific ligands and stabilizers bias the symmetric/asymmetric equilibrium not fully mapped"]},{"year":2024,"claim":"USP3 was identified as a deubiquitinase that stabilizes EphA2 to drive PI3K/AKT signaling, adding to the network of stability regulators counteracting Cbl.","evidence":"Co-IP with truncation mapping, ubiquitination and AKT assays, knockdown-rescue, and in vivo tumor model","pmids":["38531846"],"confidence":"Medium","gaps":["DUB site specificity on EphA2 not mapped","Interplay with ANXA1/CLDN1 stabilizers not tested"]},{"year":null,"claim":"How the diverse stabilizers, kinases, lipids, and ectodomain interaction modes are quantitatively integrated to set the symmetric/asymmetric oligomeric balance and thereby select tumor-suppressive versus oncogenic output in a given tissue context remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified quantitative model linking oligomeric state to signaling output","Tissue-specific determinants of suppressor-versus-oncogene behavior unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,4,32,33,35]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[8,16]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[15,27,23]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[22]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,20,36]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4,14,36]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[14,31]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,4,6,11,36]},{"term_id":"R-HSA-168256","term_label":"Immune 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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. Activated by the ligand ephrin-A1/EFNA1 regulates migration, integrin-mediated adhesion, proliferation and differentiation of cells. Regulates cell adhesion and differentiation through DSG1/desmoglein-1 and inhibition of the ERK1/ERK2 (MAPK3/MAPK1, respectively) signaling pathway. May also participate in UV radiation-induced apoptosis and have a ligand-independent stimulatory effect on chemotactic cell migration. During development, may function in distinctive aspects of pattern formation and subsequently in development of several fetal tissues. Involved for instance in angiogenesis, in early hindbrain development and epithelial proliferation and branching morphogenesis during mammary gland development. Engaged by the ligand ephrin-A5/EFNA5 may regulate lens fiber cells shape and interactions and be important for lens transparency development and maintenance. With ephrin-A2/EFNA2 may play a role in bone remodeling through regulation of osteoclastogenesis and osteoblastogenesis (Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry. Mediates HCV entry by promoting the formation of the CD81-CLDN1 receptor complexes that are essential for HCV entry and by enhancing membrane fusion of cells expressing HCV envelope glycoproteins Acts as a receptor for human cytomegalovirus (HCMV) to mediate viral entry and fusion in glioblastoma cells","subcellular_location":"Cell membrane; Cell projection, ruffle membrane; Cell projection, lamellipodium membrane; Cell junction, focal adhesion","url":"https://www.uniprot.org/uniprotkb/P29317/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EPHA2","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/EPHA2","total_profiled":1310},"omim":[{"mim_id":"618871","title":"RHO GUANINE NUCLEOTIDE EXCHANGE FACTOR 16; ARHGEF16","url":"https://www.omim.org/entry/618871"},{"mim_id":"611624","title":"NECAP ENDOCYTOSIS-ASSOCIATED PROTEIN 2; NECAP2","url":"https://www.omim.org/entry/611624"},{"mim_id":"611258","title":"TUDOR DOMAIN-CONTAINING PROTEIN 7; TDRD7","url":"https://www.omim.org/entry/611258"},{"mim_id":"611162","title":"MALARIA, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/611162"},{"mim_id":"609532","title":"HEPATITIS C VIRUS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/609532"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Additional"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":142.7}],"url":"https://www.proteinatlas.org/search/EPHA2"},"hgnc":{"alias_symbol":[],"prev_symbol":["ECK"]},"alphafold":{"accession":"P29317","domains":[{"cath_id":"2.60.120.260","chopping":"25-200","consensus_level":"high","plddt":87.7027,"start":25,"end":200},{"cath_id":"2.60.40.1770","chopping":"203-262","consensus_level":"medium","plddt":90.2922,"start":203,"end":262},{"cath_id":"2.60.40.10","chopping":"331-433","consensus_level":"high","plddt":91.9615,"start":331,"end":433},{"cath_id":"2.60.40.10","chopping":"440-524","consensus_level":"high","plddt":85.8553,"start":440,"end":524},{"cath_id":"3.30.200.20","chopping":"590-692","consensus_level":"high","plddt":85.0107,"start":590,"end":692},{"cath_id":"1.10.510.10","chopping":"697-886","consensus_level":"high","plddt":84.4113,"start":697,"end":886},{"cath_id":"1.10.150.50","chopping":"890-971","consensus_level":"high","plddt":67.8838,"start":890,"end":971}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P29317","model_url":"https://alphafold.ebi.ac.uk/files/AF-P29317-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P29317-F1-predicted_aligned_error_v6.png","plddt_mean":82.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EPHA2","jax_strain_url":"https://www.jax.org/strain/search?query=EPHA2"},"sequence":{"accession":"P29317","fasta_url":"https://rest.uniprot.org/uniprotkb/P29317.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P29317/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P29317"}},"corpus_meta":[{"pmid":"10655584","id":"PMC_10655584","title":"Activation 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\"Receptor affinity chromatography, surface plasmon resonance, autophosphorylation assay in intact cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical reconstitution (affinity purification + autophosphorylation assay), foundational ligand-receptor identification replicated by subsequent work\",\n      \"pmids\": [\"8139691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Activation of the ECK (EphA2) receptor stimulates phosphatidylinositol 3-kinase (PI3K) activity; the p85 subunit of PI3K binds the cytoplasmic domain of ECK via its C-terminal SH2 domain, and this interaction is confirmed by co-immunoprecipitation in ligand-activated cells.\",\n      \"method\": \"Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, PI3K activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods (Y2H, GST fusion, co-IP, enzymatic assay) in a single rigorous study\",\n      \"pmids\": [\"7982920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"B61/ephrin-A1 can exist as a GPI-linked cell-surface protein capable of activating the ECK (EphA2) receptor, representing the first GPI-linked ligand for a receptor protein-tyrosine kinase.\",\n      \"method\": \"Biochemical characterization, in situ hybridization, receptor activation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical characterization with functional validation, single lab\",\n      \"pmids\": [\"7890684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"SLAP (Src-like adapter protein), a novel protein with SH3 and SH2 adapter modules but no kinase domain, was identified as an interactor of activated ECK (EphA2) receptor via GST fusion protein binding.\",\n      \"method\": \"Yeast two-hybrid screen, GST pulldown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — two complementary binding methods (Y2H + GST pulldown), single lab, no functional follow-up in same paper\",\n      \"pmids\": [\"7543898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Activation of endogenous EphA2 kinase by ephrin-A1 induces an inactive conformation of integrins and inhibits cell spreading, migration and integrin-mediated adhesion. EphA2 is constitutively associated with FAK in resting cells; within one minute of ephrin-A1 stimulation, SHP2 is recruited to EphA2, followed by dephosphorylation of FAK and paxillin, and dissociation of the FAK-EphA2 complex.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, cell spreading/migration assays, integrin conformation assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, kinase assay, functional cellular assays), mechanistically detailed, widely replicated in subsequent literature\",\n      \"pmids\": [\"10655584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"EphA2 is a transcriptional target of the p53 family (p53, p73, p63); a p53 response element in the EphA2 promoter is responsive to wild-type p53, p73, and p63 but not mutant p53. EphA2 induction correlates with p53 activation after DNA damage, and forced EphA2 expression increases apoptosis.\",\n      \"method\": \"Promoter analysis, reporter assay, Western blot, stable inducible cell lines, apoptosis assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter/reporter assay identifies p53 response element, inducible expression system links EphA2 to apoptosis, single lab\",\n      \"pmids\": [\"11641774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Ligand stimulation of EphA2 promotes ERK kinase nuclear translocation and phosphorylation, and activation of the Elk-1 transcription factor. EphA2 forms a molecular complex with SHC (via PTB and SH2 domains) and GRB2 (indirectly via SHC), and this complex is required for EphA2-mediated ERK activation.\",\n      \"method\": \"Co-immunoprecipitation, Western blot for nuclear translocation, Elk-1 reporter assay, domain mapping with SHC mutants\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping and functional readout (ERK activation/Elk-1), single lab\",\n      \"pmids\": [\"12400011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"EphA2 is negatively regulated by the ubiquitin ligase Cbl; kinase-active EphA2 recruits Cbl via Cbl's TKB domain and the RING finger domain of Cbl is required for its negative regulatory function. Kinase-inactive EphA2 cannot be regulated by Cbl.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis (G306E-Cbl, 70Z-Cbl dominant negative, kinase-inactive EphA2), Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of both receptor and E3 ligase with domain requirements established, single lab\",\n      \"pmids\": [\"12147253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"EphA2 receptor kinase activity and phosphorylation are required for its tumor-promoting functions; kinase-dead or cytoplasmic-domain-deleted EphA2 mutants reduce tumor volume, increase apoptosis, reduce lung metastases, and abolish RhoA GTPase activation and cell migration in breast cancer models.\",\n      \"method\": \"Site-directed mutagenesis, in vivo xenograft and metastasis models, RhoA activation assay, cell migration assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis with multiple in vivo and in vitro functional readouts, identifies RhoA as downstream effector\",\n      \"pmids\": [\"16103880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"EphA2 engages Git1 via Nck1 to suppress Arf6 activity and regulate E-cadherin-based cell-cell adhesion. Ligand-activated EphA2 phosphorylated on Tyr594 binds the SH2 domain of Nck1, which via its SH3 domain recruits Git1 to suppress Arf6 activity, inducing cell compaction and polarization.\",\n      \"method\": \"Co-immunoprecipitation, Arf6 activity assay, domain mapping, phospho-mutant analysis, MDCK cell density/calcium experiments\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, domain mapping with phospho-site identification, functional Arf6 activity assay, multiple orthogonal methods\",\n      \"pmids\": [\"19193766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Trastuzumab resistance in breast cancer cells is mediated by elevated EphA2; trastuzumab treatment promotes EphA2 phosphorylation by activating Src kinase, which amplifies PI3K/Akt and MAPK signaling in resistant cells.\",\n      \"method\": \"Western blot, Src kinase assay, siRNA knockdown, in vivo xenograft with trastuzumab treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling assays and in vivo validation, identifies Src as writer of EphA2 phosphorylation in resistance context, single lab\",\n      \"pmids\": [\"20028874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Ephexin4 is a guanine nucleotide exchange factor for RhoG that interacts with EphA2 in breast cancer cells and acts downstream of EphA2 to promote ligand-independent cell migration and invasion via RhoG activation. RhoG recruits effector ELMO2 and Rac GEF Dock4 to form a complex with EphA2, and Dock4-mediated Rac activation is required for migration.\",\n      \"method\": \"Co-immunoprecipitation, GEF activity assay, knockdown-rescue experiments, cell migration/invasion assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockdown-rescue with GEF activity assay and complex characterization by co-IP, multiple orthogonal methods, clearly defines pathway\",\n      \"pmids\": [\"20679435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Ephexin4 mediates resistance to anoikis downstream of EphA2 through activation of RhoG and PI3K/Akt; Ephexin4 knockdown promotes anoikis with decreased RhoG activity and Akt phosphorylation in suspended cells.\",\n      \"method\": \"RhoG activity assay, Akt phosphorylation assay, siRNA knockdown, anoikis assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with functional readout and signaling pathway placed, single lab\",\n      \"pmids\": [\"21621533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EphA2 and Src cooperate in equatorial lens cell morphogenesis; EphA2 regulates Src/cortactin/F-actin complexes at cell vertices of hexagonal epithelial cells. Loss of EphA2 abolishes phosphorylated Src-Y424 and cortactin-Y466 at cell vertices, disrupts F-actin distribution, and leads to mislocalized E-cadherin junctions.\",\n      \"method\": \"Epha2-/- mouse model, immunofluorescence, phospho-specific antibodies, confocal microscopy\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined cellular and molecular phenotype, multiple readouts, single lab\",\n      \"pmids\": [\"24026120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Spatial organization of EphA2 at the cell-cell interface modulates trans-endocytosis of ephrinA1; EphA2-ephrinA1 trans-endocytosis is sensitive to lateral reorganization and is not efficiently internalized when spatial reorganization at contact sites is physically hindered.\",\n      \"method\": \"Supported lipid bilayer reconstitution, 3D fluorescence microscopy trans-endocytosis assay, receptor clustering analysis\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biophysical reconstitution with quantitative assay, single lab but rigorous methodology\",\n      \"pmids\": [\"24853748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EphA2 is a cell-surface receptor and intracellular signaling receptor for Chlamydia trachomatis; C. trachomatis activates EphA2, inducing PI3K/Akt signaling via the p85 subunit, promoting chlamydial replication. EphA2 lacking the intracellular cytoplasmic domain does not enhance PI3K activation or infection.\",\n      \"method\": \"siRNA knockdown, overexpression of wild-type vs. cytoplasmic-domain-deleted mutant, PI3K/Akt assays, infection quantification\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain deletion mutant distinguishes extracellular from intracellular functions, multiple infection and signaling assays, single lab\",\n      \"pmids\": [\"25906164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Unliganded EphA2 forms dimers in the plasma membrane; a dimerization-deficient EphA2 mutant shows enhanced cell migration with increased Ser897 phosphorylation and decreased tyrosine phosphorylation, indicating that EphA2 pro-tumorigenic activity is mediated by the EphA2 monomer.\",\n      \"method\": \"FRET-based dimerization assay in HEK293T cells, mutagenesis, Western blot for phosphorylation, cell migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative FRET with mutagenesis and functional readout, single lab\",\n      \"pmids\": [\"26363067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The EphA2 SAM domain inhibits receptor dimerization and decreases tyrosine phosphorylation; SAM domain deletion increases EphA2 oligomerization and constitutive kinase activation, as shown by FRET and phosphorylation assays.\",\n      \"method\": \"FRET-based dimerization measurement, SAM domain deletion mutant, Western blot for tyrosine phosphorylation\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative FRET with mutant analysis, single lab, two orthogonal readouts\",\n      \"pmids\": [\"27776928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EphA2 SAM domain deletion induces constitutive kinase activation (elevated tyrosine autophosphorylation) and increases receptor oligomerization; ephrinA1 stimulation further increases oligomerization of SAM-deleted EphA2 to larger oligomers than wild-type.\",\n      \"method\": \"Fluorescence correlation spectroscopy in live cells, Western blot for tyrosine phosphorylation, multiple cell lines\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative live-cell spectroscopy with multiple cell lines and phosphorylation assays, single lab\",\n      \"pmids\": [\"28338017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Protein kinase A (PKA), activated via the β2-adrenoceptor/cAMP axis, phosphorylates EphA2 at Ser897 (and nearby Ser/Thr residues), and this S897 phosphorylation can coexist with EphA2 tyrosine phosphorylation and block ephrin-A1-induced cell retraction mediated by EphA2 kinase activity.\",\n      \"method\": \"High-content screening, phospho-specific Western blot, cAMP elevation, pharmacological PKA activation/inhibition, cell retraction assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection with phospho-site specific assays and functional cell readout, single lab\",\n      \"pmids\": [\"27385333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EphA2 is a functional signaling receptor for the growth factor progranulin; progranulin binds EphA2 with high affinity, causes prolonged receptor activation, stimulates MAPK and Akt downstream, and promotes capillary morphogenesis in an EphA2-dependent manner.\",\n      \"method\": \"Solid-phase and solution binding assays, Western blot for MAPK/Akt phosphorylation, capillary morphogenesis assay, EphA2 knockdown\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple binding assay formats, functional downstream signaling, loss-of-function confirmation, single lab with orthogonal methods\",\n      \"pmids\": [\"27903606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structures of 24 clinical kinase inhibitors bound to the EPHA2 kinase domain were determined; key, scaffold, potency, and selectivity residues in the ATP-binding site were defined, providing a structural classification system for EPHA2 inhibitor interactions.\",\n      \"method\": \"Chemical proteomics (kinase selectivity profiling), X-ray crystallography (9 co-crystal structures), NMR conformational dynamics\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple co-crystal structures with chemical proteomics validation and NMR, multiple orthogonal methods\",\n      \"pmids\": [\"27768280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EphA2 functions as a pattern recognition receptor (PRR) for fungal β-glucans on Candida albicans in oral epithelial cells; β-glucan binding to EphA2 activates STAT3 and MAPK signaling in an inoculum-dependent manner, and EphA2-/- mice show impaired inflammatory response and reduced IL-17 signaling during oropharyngeal candidiasis.\",\n      \"method\": \"EphA2-/- mouse model, β-glucan binding assay, STAT3/MAPK signaling assays, in vivo infection model\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mouse in vivo model combined with direct binding and signaling assays, replicated across in vitro and in vivo systems\",\n      \"pmids\": [\"29133884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"C. neoformans promotes EphA2 activity via CD44-dependent phosphorylation of EphA2 at the blood-brain barrier, inducing receptor clustering and internalization that creates a permeable barrier facilitating fungal transmigration.\",\n      \"method\": \"EphA2 silencing, chemical inhibition, EphA2 agonist treatment, HEK293T overexpression, in vitro BBB transmigration assay\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple perturbation approaches (siRNA, inhibitor, agonist, overexpression) with functional transmigration readout, single lab\",\n      \"pmids\": [\"29197141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Molecular dynamics simulations and biochemical studies reveal that PIP lipids interact with the EphA2 transmembrane, juxtamembrane, and kinase domains; positively charged patches on the kinase domain and juxtamembrane region induce nanoclusters of PIP molecules, and the kinase domain orientation relative to the membrane is modulated by the juxtamembrane region.\",\n      \"method\": \"Molecular dynamics simulation, biochemical membrane interaction studies\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — MD simulation with biochemical validation but limited experimental depth reported in abstract\",\n      \"pmids\": [\"29887500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structures of the YSA peptide and derivatives in complex with EphA2 LBD show YSA targets the ephrin-binding pocket of EphA2 mimicking ephrin-A ligand contacts. C-terminal modifications convert YSA from antagonist to agonist by promoting bivalent EphA2 oligomerization and autophosphorylation, confirmed by quantitative FRET in live cells.\",\n      \"method\": \"X-ray crystallography (1.53–2.20 Å resolution), quantitative FRET in live cells, receptor autophosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structures plus live-cell FRET and phosphorylation assays, multiple orthogonal methods in single study\",\n      \"pmids\": [\"31015204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EphA2 regulates PTGS2 (COX-2) expression downstream through TGFβ signaling; EPHA2 deletion in pancreatic tumors reversed T cell exclusion and sensitized tumors to immunotherapy, and PTGS2 deletion recapitulated this phenotype.\",\n      \"method\": \"EPHA2 and PTGS2 genetic deletion in mouse tumor models, T cell infiltration analysis, immunotherapy combination experiments\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via parallel KO of EPHA2 and PTGS2 with defined immune phenotype readout, single lab\",\n      \"pmids\": [\"31162144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structures of KSHV gHgL and EBV gHgL in complex with the EphA2 ligand-binding domain (LBD) show both viral glycoproteins bind the channel and peripheral regions of the LBD primarily using gL; binding was verified by cell-based fusion assays with mutations in key EphA2 residues.\",\n      \"method\": \"X-ray crystallography, surface plasmon resonance/affinity measurements, cell-based fusion assay with site-directed mutagenesis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with functional validation by mutagenesis in cell-based assay, multiple orthogonal methods\",\n      \"pmids\": [\"33235207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANXA1 competes with Cbl for binding to EphA2, inhibiting Cbl-mediated EphA2 ubiquitination and proteasomal degradation, thereby stabilizing EphA2 and increasing its oncogenic S897 phosphorylation in nasopharyngeal carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, protein stability assay, ANXA1 peptide competition, in vivo xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, and domain-mapping peptide competition, single lab\",\n      \"pmids\": [\"32737118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RSK1/2 phosphorylates EphA2 at Ser897 in response to chemotherapy (cisplatin/carboplatin), driving an oncogenic ERK1/2-RSK1/2-EphA2-GPRC5A signaling switch; pharmacological RSK inhibition prevents EphA2-S897 phosphorylation and shifts signaling to canonical tumor-suppressive tyrosine phosphorylation with EphA2 downregulation.\",\n      \"method\": \"Patient tumor analysis, pharmacological RSK inhibition, siRNA knockdown, phospho-specific Western blot\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic inhibition with phospho-site readout in patient material and cell lines, single lab\",\n      \"pmids\": [\"32115889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PIP2 promotes EphA2 transmembrane domain dimerization specifically in the small crossing-angle (ligand-independent) conformation, likely by alleviating electrostatic repulsion from juxtamembrane positively charged segments; this suggests PIP2 directly regulates EphA2 activation in the ligand-independent state.\",\n      \"method\": \"Hydrophobic matching peptide system, styrene maleic acid lipid particles single-molecule dimerization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — novel biophysical assay with conformational specificity, single lab\",\n      \"pmids\": [\"33277361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EphA2 forms a protein complex with pendrin (SLC26A4), controlling pendrin localization. Ephrin-B2 binding to EphA2 triggers EphA2 autophosphorylation and co-internalization with pendrin. EphA2 mutants found in Pendred syndrome patients attenuate ephrin-B2-induced but not ephrin-A1-induced EphA2 internalization with pendrin.\",\n      \"method\": \"Co-immunoprecipitation, internalization assay, autophosphorylation assay, patient mutation characterization\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of complex plus functional internalization assay and patient mutation validation, single lab\",\n      \"pmids\": [\"32165640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EphA2 directly binds NLRP3 and phosphorylates it at Tyr132, interfering with ASC speck formation and blocking NLRP3-inflammasome activation in airway epithelial cells during reovirus infection.\",\n      \"method\": \"Co-immunoprecipitation, phospho-specific Western blot, inflammasome activation assay, EphA2-/- mouse model, ASC speck formation assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP of EphA2-NLRP3 complex with site-specific phosphorylation mapping and in vivo genetic KO validation, multiple orthogonal methods\",\n      \"pmids\": [\"32352641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EphA2 phosphorylates YES1 kinase, which in turn phosphorylates ANXA2 at Tyr24, increasing ANXA2 nuclear distribution and driving gastric cancer invasion/migration; reexpression of ANXA2-Tyr24F mutant fails to rescue YES1-induced invasion, establishing the phosphorylation site's requirement.\",\n      \"method\": \"Co-immunoprecipitation, phospho-specific Western blot, knockdown-rescue with wild-type vs. Tyr24F ANXA2 mutant, in vitro migration/invasion assays, mouse xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis-based epistasis with co-IP and in vivo validation, single lab\",\n      \"pmids\": [\"33941853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Accumulation of multiple negative charges in the EphA2 kinase-SAM linker (mimicking phosphorylation) induces cooperative conformational changes from closed to extended in the intracellular region, perturbs the juxtamembrane and kinase domains, and promotes EphA2 oligomerization in cells. Multiple kinases catalyze linker phosphorylation.\",\n      \"method\": \"Integrative structural biology (NMR, SAXS, crystallography), phosphomimetic mutagenesis, FRET-based oligomerization assay in cells, kinase identification assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — integrative structural biology with multiple biophysical methods plus cell-based functional validation, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"34857764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EphA2 interacts with and phosphorylates YAP, leading to YAP stabilization, nuclear translocation, and activation in gastric cancer cells; EphA2-induced YAP activity drives chemotherapy resistance and tumor growth.\",\n      \"method\": \"Co-immunoprecipitation, nuclear fractionation, YAP phosphorylation assay, YAP knockdown in EphA2-overexpressing xenograft models\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, fractionation, and in vivo rescue, single lab\",\n      \"pmids\": [\"31376289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ligand-free EphA2 assembles into multimers through two types of ectodomain interactions: (1) extended symmetric interactions required for ligand-induced clustering and tumor-suppressive signaling (inhibiting ERK/AKT, suppressing migration), and (2) asymmetric interactions between the amino terminus and membrane-proximal domain of neighboring receptors supporting oncogenic signaling and promoting migration and tumor invasiveness.\",\n      \"method\": \"Time-resolved live-cell fluorescence spectroscopy, mutagenesis of ectodomain interactions, cell migration assays, in vivo tumor invasiveness model\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — novel quantitative live-cell spectroscopy with domain-specific mutagenesis and both in vitro and in vivo functional validation\",\n      \"pmids\": [\"37972196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP3 deubiquitinase binds EPHA2 (via its F2 domain, with amino acid 203 critical) and reduces EphA2 protein degradation, leading to activation of the PI3K/AKT signaling pathway in osteosarcoma; EphA2 knockdown reverses the pro-tumor effects of USP3 overexpression.\",\n      \"method\": \"Co-immunoprecipitation, USP3 truncation mutant mapping, Western blot for ubiquitination and AKT signaling, knockdown-rescue experiments, in vivo tumor model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping and functional rescue, single lab\",\n      \"pmids\": [\"38531846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Loss of EphA2 in mouse skin increases susceptibility to chemical carcinogenesis with enhanced tumor frequency, shortened latency, and faster growth; ephrin-A1 stimulation suppresses keratinocyte proliferation and inhibits ERK1/2 activities in wild-type but not EphA2-null keratinocytes, indicating ERK inhibition is one mechanism of EphA2 tumor suppression.\",\n      \"method\": \"EphA2 knockout mouse in two-stage skin carcinogenesis model (DMBA/TPA), primary keratinocyte ephrin-A1 stimulation, ERK1/2 activity assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in vivo with primary cell mechanistic follow-up, single lab\",\n      \"pmids\": [\"16849550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EGF stimulation induces binding of the RR domain of EGFR to the kinase domain of EphA2, and this interaction is promoted by Ephexin1 and by AKT-mediated Ser897 phosphorylation of EphA2; EGFR mutations L858R and T790M also promote EphA2 binding in an Ephexin1-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation with domain mapping, phospho-mutant analysis, patient tissue analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP with domain and mutant analysis, but limited functional follow-up in abstract, single lab\",\n      \"pmids\": [\"35668076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CLDN1 directly interacts with EphA2 via its PDZ-binding motif, increases EphA2 protein expression by inhibiting its degradation, and enhances downstream AKT signaling and CD44 expression to promote cancer stemness and chemoresistance in colorectal cancer.\",\n      \"method\": \"Co-immunoprecipitation, biophysical binding assays, proteomics, mutagenesis of PDZ-binding motif, patient-derived organoids\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding and functional methods including patient organoids, single lab\",\n      \"pmids\": [\"37924938\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EphA2 is a receptor tyrosine kinase that signals through two opposing pathways: a canonical ligand-dependent pathway (ephrin-A binding triggers autophosphorylation, SHP2/FAK dephosphorylation, integrin inactivation, ERK/PI3K activation via SHC-GRB2, Arf6 suppression via Nck1-Git1, and tumor suppression) and a noncanonical ligand-independent pathway driven by Ser897 phosphorylation (by AKT, RSK, and PKA) that promotes migration via Ephexin4-RhoG-Rac and EGFR/Ephexin1 complexes; receptor oligomeric state—determined by ectodomain symmetric vs. asymmetric interactions, SAM domain inhibition, TM domain conformation regulated by PIP2, and linker phosphorylation—dictates which pathway predominates, while protein stability is regulated by Cbl-mediated ubiquitination (opposed by ANXA1 and USP3), and the receptor additionally functions as a PRR for fungal β-glucans and an entry receptor for multiple pathogens.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EphA2 is a receptor tyrosine kinase that operates as a bidirectional signaling hub controlling cell adhesion, migration, and proliferation, with opposing outputs determined by its activation mode [#0, #36]. In the canonical ligand-dependent pathway, binding of GPI-anchored ephrin-A1 (B61) induces receptor autophosphorylation [#0, #2] and engages downstream effectors: the p85 subunit of PI3K binds the cytoplasmic domain via its SH2 module [#1], an SHC-GRB2 complex drives ERK nuclear translocation and Elk-1 activation [#6], and rapid recruitment of SHP2 dephosphorylates FAK and paxillin to inactivate integrins and suppress spreading and migration [#4]. Ligand engagement also drives Nck1-mediated recruitment of Git1 to suppress Arf6 and promote E-cadherin-based cell compaction [#9], and inhibits ERK to restrain proliferation, accounting for its tumor-suppressive role in skin carcinogenesis [#38]. A noncanonical, ligand-independent pathway is driven by Ser897 phosphorylation, catalyzed by PKA via the β2-adrenoceptor/cAMP axis [#19], by RSK1/2 in response to chemotherapy [#29], and downstream of AKT [#39]; Ser897-phosphorylated EphA2 acts through the RhoG GEF Ephexin4, which assembles ELMO2 and the Rac GEF Dock4 to drive migration, invasion, and anoikis resistance [#11, #12], and forms EGFR-Ephexin1 complexes [#39]. These opposing outputs are dictated by receptor oligomeric state: unliganded monomers favor pro-tumorigenic signaling [#16], symmetric ectodomain interactions support tumor-suppressive clustering whereas asymmetric interactions drive oncogenic migration [#36], the SAM domain restrains dimerization and kinase activation [#17, #18], PIP2 promotes transmembrane dimerization in the ligand-independent conformation [#30], and negative charge in the kinase-SAM linker triggers a closed-to-extended conformational switch promoting oligomerization [#34]. Receptor abundance is set by Cbl-mediated ubiquitination and degradation, which requires kinase activity [#7] and is antagonized by ANXA1 [#28], USP3 [#37], and CLDN1 [#40] to stabilize EphA2 and amplify oncogenic AKT signaling. EphA2 additionally functions as a pattern recognition receptor for fungal β-glucans, activating STAT3/MAPK and IL-17 immunity [#22], phosphorylates NLRP3 at Tyr132 to block inflammasome activation [#32], and serves as an entry/signaling receptor co-opted by Chlamydia trachomatis [#15], Cryptococcus neoformans [#23], and herpesviruses KSHV and EBV [#27].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing the ligand for EphA2 (then ECK) defined it as a functional receptor tyrosine kinase and opened mechanistic study of its signaling.\",\n      \"evidence\": \"Receptor affinity chromatography, SPR, and autophosphorylation assays identifying B61/ephrin-A1, including its GPI-anchored cell-surface form\",\n      \"pmids\": [\"8139691\", \"7890684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve downstream effectors\", \"Did not address oligomeric requirements for activation\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Identifying p85/PI3K and the adapter SLAP as binders of the activated cytoplasmic domain began mapping the proximal signaling complex.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, co-IP, and PI3K activity assays in ligand-activated cells\",\n      \"pmids\": [\"7982920\", \"7543898\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SLAP function downstream of EphA2 not established\", \"Phosphosites mediating these interactions not defined here\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defining the SHP2-FAK axis showed how ligand-activated EphA2 inactivates integrins and suppresses adhesion and migration, the basis of its anti-migratory output.\",\n      \"evidence\": \"Co-IP, kinase/phosphorylation assays, and integrin conformation and migration assays with endogenous EphA2\",\n      \"pmids\": [\"10655584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphatase substrate specificity not dissected\", \"Link to oligomeric state not addressed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Placing EphA2 as a p53-family transcriptional target connected its expression to DNA-damage responses and apoptosis.\",\n      \"evidence\": \"Promoter/reporter assays with a p53 response element and inducible expression with apoptosis readout\",\n      \"pmids\": [\"11641774\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of p53-EphA2 axis untested\", \"Mechanism linking EphA2 to apoptosis not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identifying the SHC-GRB2-ERK and Cbl-ubiquitination modules established both a positive transcriptional effector arm and a negative stability control on EphA2.\",\n      \"evidence\": \"Co-IP with domain mapping, Elk-1 reporter assays, and Cbl/EphA2 mutagenesis\",\n      \"pmids\": [\"12400011\", \"12147253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinetics of ERK activation versus degradation not integrated\", \"Cbl ubiquitination sites on EphA2 not mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating that kinase activity is required for tumor promotion and RhoA activation linked EphA2 catalytic function to invasive phenotypes in vivo.\",\n      \"evidence\": \"Kinase-dead and domain-deletion mutants in xenograft/metastasis models with RhoA and migration assays\",\n      \"pmids\": [\"16103880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not distinguish tyrosine versus serine phosphorylation contributions\", \"RhoA GEF not identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Genetic loss-of-function in mouse skin revealed a tumor-suppressive role for EphA2 via ERK inhibition, contrasting with its pro-tumor kinase functions.\",\n      \"evidence\": \"EphA2 knockout in DMBA/TPA carcinogenesis with keratinocyte ERK1/2 assays\",\n      \"pmids\": [\"16849550\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of suppressor versus oncogenic outputs left unresolved\", \"Tissue-context dependence not explained mechanistically\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The Nck1-Git1-Arf6 module showed how phospho-Tyr594 EphA2 controls E-cadherin junctions and epithelial compaction.\",\n      \"evidence\": \"Reciprocal co-IP, domain mapping, phospho-mutants, and Arf6 activity assays in MDCK cells\",\n      \"pmids\": [\"19193766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of Arf6 suppression not tested\", \"Crosstalk with SHP2/FAK arm not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linking elevated EphA2 and Src-driven phosphorylation to trastuzumab resistance gave a therapeutic context to EphA2 signaling amplification.\",\n      \"evidence\": \"Western blot, Src kinase assays, siRNA, and trastuzumab xenografts\",\n      \"pmids\": [\"20028874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific Src-targeted EphA2 sites not mapped\", \"Single resistance context\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defining Ephexin4-RhoG signaling established the ligand-independent migratory and anoikis-resistance arm of EphA2.\",\n      \"evidence\": \"Co-IP, GEF activity assays, knockdown-rescue, and migration/invasion/anoikis assays defining the RhoG-ELMO2-Dock4-Rac axis\",\n      \"pmids\": [\"20679435\", \"21621533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for ligand-independent Ephexin4 recruitment not defined here\", \"Relationship to Ser897 not yet established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"An Epha2-null lens phenotype connected EphA2 to Src/cortactin/F-actin organization and junctional E-cadherin in epithelial morphogenesis in vivo.\",\n      \"evidence\": \"Knockout mouse with phospho-specific immunofluorescence and confocal imaging\",\n      \"pmids\": [\"24026120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect control of Src at vertices unresolved\", \"Kinase dependence not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Reconstitution showed that spatial reorganization at cell-cell contacts governs trans-endocytosis of ephrinA1, linking receptor clustering geometry to internalization.\",\n      \"evidence\": \"Supported lipid bilayer reconstitution with 3D fluorescence trans-endocytosis assays\",\n      \"pmids\": [\"24853748\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular machinery of internalization not identified\", \"Signaling consequences of endocytosis not measured\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Quantitative biophysics and pathogen studies established that unliganded EphA2 dimerizes and that the monomer favors pro-tumorigenic Ser897 signaling, while its cytoplasmic domain is exploited by Chlamydia for PI3K/Akt-driven replication.\",\n      \"evidence\": \"FRET dimerization with mutagenesis and migration assays; domain-deletion mutants in Chlamydia infection and PI3K/Akt assays\",\n      \"pmids\": [\"26363067\", \"25906164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of monomer-biased signaling not resolved\", \"Pathogen ligand on EphA2 not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Multiple studies converged on oligomeric-state control: the SAM domain restrains dimerization/kinase activity, while PKA Ser897 phosphorylation and progranulin binding diversify EphA2 inputs.\",\n      \"evidence\": \"FRET and fluorescence correlation spectroscopy with SAM deletion; pharmacological PKA dissection with phospho-specific assays; progranulin binding and capillary morphogenesis assays; plus EphA2 kinase-domain inhibitor co-crystal structures\",\n      \"pmids\": [\"27776928\", \"28338017\", \"27385333\", \"27903606\", \"27768280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SAM and Ser897 inputs are integrated not resolved\", \"Progranulin binding site on EphA2 not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying EphA2 as a β-glucan pattern recognition receptor extended its role beyond development and cancer into innate antifungal immunity.\",\n      \"evidence\": \"EphA2-/- mice, β-glucan binding, STAT3/MAPK assays, and oropharyngeal candidiasis model\",\n      \"pmids\": [\"29133884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"β-glucan binding interface on EphA2 not structurally defined\", \"Coreceptor requirements not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"BBB transmigration and membrane-simulation studies tied EphA2 phosphorylation and PIP lipid interactions to barrier permeability and kinase-domain orientation.\",\n      \"evidence\": \"CD44-dependent transmigration assays with EphA2 perturbation; molecular dynamics and biochemical membrane interaction studies\",\n      \"pmids\": [\"29197141\", \"29887500\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MD predictions on PIP nanoclusters await direct structural confirmation\", \"Mechanism of CD44-EphA2 coupling not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Structural and genetic work defined the ephrin-binding pocket as a drug target, established viral glycoprotein recognition, and linked EphA2 to immune evasion via PTGS2.\",\n      \"evidence\": \"YSA peptide co-crystal structures with FRET/autophosphorylation; KSHV/EBV gHgL-LBD structures with fusion assays; EPHA2/PTGS2 epistasis in tumor immunotherapy models\",\n      \"pmids\": [\"31015204\", \"33235207\", \"31162144\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TGFβ-PTGS2 mechanistic link downstream of EphA2 not fully resolved\", \"Generalizability of viral binding mode across herpesviruses untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Multiple studies resolved stability and conformational control (ANXA1 versus Cbl, PIP2-driven TM dimerization), the EphA2-pendrin complex underlying Pendred syndrome, RSK-driven Ser897 signaling, and NLRP3 inflammasome suppression, broadening EphA2's mechanistic and disease roles.\",\n      \"evidence\": \"Co-IP/ubiquitination/stability assays; single-molecule TM dimerization assays; pendrin co-internalization with patient mutations; RSK pharmacology with phospho-readout; EphA2-NLRP3 phosphosite mapping with KO mouse\",\n      \"pmids\": [\"32737118\", \"33277361\", \"32165640\", \"32115889\", \"32352641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of stability control with oligomeric-state switching incomplete\", \"Direct NLRP3 phosphorylation effect in vivo across diseases not generalized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Substrate identification (YES1-ANXA2, YAP) and integrative structural analysis of the kinase-SAM linker connected EphA2 catalytic output to invasion/chemoresistance and defined a conformational switch driving oligomerization.\",\n      \"evidence\": \"Co-IP with phosphosite mutagenesis and rescue, nuclear fractionation, xenografts; NMR/SAXS/crystallography with phosphomimetics and FRET\",\n      \"pmids\": [\"33941853\", \"31376289\", \"34857764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect YAP phosphorylation not fully resolved\", \"Identity of all linker-phosphorylating kinases not enumerated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defining the EGFR-EphA2 interaction promoted by Ephexin1 and Ser897 phosphorylation linked receptor crosstalk to oncogenic EGFR mutations.\",\n      \"evidence\": \"Co-IP with domain mapping, phospho-mutant analysis, and patient tissue analysis\",\n      \"pmids\": [\"35668076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional output of the EGFR-EphA2 complex not quantified\", \"Single co-IP-based study with limited functional follow-up\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Distinguishing symmetric versus asymmetric ectodomain interactions provided a unifying structural basis for the switch between tumor-suppressive and oncogenic EphA2 signaling.\",\n      \"evidence\": \"Time-resolved live-cell fluorescence spectroscopy with ectodomain mutagenesis, migration assays, and in vivo invasiveness; plus CLDN1 PDZ-motif binding stabilizing EphA2\",\n      \"pmids\": [\"37972196\", \"37924938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How specific ligands and stabilizers bias the symmetric/asymmetric equilibrium not fully mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"USP3 was identified as a deubiquitinase that stabilizes EphA2 to drive PI3K/AKT signaling, adding to the network of stability regulators counteracting Cbl.\",\n      \"evidence\": \"Co-IP with truncation mapping, ubiquitination and AKT assays, knockdown-rescue, and in vivo tumor model\",\n      \"pmids\": [\"38531846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DUB site specificity on EphA2 not mapped\", \"Interplay with ANXA1/CLDN1 stabilizers not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse stabilizers, kinases, lipids, and ectodomain interaction modes are quantitatively integrated to set the symmetric/asymmetric oligomeric balance and thereby select tumor-suppressive versus oncogenic output in a given tissue context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified quantitative model linking oligomeric state to signaling output\", \"Tissue-specific determinants of suppressor-versus-oncogene behavior unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 4, 32, 33, 35]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [8, 16]},\n      {\"term_id\": \"GO:0004672\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [15, 27, 23]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 20, 36]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4, 14, 36]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [14, 31]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 4, 6, 11, 36]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [22, 32]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 15, 27, 31]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 28, 37]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EFNA1\", \"PIK3R1\", \"CBL\", \"NCK1\", \"GIT1\", \"NLRP3\", \"EGFR\", \"ANXA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}