Affinage

EPHA2

Ephrin type-A receptor 2 · UniProt P29317

Length
976 aa
Mass
108.3 kDa
Annotated
2026-06-09
100 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1994 High

    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

    PMID:7890684 PMID:8139691

    Open questions at the time
    • Did not resolve downstream effectors
    • Did not address oligomeric requirements for activation
  2. 1994 Medium

    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

    PMID:7543898 PMID:7982920

    Open questions at the time
    • SLAP function downstream of EphA2 not established
    • Phosphosites mediating these interactions not defined here
  3. 2000 High

    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

    PMID:10655584

    Open questions at the time
    • Direct phosphatase substrate specificity not dissected
    • Link to oligomeric state not addressed
  4. 2001 Medium

    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

    PMID:11641774

    Open questions at the time
    • In vivo relevance of p53-EphA2 axis untested
    • Mechanism linking EphA2 to apoptosis not resolved
  5. 2002 Medium

    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

    PMID:12147253 PMID:12400011

    Open questions at the time
    • Kinetics of ERK activation versus degradation not integrated
    • Cbl ubiquitination sites on EphA2 not mapped
  6. 2005 High

    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

    PMID:16103880

    Open questions at the time
    • Did not distinguish tyrosine versus serine phosphorylation contributions
    • RhoA GEF not identified
  7. 2006 Medium

    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

    PMID:16849550

    Open questions at the time
    • Reconciliation of suppressor versus oncogenic outputs left unresolved
    • Tissue-context dependence not explained mechanistically
  8. 2009 High

    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

    PMID:19193766

    Open questions at the time
    • In vivo relevance of Arf6 suppression not tested
    • Crosstalk with SHP2/FAK arm not addressed
  9. 2010 Medium

    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

    PMID:20028874

    Open questions at the time
    • Specific Src-targeted EphA2 sites not mapped
    • Single resistance context
  10. 2011 High

    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

    PMID:20679435 PMID:21621533

    Open questions at the time
    • Trigger for ligand-independent Ephexin4 recruitment not defined here
    • Relationship to Ser897 not yet established
  11. 2013 Medium

    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

    PMID:24026120

    Open questions at the time
    • Direct versus indirect control of Src at vertices unresolved
    • Kinase dependence not tested
  12. 2014 Medium

    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

    PMID:24853748

    Open questions at the time
    • Cellular machinery of internalization not identified
    • Signaling consequences of endocytosis not measured
  13. 2015 Medium

    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

    PMID:25906164 PMID:26363067

    Open questions at the time
    • Structural basis of monomer-biased signaling not resolved
    • Pathogen ligand on EphA2 not defined
  14. 2016 High

    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

    PMID:27385333 PMID:27768280 PMID:27776928 PMID:27903606 PMID:28338017

    Open questions at the time
    • How SAM and Ser897 inputs are integrated not resolved
    • Progranulin binding site on EphA2 not mapped
  15. 2017 High

    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

    PMID:29133884

    Open questions at the time
    • β-glucan binding interface on EphA2 not structurally defined
    • Coreceptor requirements not established
  16. 2018 Medium

    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

    PMID:29197141 PMID:29887500

    Open questions at the time
    • MD predictions on PIP nanoclusters await direct structural confirmation
    • Mechanism of CD44-EphA2 coupling not defined
  17. 2019 High

    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

    PMID:31015204 PMID:31162144 PMID:33235207

    Open questions at the time
    • TGFβ-PTGS2 mechanistic link downstream of EphA2 not fully resolved
    • Generalizability of viral binding mode across herpesviruses untested
  18. 2020 High

    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

    PMID:32115889 PMID:32165640 PMID:32352641 PMID:32737118 PMID:33277361

    Open questions at the time
    • Integration of stability control with oligomeric-state switching incomplete
    • Direct NLRP3 phosphorylation effect in vivo across diseases not generalized
  19. 2021 High

    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

    PMID:31376289 PMID:33941853 PMID:34857764

    Open questions at the time
    • Direct versus indirect YAP phosphorylation not fully resolved
    • Identity of all linker-phosphorylating kinases not enumerated
  20. 2022 Medium

    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

    PMID:35668076

    Open questions at the time
    • Functional output of the EGFR-EphA2 complex not quantified
    • Single co-IP-based study with limited functional follow-up
  21. 2023 High

    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

    PMID:37924938 PMID:37972196

    Open questions at the time
    • How specific ligands and stabilizers bias the symmetric/asymmetric equilibrium not fully mapped
  22. 2024 Medium

    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

    PMID:38531846

    Open questions at the time
    • DUB site specificity on EphA2 not mapped
    • Interplay with ANXA1/CLDN1 stabilizers not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No unified quantitative model linking oligomeric state to signaling output
  • Tissue-specific determinants of suppressor-versus-oncogene behavior unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0001618 virus receptor activity 3 GO:0060089 molecular transducer activity 3 GO:0140657 ATP-dependent activity 2 GO:0140299 molecular sensor activity 1
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-168256 Immune System 2
Partners
ANXA1CBLEFNA1EGFRGIT1NCK1NLRP3PIK3R1

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 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. Receptor affinity chromatography, surface plasmon resonance, autophosphorylation assay in intact cells Nature High 8139691
1994 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. Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, PI3K activity assay The Journal of biological chemistry High 7982920
1994 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. Biochemical characterization, in situ hybridization, receptor activation assay The Journal of biological chemistry Medium 7890684
1995 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. Yeast two-hybrid screen, GST pulldown The Journal of biological chemistry Medium 7543898
2000 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. Co-immunoprecipitation, phosphorylation assays, cell spreading/migration assays, integrin conformation assay Nature cell biology High 10655584
2001 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. Promoter analysis, reporter assay, Western blot, stable inducible cell lines, apoptosis assay Oncogene Medium 11641774
2002 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. Co-immunoprecipitation, Western blot for nuclear translocation, Elk-1 reporter assay, domain mapping with SHC mutants Oncogene Medium 12400011
2002 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. Co-immunoprecipitation, mutagenesis (G306E-Cbl, 70Z-Cbl dominant negative, kinase-inactive EphA2), Western blot Biochemical and biophysical research communications Medium 12147253
2005 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. Site-directed mutagenesis, in vivo xenograft and metastasis models, RhoA activation assay, cell migration assay Oncogene High 16103880
2009 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. Co-immunoprecipitation, Arf6 activity assay, domain mapping, phospho-mutant analysis, MDCK cell density/calcium experiments Molecular biology of the cell High 19193766
2009 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. Western blot, Src kinase assay, siRNA knockdown, in vivo xenograft with trastuzumab treatment Cancer research Medium 20028874
2010 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. Co-immunoprecipitation, GEF activity assay, knockdown-rescue experiments, cell migration/invasion assays The Journal of cell biology High 20679435
2011 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. RhoG activity assay, Akt phosphorylation assay, siRNA knockdown, anoikis assay Experimental cell research Medium 21621533
2013 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. Epha2-/- mouse model, immunofluorescence, phospho-specific antibodies, confocal microscopy Development Medium 24026120
2014 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. Supported lipid bilayer reconstitution, 3D fluorescence microscopy trans-endocytosis assay, receptor clustering analysis Biophysical journal Medium 24853748
2015 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. siRNA knockdown, overexpression of wild-type vs. cytoplasmic-domain-deleted mutant, PI3K/Akt assays, infection quantification PLoS pathogens Medium 25906164
2015 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. FRET-based dimerization assay in HEK293T cells, mutagenesis, Western blot for phosphorylation, cell migration assay The Journal of biological chemistry Medium 26363067
2016 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. FRET-based dimerization measurement, SAM domain deletion mutant, Western blot for tyrosine phosphorylation Biochimica et biophysica acta. Molecular cell research Medium 27776928
2016 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. Fluorescence correlation spectroscopy in live cells, Western blot for tyrosine phosphorylation, multiple cell lines Scientific reports Medium 28338017
2016 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. High-content screening, phospho-specific Western blot, cAMP elevation, pharmacological PKA activation/inhibition, cell retraction assay Molecular biology of the cell Medium 27385333
2016 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. Solid-phase and solution binding assays, Western blot for MAPK/Akt phosphorylation, capillary morphogenesis assay, EphA2 knockdown The Journal of cell biology High 27903606
2016 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. Chemical proteomics (kinase selectivity profiling), X-ray crystallography (9 co-crystal structures), NMR conformational dynamics ACS chemical biology High 27768280
2017 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. EphA2-/- mouse model, β-glucan binding assay, STAT3/MAPK signaling assays, in vivo infection model Nature microbiology High 29133884
2018 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. EphA2 silencing, chemical inhibition, EphA2 agonist treatment, HEK293T overexpression, in vitro BBB transmigration assay Cellular microbiology Medium 29197141
2018 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. Molecular dynamics simulation, biochemical membrane interaction studies Structure Medium 29887500
2019 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. X-ray crystallography (1.53–2.20 Å resolution), quantitative FRET in live cells, receptor autophosphorylation assay The Journal of biological chemistry High 31015204
2019 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. EPHA2 and PTGS2 genetic deletion in mouse tumor models, T cell infiltration analysis, immunotherapy combination experiments The Journal of clinical investigation Medium 31162144
2019 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. X-ray crystallography, surface plasmon resonance/affinity measurements, cell-based fusion assay with site-directed mutagenesis Nature communications High 33235207
2020 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. Co-immunoprecipitation, ubiquitination assay, protein stability assay, ANXA1 peptide competition, in vivo xenograft Cancer research Medium 32737118
2020 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. Patient tumor analysis, pharmacological RSK inhibition, siRNA knockdown, phospho-specific Western blot EMBO molecular medicine Medium 32115889
2020 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. Hydrophobic matching peptide system, styrene maleic acid lipid particles single-molecule dimerization assay The Journal of biological chemistry Medium 33277361
2020 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. Co-immunoprecipitation, internalization assay, autophosphorylation assay, patient mutation characterization Nature communications Medium 32165640
2020 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. Co-immunoprecipitation, phospho-specific Western blot, inflammasome activation assay, EphA2-/- mouse model, ASC speck formation assay EMBO reports High 32352641
2021 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. Co-immunoprecipitation, phospho-specific Western blot, knockdown-rescue with wild-type vs. Tyr24F ANXA2 mutant, in vitro migration/invasion assays, mouse xenograft Oncogene Medium 33941853
2021 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. Integrative structural biology (NMR, SAXS, crystallography), phosphomimetic mutagenesis, FRET-based oligomerization assay in cells, kinase identification assays Nature communications High 34857764
2021 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. Co-immunoprecipitation, nuclear fractionation, YAP phosphorylation assay, YAP knockdown in EphA2-overexpressing xenograft models International journal of cancer Medium 31376289
2023 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. Time-resolved live-cell fluorescence spectroscopy, mutagenesis of ectodomain interactions, cell migration assays, in vivo tumor invasiveness model Science High 37972196
2024 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. Co-immunoprecipitation, USP3 truncation mutant mapping, Western blot for ubiquitination and AKT signaling, knockdown-rescue experiments, in vivo tumor model Cell death & disease Medium 38531846
2006 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. EphA2 knockout mouse in two-stage skin carcinogenesis model (DMBA/TPA), primary keratinocyte ephrin-A1 stimulation, ERK1/2 activity assay Cancer research Medium 16849550
2022 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. Co-immunoprecipitation with domain mapping, phospho-mutant analysis, patient tissue analysis Cell death & disease Medium 35668076
2023 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. Co-immunoprecipitation, biophysical binding assays, proteomics, mutagenesis of PDZ-binding motif, patient-derived organoids Cancer letters Medium 37924938

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nature cell biology 476 10655584
2000 The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization. Oncogene 325 11146556
2008 The EphA2 receptor and ephrinA1 ligand in solid tumors: function and therapeutic targeting. Molecular cancer research : MCR 255 19074825
1994 B61 is a ligand for the ECK receptor protein-tyrosine kinase. Nature 224 8139691
2011 Emerging strategies for EphA2 receptor targeting for cancer therapeutics. Expert opinion on therapeutic targets 213 21142802
2020 Targeting EphA2 in cancer. Journal of hematology & oncology 182 32811512
2009 Elevation of receptor tyrosine kinase EphA2 mediates resistance to trastuzumab therapy. Cancer research 172 20028874
2005 EphA2 receptor tyrosine kinase as a promising target for cancer therapeutics. Current cancer drug targets 159 15892616
2017 EphA2 is an epithelial cell pattern recognition receptor for fungal β-glucans. Nature microbiology 145 29133884
2004 Antiangiogenic and antitumor efficacy of EphA2 receptor antagonist. Cancer research 144 14871820
2019 Tumor cell-intrinsic EPHA2 suppresses anti-tumor immunity by regulating PTGS2 (COX-2). The Journal of clinical investigation 132 31162144
2021 Oncogenic functions and therapeutic targeting of EphA2 in cancer. Oncogene 131 33686241
2008 The EPHA2 gene is associated with cataracts linked to chromosome 1p. Molecular vision 130 19005574
2009 EPHA2 is associated with age-related cortical cataract in mice and humans. PLoS genetics 129 19649315
1994 Activation of the Eck receptor protein tyrosine kinase stimulates phosphatidylinositol 3-kinase activity. The Journal of biological chemistry 128 7982920
2010 Ephexin4 and EphA2 mediate cell migration through a RhoG-dependent mechanism. The Journal of cell biology 127 20679435
2005 EPHA2/EFNA1 expression in human gastric cancer. Cancer science 126 15649254
2001 Receptor tyrosine kinase EphA2 is regulated by p53-family proteins and induces apoptosis. Oncogene 123 11641774
2018 Chemoresistance Transmission via Exosome-Mediated EphA2 Transfer in Pancreatic Cancer. Theranostics 118 30613276
2002 Activation of the EphA2 tyrosine kinase stimulates the MAP/ERK kinase signaling cascade. Oncogene 117 12400011
2003 Overexpression and functional alterations of the EphA2 tyrosine kinase in cancer. Clinical & experimental metastasis 115 12650608
2006 Disruption of EphA2 receptor tyrosine kinase leads to increased susceptibility to carcinogenesis in mouse skin. Cancer research 114 16849550
1995 Characterization of a novel Src-like adapter protein that associates with the Eck receptor tyrosine kinase. The Journal of biological chemistry 112 7543898
2005 A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis. Oncogene 111 16103880
2016 EphA2 is a functional receptor for the growth factor progranulin. The Journal of cell biology 109 27903606
2003 High-level expression of EphA2 receptor tyrosine kinase in prostatic intraepithelial neoplasia. The American journal of pathology 107 14633601
2014 Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC. The Journal of clinical investigation 100 24713656
2014 EPHA2 is a mediator of vemurafenib resistance and a novel therapeutic target in melanoma. Cancer discovery 99 25542448
1994 The expression of the receptor-protein tyrosine kinase gene, eck, is highly restricted during early mouse development. Mechanisms of development 97 7918100
2006 Expression of EphA2 and Ephrin A-1 in carcinoma of the urinary bladder. Clinical cancer research : an official journal of the American Association for Cancer Research 95 16428472
2015 EphrinA2 receptor (EphA2) is an invasion and intracellular signaling receptor for Chlamydia trachomatis. PLoS pathogens 93 25906164
1994 The Eck receptor tyrosine kinase is implicated in pattern formation during gastrulation, hindbrain segmentation and limb development. Oncogene 90 8183555
2005 EphA2 as a target for ovarian cancer therapy. Expert opinion on therapeutic targets 84 16300469
2017 Emerging and Diverse Functions of the EphA2 Noncanonical Pathway in Cancer Progression. Biological & pharmaceutical bulletin 79 28966234
2004 Expression of EphA2 and E-cadherin in colorectal cancer: correlation with cancer metastasis. Oncology reports 79 14767510
2016 Protein kinase A can block EphA2 receptor-mediated cell repulsion by increasing EphA2 S897 phosphorylation. Molecular biology of the cell 74 27385333
2010 EFNA1 ligand and its receptor EphA2: potential biomarkers for hepatocellular carcinoma. International journal of cancer 73 19642143
2021 EphA2-YES1-ANXA2 pathway promotes gastric cancer progression and metastasis. Oncogene 69 33941853
2013 EphA2 and Src regulate equatorial cell morphogenesis during lens development. Development (Cambridge, England) 66 24026120
2017 EphA2 Expression Regulates Inflammation and Fibroproliferative Remodeling in Atherosclerosis. Circulation 63 28487392
2009 EphA2 engages Git1 to suppress Arf6 activity modulating epithelial cell-cell contacts. Molecular biology of the cell 61 19193766
2019 EphA2-to-YAP pathway drives gastric cancer growth and therapy resistance. International journal of cancer 60 31376289
2002 Negative regulation of EphA2 receptor by Cbl. Biochemical and biophysical research communications 59 12147253
2018 The blood-brain barrier internalises Cryptococcus neoformans via the EphA2-tyrosine kinase receptor. Cellular microbiology 55 29197141
1995 Characterization of B61, the ligand for the Eck receptor protein-tyrosine kinase. The Journal of biological chemistry 55 7890684
2012 A role for epha2 in cell migration and refractive organization of the ocular lens. Investigative ophthalmology & visual science 53 22167091
2008 EphA2 overexpression promotes ovarian cancer growth. Cancer biology & therapy 53 18443431
2010 Clinical and biological impact of EphA2 overexpression and angiogenesis in endometrial cancer. Cancer biology & therapy 52 20948320
2015 EphA2 Receptor Unliganded Dimers Suppress EphA2 Pro-tumorigenic Signaling. The Journal of biological chemistry 51 26363067
2020 ANXA1 Binds and Stabilizes EphA2 to Promote Nasopharyngeal Carcinoma Growth and Metastasis. Cancer research 50 32737118
2020 Adaptive RSK-EphA2-GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer. EMBO molecular medicine 49 32115889
2019 Morphological characteristics of vasculogenic mimicry and its correlation with EphA2 expression in gastric adenocarcinoma. Scientific reports 49 30833656
2016 The SAM domain inhibits EphA2 interactions in the plasma membrane. Biochimica et biophysica acta. Molecular cell research 48 27776928
2022 A novel TanCAR targeting IL13Rα2 and EphA2 for enhanced glioblastoma therapy. Molecular therapy oncolytics 47 35317513
2011 Ephexin4 and EphA2 mediate resistance to anoikis through RhoG and phosphatidylinositol 3-kinase. Experimental cell research 47 21621533
2006 Silencing the receptor EphA2 suppresses the growth and haptotaxis of malignant mesothelioma cells. Cancer 47 17041885
2009 Cell adhesion and EGFR activation regulate EphA2 expression in cancer. Cellular signalling 45 19948216
2021 EphA2: A promising therapeutic target in breast cancer. Journal of genetics and genomics = Yi chuan xue bao 43 33962882
2011 EphA2-dependent molecular targeting therapy for malignant tumors. Current cancer drug targets 43 21933105
2023 Claudin-1 interacts with EPHA2 to promote cancer stemness and chemoresistance in colorectal cancer. Cancer letters 42 37924938
2017 A role of the SAM domain in EphA2 receptor activation. Scientific reports 42 28338017
2016 Chemical Proteomics and Structural Biology Define EPHA2 Inhibition by Clinical Kinase Drugs. ACS chemical biology 42 27768280
2016 Novel anti-EPHA2 antibody, DS-8895a for cancer treatment. Cancer biology & therapy 41 27653549
2020 Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome. Nature communications 40 32165640
2020 EphA2 phosphorylates NLRP3 and inhibits inflammasomes in airway epithelial cells. EMBO reports 37 32352641
2014 Spatial organization of EphA2 at the cell-cell interface modulates trans-endocytosis of ephrinA1. Biophysical journal 37 24853748
2020 Molecular basis of EphA2 recognition by gHgL from gammaherpesviruses. Nature communications 36 33235207
2023 Time-resolved live-cell spectroscopy reveals EphA2 multimeric assembly. Science (New York, N.Y.) 35 37972196
2014 Design, synthesis and bioevaluation of an EphA2 receptor-based targeted delivery system. ChemMedChem 35 24677792
2020 PIP2 promotes conformation-specific dimerization of the EphA2 membrane region. The Journal of biological chemistry 33 33277361
2019 Engineering nanomolar peptide ligands that differentially modulate EphA2 receptor signaling. The Journal of biological chemistry 32 31015204
2020 Progranulin/EphA2 axis: A novel oncogenic mechanism in bladder cancer. Matrix biology : journal of the International Society for Matrix Biology 30 32417448
2018 Epha2 and Efna5 participate in lens cell pattern-formation. Differentiation; research in biological diversity 30 29800803
2018 Interactions of the EphA2 Kinase Domain with PIPs in Membranes: Implications for Receptor Function. Structure (London, England : 1993) 30 29887500
2017 Chemoproteomics-Aided Medicinal Chemistry for the Discovery of EPHA2 Inhibitors. ChemMedChem 29 28544567
2016 Molecular Imaging and Quantitation of EphA2 Expression in Xenograft Models with 89Zr-DS-8895a. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 29 26940768
2024 USP3 promotes osteosarcoma progression via deubiquitinating EPHA2 and activating the PI3K/AKT signaling pathway. Cell death & disease 28 38531846
2020 Spatial organization-dependent EphA2 transcriptional responses revealed by ligand nanocalipers. Nucleic acids research 27 32352518
2017 Design and synthesis of small molecule agonists of EphA2 receptor. European journal of medicinal chemistry 27 29128116
2021 EphA2 and EGFR: Friends in Life, Partners in Crime. Can EphA2 Be a Predictive Biomarker of Response to Anti-EGFR Agents? Cancers 26 33572284
2021 Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker. Nature communications 25 34857764
2020 Serum Exo-EphA2 as a Potential Diagnostic Biomarker for Pancreatic Cancer. Pancreas 25 32898008
2016 A small peptide promotes EphA2 kinase-dependent signaling by stabilizing EphA2 dimers. Biochimica et biophysica acta 25 27281300
2022 Interactions between EGFR and EphA2 promote tumorigenesis through the action of Ephexin1. Cell death & disease 24 35668076
2017 EphA2 and ephrin-A5 are not a receptor-ligand pair in the ocular lens. Experimental eye research 24 28648759
2016 The Sam Domain of EphA2 Receptor and its Relevance to Cancer: A Novel Challenge for Drug Discovery? Current medicinal chemistry 24 27804871
2019 EPHA2 mutations with oncogenic characteristics in squamous cell lung cancer and malignant pleural mesothelioma. Oncogenesis 23 31484920
2022 EPHA2, EPHA4, and EPHA7 Expression in Triple-Negative Breast Cancer. Diagnostics (Basel, Switzerland) 22 35204461
2024 EphA2 in Cancer: Molecular Complexity and Therapeutic Opportunities. International journal of molecular sciences 21 39596256
2023 EphA2 is a functional entry receptor for HCMV infection of glioblastoma cells. PLoS pathogens 21 37146061
2020 Helicobacter Pylori Targets the EPHA2 Receptor Tyrosine Kinase in Gastric Cells Modulating Key Cellular Functions. Cells 21 32102381
2019 EPHB6 mutation induces cell adhesion-mediated paclitaxel resistance via EPHA2 and CDH11 expression. Experimental & molecular medicine 21 31160603
2018 TR4 nuclear receptor suppresses HCC cell invasion via downregulating the EphA2 expression. Cell death & disease 21 29449527
2018 Roles of EphA2 Receptor in Angiogenesis Signaling Pathway of Glioblastoma Multiforme. The Malaysian journal of medical sciences : MJMS 21 30914876
2016 Inhibition of EphA2/EphrinA1 signal attenuates lipopolysaccharide-induced lung injury. Clinical science (London, England : 1979) 21 27549114
2022 MFSD4A inhibits the malignant progression of nasopharyngeal carcinoma by targeting EPHA2. Cell death & disease 20 35410462
2009 Loss of EphA2 receptor tyrosine kinase reduces ApcMin/+ tumorigenesis. International journal of cancer 20 19089910
2024 Development and preclinical characterization of a novel radiotheranostic EphA2-targeting bicyclic peptide. Theranostics 19 39239524
2023 EphA2 as a phase separation protein associated with ferroptosis and immune cell infiltration in colorectal cancer. Aging 19 37980165
2021 EphA2 promotes tumorigenicity of cervical cancer by up-regulating CDK6. Journal of cellular and molecular medicine 19 33586348

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