Affinage

EPHA2

Ephrin type-A receptor 2 · UniProt P29317

Length
976 aa
Mass
108.3 kDa
Annotated
2026-04-28
100 papers in source corpus 42 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EphA2 is a receptor tyrosine kinase that operates through two opposing signaling modes—canonical ligand-dependent and non-canonical ligand-independent—to regulate cell adhesion, migration, proliferation, and immune responses across epithelial, vascular, and neural tissues. In canonical signaling, ephrin-A1, progranulin, or fungal β-glucans induce receptor oligomerization and tyrosine phosphorylation, activating SHC-GRB2-ERK, Nck1-Git1-Arf6, and RhoA pathways that suppress proliferation, promote cell compaction, and drive antifungal innate immunity (PMID:7536959, PMID:19193766, PMID:16849550, PMID:29133884, PMID:27903606). In non-canonical signaling, Akt- or RSK-mediated Ser897 phosphorylation of monomeric EphA2 engages Ephexin4-RhoG-Rac1 and YES1-ANXA2 axes to promote migration, invasion, chemoresistance, and immune evasion through PTGS2/COX-2 induction (PMID:20679435, PMID:33941853, PMID:31162144, PMID:27132626). Receptor activity is tuned by SAM domain–mediated inhibition of dimerization, PIP2-dependent transmembrane conformational coupling, Cbl-mediated ubiquitination counteracted by USP3 and ANXA1, MT1-MMP proteolytic cleavage, and cooperative phosphorylation of the kinase-SAM linker; EphA2 also serves as an entry receptor for KSHV, EBV, and HCMV via its ligand-binding domain, and loss-of-function mutations cause congenital cataract (PMID:26724997, PMID:34857764, PMID:32737118, PMID:23629968, PMID:26363067, PMID:33235207, PMID:19649315).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1995 High

    Identifying ephrin-A1 as the cognate ligand for EphA2 established the receptor's signaling identity, revealing a TNF-α-inducible autocrine/paracrine angiogenic loop.

    Evidence B61-Ig chimera binding assay and in vivo angiogenesis assay with antibody neutralization

    PMID:7536959

    Open questions at the time
    • Downstream intracellular signaling cascade not yet mapped
    • Other potential ligands not excluded
  2. 2002 Medium

    Demonstration that EphA2 possesses ligand-independent kinase activity on tumor cells, and that antibody-induced phosphorylation triggers receptor degradation, established the concept of dual signaling modes and identified receptor turnover as a regulatory mechanism.

    Evidence Monoclonal antibody treatment, soft agar assay, and antisense knockdown in tumor cell lines; parallel identification of Cbl as the E3 ligase mediating kinase-dependent EphA2 degradation via TKB/RING domains

    PMID:12019162 PMID:12147253

    Open questions at the time
    • Ubiquitin chain type and degradation route (lysosomal vs proteasomal) not defined
    • In vivo relevance of antibody-induced degradation not established
  3. 2002 Medium

    Mapping the SHC-GRB2-ERK-Elk-1 cascade downstream of ligand-activated EphA2 provided the first defined canonical signaling pathway.

    Evidence Co-immunoprecipitation with domain mapping (PTB and SH2), nuclear translocation, and reporter assay

    PMID:12400011

    Open questions at the time
    • ERK activation context-dependence (proliferative vs. anti-proliferative) not resolved
    • In vivo relevance not tested
  4. 2006 High

    Genetic knockout in mice proved EphA2 functions as a tumor suppressor in skin by suppressing ERK1/2 and keratinocyte proliferation upon ephrin-A1 stimulation, resolving the apparent paradox of an RTK with anti-proliferative activity.

    Evidence EphA2 knockout mouse, DMBA/TPA carcinogenesis model, ERK activity assay in primary keratinocytes

    PMID:16849550

    Open questions at the time
    • Mechanism by which EphA2 suppresses rather than activates ERK not fully dissected
    • Tumor-suppressive role in tissues other than skin not established
  5. 2009 High

    Identification of the Nck1-Git1-Arf6 axis downstream of EphA2 pTyr594 explained how canonical signaling promotes epithelial compaction and polarization, while the RhoA-ROCK pathway was shown to mediate EphA2-dependent mammary branching morphogenesis downstream of HGF.

    Evidence Co-IP with phosphosite and domain mutants, Arf6 activity assays in MDCK cells; EphA2 KO mammary transplantation with ROCK inhibitor rescue

    PMID:19193766 PMID:19321667

    Open questions at the time
    • Whether Nck1-Git1 and RhoA-ROCK pathways operate in the same or distinct cellular contexts not clarified
    • Direct EphA2 interaction with HGF receptor not addressed
  6. 2009 High

    EphA2 knockout mice develop progressive cortical cataract with HSP25 stress marker upregulation, establishing EphA2 as essential for lens transparency and linking it to congenital cataract in humans.

    Evidence Two independent Epha2 KO mouse strains, retroillumination imaging, Western blot, human population genetics

    PMID:19649315

    Open questions at the time
    • Specific lens fiber cell signaling pathway disrupted not fully defined
    • Genotype-phenotype correlation for different human EPHA2 mutations incomplete
  7. 2010 High

    Discovery of the Ephexin4-RhoG-ELMO2-Dock4-Rac1 axis as the effector of ligand-independent EphA2 signaling in breast cancer established the molecular basis of EphA2's pro-migratory, oncogenic mode.

    Evidence Co-IP, GEF activity assay, knockdown/rescue, migration assay in breast cancer cells

    PMID:20679435

    Open questions at the time
    • Signal that switches EphA2 from canonical to non-canonical mode not identified
    • Structural basis of EphA2-Ephexin4 interaction not determined
  8. 2013 High

    MT1-MMP cleavage of EphA2 at the FN-III domain was shown to switch breast carcinoma invasion from collective to single-cell mode by triggering receptor internalization and RhoA activation, revealing proteolytic regulation as a distinct signaling switch.

    Evidence Cleavage site identification, cleavage-resistant mutant, RhoA activity assay, collagen invasion assay, in vivo model

    PMID:23629968

    Open questions at the time
    • Whether cleaved EphA2 fragment has autonomous signaling activity not determined
    • Regulation of MT1-MMP access to EphA2 not defined
  9. 2014 High

    Akt-mediated Ser897 phosphorylation was identified as the molecular switch for non-canonical oncogenic signaling, promoting anoikis resistance via Ephexin4-RhoG; an ATP-competitive EphA2 inhibitor achieved tumor regression in NSCLC xenografts through the S6K1-BAD apoptotic axis.

    Evidence S897A mutant, anoikis assay, EphB6 interaction studies; conditional KO and ALW-II-41-27 inhibitor in NSCLC models

    PMID:24713656 PMID:25239188

    Open questions at the time
    • Therapeutic window for kinase inhibition versus maintaining tumor-suppressive canonical signaling not defined
    • Whether Akt and RSK phosphorylate S897 in the same or different cellular contexts not resolved
  10. 2015 High

    FRET-based measurement of EphA2 dimers in live cells revealed that ligand-free EphA2 forms dimers, and that dimerization-deficient monomers show enhanced Ser897 phosphorylation and migration, directly linking the monomeric state to oncogenic signaling.

    Evidence FRET dimerization measurement in HEK293T, dimerization-deficient mutant, migration assay

    PMID:26363067

    Open questions at the time
    • Precise transmembrane helix interface mediating ligand-free dimerization not atomically resolved
    • Population-level monomer-dimer equilibrium not quantified in tumor tissue
  11. 2016 High

    The SAM domain was shown to inhibit EphA2 dimerization and kinase activation, and progranulin was identified as a second high-affinity ligand that prolongs receptor activation and MAPK/Akt signaling, expanding the receptor's ligand repertoire and regulatory complexity.

    Evidence FRET-based dimerization assay with SAM deletion mutant; solid-phase/solution-phase binding assays and tube formation assay for progranulin

    PMID:27776928 PMID:27903606

    Open questions at the time
    • SAM domain structural mechanism of dimerization inhibition not atomically resolved
    • Physiological contexts where progranulin-EphA2 signaling dominates over ephrin signaling not mapped
  12. 2017 High

    EphA2 was identified as a pattern recognition receptor for fungal β-glucans, activating STAT3/MAPK and IL-17 signaling for antifungal defense, establishing an unexpected innate immune function for this RTK.

    Evidence EphA2 KO mouse oropharyngeal candidiasis model, β-glucan binding assay, signaling analysis

    PMID:29133884

    Open questions at the time
    • Whether β-glucan binding site overlaps with ephrin-binding pocket not structurally resolved
    • Role of EphA2 in systemic versus mucosal antifungal immunity not compared
  13. 2018 Medium

    The FN-III domain 2 was shown to interact with PIP2 via specific residues, anchoring the ectodomain at the membrane surface, while PIP2 also promotes transmembrane domain dimerization in a conformation-specific manner, establishing lipid-mediated allosteric regulation.

    Evidence Multiscale MD simulations with experimental lipid binding/mutagenesis; single-molecule SMA lipid particle dimerization assay

    PMID:26724997 PMID:33277361

    Open questions at the time
    • In vivo relevance of PIP2-EphA2 interaction in signaling regulation not demonstrated
    • Coordination between ectodomain-PIP2 and TM-PIP2 interactions not experimentally linked
  14. 2019 High

    EphA2-TGFβ-PTGS2 signaling was shown to drive T cell exclusion from pancreatic tumors, and genetic deletion of either Epha2 or Ptgs2 sensitized tumors to immunotherapy, revealing EphA2 as a targetable immune evasion node.

    Evidence Epha2 and Ptgs2 genetic deletions, pharmacological inhibition, tumor immune profiling, immunotherapy combination

    PMID:31162144

    Open questions at the time
    • Direct mechanism by which EphA2 activates TGFβ pathway not fully defined
    • Whether this immune evasion mechanism operates in tumor types beyond pancreatic cancer not tested
  15. 2020 High

    Multiple regulatory mechanisms were defined: ANXA1 competes with Cbl to stabilize EphA2 and enhance oncogenic pS897 signaling; EphA2 directly phosphorylates NLRP3 at Tyr132 to suppress inflammasome activation; and crystal structures of KSHV/EBV gHgL-EphA2 LBD complexes revealed the structural basis for viral entry receptor function.

    Evidence Competition co-IP/ubiquitination assay for ANXA1-Cbl; phosphosite mutagenesis and ASC speck assay for NLRP3; crystal structures with cell-based fusion assays for viral complexes

    PMID:32352641 PMID:32737118 PMID:33235207

    Open questions at the time
    • Whether NLRP3 phosphorylation occurs in non-epithelial immune cells not tested
    • Whether ANXA1 regulation of EphA2 is tissue-specific not determined
    • Structural basis for differential viral gL usage of EphA2 LBD subsites not fully exploited for therapeutic design
  16. 2021 High

    Cooperative phosphorylation of the kinase-SAM linker was shown to induce a closed-to-extended conformational switch that promotes EphA2 oligomerization, providing an integrative structural model for how phosphorylation tunes receptor architecture; simultaneously, EphA2-YES1-ANXA2 and EphA2-FAK-Y772-RhoA pathways were defined for invasion and fibronectin fibrillogenesis.

    Evidence Integrative structural biology (SAXS, NMR, crystallography) with FRET and phosphomimetic mutants; co-IP with Y772 and Y24F mutant analysis in xenograft models; RhoA/p190RhoGAP assays in KO cells

    PMID:33941853 PMID:34537369 PMID:34857764

    Open questions at the time
    • Full-length EphA2 structure integrating all domains not available
    • How linker phosphorylation intersects with S897 and Y772 phosphorylation in the same molecule not resolved
  17. 2023 High

    Time-resolved fluorescence spectroscopy in live cells resolved two distinct ligand-free EphA2 ectodomain interaction modes: symmetric interactions that support canonical tumor-suppressive signaling and asymmetric interactions that support oncogenic signaling, providing a structural explanation for the dual signaling paradigm.

    Evidence Time-resolved live-cell fluorescence spectroscopy, interaction-disrupting mutants, migration assay, in vivo tumor invasion model

    PMID:37972196

    Open questions at the time
    • Atomic-resolution structures of these two distinct oligomeric assemblies not determined
    • Factors that shift the equilibrium between symmetric and asymmetric assemblies in tumors not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length structure of EphA2 in both signaling states, the molecular determinants that shift signaling between canonical and non-canonical modes in vivo, the integration of multiple phosphorylation events (S897, Y772, Y594, linker sites) on a single receptor molecule, and whether therapeutic strategies can selectively ablate oncogenic non-canonical signaling while preserving tumor-suppressive and immune functions.
  • No full-length EphA2 structure available
  • In vivo determinants of signaling mode switching unknown
  • Therapeutic selectivity for non-canonical vs canonical signaling not achieved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 3 GO:0001618 virus receptor activity 2
Localization
GO:0005886 plasma membrane 7
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-1500931 Cell-Cell communication 4 R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 3
Partners
ANXA1ARHGEF16CBLEFNA1GIT1GRB2NCK1SHC1

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 B61 (ephrin-A1) is the ligand for the Eck (EphA2) receptor protein tyrosine kinase; TNF-alpha activates EphA2 through induction of B61, creating an autocrine/paracrine signaling loop that promotes angiogenesis. B61-immunoglobulin chimera binding assay, in vivo angiogenesis assay, antibody neutralization Science High 7536959
2000 EphA2 is tyrosine-phosphorylated and activated by ephrin-A1 in tumor vasculature; a dominant-negative EphA2 inhibits capillary tube formation by HUVECs, demonstrating a requirement for EphA receptor signaling in angiogenesis. Immunohistochemistry, dominant-negative overexpression, in vitro angiogenesis assay Oncogene High 11146556
2002 EphA2 on malignant cells exhibits ligand-independent kinase activity; antibody-mediated EphA2 phosphorylation triggers receptor degradation and inhibits malignant cell behavior including soft agar colonization and tubular network formation. Monoclonal antibody treatment, Western blot, soft agar colony assay, antisense knockdown Cancer research Medium 12019162
2002 Ligand stimulation of EphA2 activates the MAP/ERK kinase signaling cascade; tyrosine-phosphorylated EphA2 forms a molecular complex with SHC (via PTB and SH2 domains) and indirectly with GRB2, leading to ERK phosphorylation and Elk-1 transcription factor induction. Co-immunoprecipitation, domain-binding assays, nuclear translocation assays, reporter assay Oncogene Medium 12400011
2002 Cbl negatively regulates EphA2 in a kinase activity-dependent manner; Cbl binding to active EphA2 requires its TKB domain and RING finger domain, and the dominant-negative 70Z-Cbl abolishes this regulation. Co-immunoprecipitation, dominant-negative mutant overexpression, kinase-dead mutant analysis Biochemical and biophysical research communications Medium 12147253
2006 EphA2 functions as a tumor suppressor in mouse skin; ephrin-A1 stimulation of EphA2 suppresses keratinocyte proliferation and inhibits ERK1/2 activity, effects abolished in EphA2-null keratinocytes, and EphA2 deletion increases susceptibility to DMBA/TPA-induced carcinogenesis. EphA2 knockout mouse model, DMBA/TPA two-stage carcinogenesis, ephrin-A1 stimulation, ERK activity assay Cancer research High 16849550
2006 p53 binds to a 10-bp palindromic decanucleotide (GTGACGTCAC) in the ECK/EphA2 promoter to transactivate EphA2 expression; ectopic EphA2 expression induces apoptosis in breast cancer cells, and a kinase-dead EphA2 mutant fails to induce apoptosis. Promoter reporter assay, electrophoretic mobility shift assay, ectopic expression with mutagenesis Molecular cancer research Medium 17050670
2009 EphA2 engages Git1 via Nck1 to suppress Arf6 activity: ligand-activated EphA2 phosphorylated at Tyr594 binds to the SH2 domain of Nck1, which via its SH3 domain binds Git1's synaptic localizing domain, suppressing Arf6 activity and promoting epithelial cell compaction and polarization. Co-immunoprecipitation, phosphorylation site mutant analysis, Arf6 activity assay, knockdown experiments Molecular biology of the cell High 19193766
2009 Homozygous deletion of Epha2 in mice causes progressive cortical cataract with increased HSP25 expression in underphosphorylated form, indicating cellular stress; a missense mutation (Arg721Gln) in the kinase domain significantly alters EphA2 function. Epha2 knockout mouse model, retroillumination imaging, Western blot, biochemical kinase assays PLoS genetics High 19649315
2009 EphA2 is required for HGF-induced mammary epithelial branching morphogenesis; EphA2 acts downstream of HGF to inhibit RhoA activity, and ROCK inhibition rescues branching defects in EphA2-deficient mammary epithelium. EphA2 knockout mouse model, mammary transplantation, 3D culture, RhoA activity assay, ROCK inhibitor rescue Molecular biology of the cell High 19321667
2009 Elevated EphA2 contributes to trastuzumab resistance; trastuzumab treatment promotes EphA2 phosphorylation by activating Src kinase, amplifying PI3K/Akt and MAPK signaling in resistant cells. Cell line models, Western blot, Src kinase inhibition, EphA2 inhibition in vivo Cancer research Medium 20028874
2010 Ligand-activated EphA2 suppresses Arf6 activity through Git1 to enhance E-cadherin-based cell-cell contacts; E-cadherin-based contacts in turn enhance EphA ephrin-A signaling, forming a positive feedback loop. Biochemical assays, phosphorylation mutant studies in MDCK cells Molecular biology of the cell Medium 19193766
2010 Ephexin4 is a GEF for RhoG that interacts with EphA2 in breast cancer cells; EphA2 promotes ligand-independent breast cancer cell migration through Ephexin4-RhoG-ELMO2-Dock4-Rac1 signaling axis. Co-immunoprecipitation, knockdown/rescue experiments, GEF activity assays, migration assay The Journal of cell biology High 20679435
2012 EphA2/Src signaling regulates equatorial lens cell morphogenesis; EphA2 activates Src, which phosphorylates cortactin to regulate F-actin distribution at cell vertices for hexagonal packing; loss of EphA2 disrupts meridional row alignment and lens fulcrum formation, resulting in cataract. Epha2/Src knockout mouse models, immunofluorescence, phospho-specific antibodies Development High 24026120
2013 MT1-MMP cleaves EphA2 at its Fibronectin type-III domain 1 upon physical interaction in the same cell-surface complexes; this cleavage coupled with EphA2-dependent Src activation triggers EphA2 intracellular translocation, increased RhoA activity, and cell junction disassembly, shifting breast carcinoma invasion from collective to single-cell mode. Co-immunoprecipitation, cleavage mutant analysis, RhoA activity assay, collagen invasion assay, in vivo model The Journal of cell biology High 23629968
2014 EphA2 promotes anoikis resistance through Akt-mediated Ser897 phosphorylation and subsequent Ephexin4-RhoG signaling; EphB6 interacts with EphA2 and suppresses this pathway by reducing EphA2 Ser897 phosphorylation and EphA2-Ephexin4 interaction. Co-immunoprecipitation, knockdown/rescue experiments, RhoG activity assay, anoikis assay Cellular signalling Medium 25239188
2014 EPHA2 inhibition in NSCLC decreases S6K1-mediated phosphorylation of BAD and induces apoptosis; an ATP-competitive EPHA2 kinase inhibitor (ALW-II-41-27) induces tumor regression in NSCLC xenografts. Conditional KO mouse model, EPHA2 KD in human cells, ATP-competitive inhibitor, Western blot, in vivo xenograft The Journal of clinical investigation High 24713656
2015 EphA2 forms dimers in the plasma membrane in the absence of ephrin ligand; dimerization-deficient EphA2 mutant shows enhanced cell migration with increased Ser897 phosphorylation and decreased tyrosine phosphorylation, indicating the EphA2 monomer mediates pro-tumorigenic activity. FRET-based dimerization measurement in HEK293T cells, mutagenesis, cell migration assay, Western blot The Journal of biological chemistry High 26363067
2015 Crystal structures of the EphA2 kinase domain in complex with clinical kinase inhibitors define drug-binding interactions; key, scaffold, potency, and selectivity residues in the EPHA2 drug-binding site are categorized. Cocrystal structures (9 new structures), NMR conformational dynamics, chemical proteomics ACS chemical biology High 27768280
2016 The EphA2 SAM domain inhibits receptor dimerization in the plasma membrane and decreases EphA2 tyrosine phosphorylation; SAM domain deletion increases oligomerization and constitutive kinase activation. FRET-based dimerization assay, SAM domain deletion mutant, Western blot for tyrosine phosphorylation Biochimica et biophysica acta High 27776928 28338017
2016 EphA2 is a functional signaling receptor for the growth factor progranulin; progranulin binds EphA2 with high affinity, causing prolonged receptor activation, downstream MAPK and Akt stimulation, and capillary morphogenesis promotion. Solid-phase binding assay, solution-phase binding assay, receptor activation assay, signaling Western blot, tube formation assay The Journal of cell biology High 27903606
2016 EphA2 acts as a key downstream effector of the MEK/ERK/RSK pathway in glioblastoma; EGF-induced EphA2 Ser897 phosphorylation is mediated by RSK kinase (not PI3K/Akt), and S897A EphA2 mutant suppresses EGF/RSK2-induced proliferation. Pharmacological inhibitor studies (MEK, RSK, PI3K), shRNA knockdown, S897A mutant overexpression, proliferation assay Cellular signalling Medium 27132626
2017 EphA2 is an oral epithelial cell pattern recognition receptor (PRR) for fungal β-glucans; EphA2 binding to C. albicans β-glucans activates STAT3 and MAPK signaling in an inoculum-dependent manner required for proinflammatory and antifungal responses; EphA2-/- mice have impaired IL-17 signaling and more severe oropharyngeal candidiasis. EphA2-/- mouse model, β-glucan binding assay, signaling pathway analysis, infection model Nature microbiology High 29133884
2018 EphA2 is activated through distinct, ligand-dependent oligomeric structures; dimeric ephrinA1-Fc, monomeric ephrinA1, and engineered peptide ligands stabilize conformationally distinct oligomers assembled through two different interfaces, all leading to increased EphA2 tyrosine phosphorylation. Quantitative FRET in plasma membrane, ligand comparison studies Communications biology High 30271902
2018 C. neoformans activates EphA2 through CD44-dependent phosphorylation, promoting EphA2 clustering and internalization; EphA2 activity facilitates blood-brain barrier transmigration of C. neoformans. EphA2 silencing, antibody/inhibitor blockade, EphA2 agonist treatment, HEK293T overexpression, transmigration assay Cellular microbiology Medium 29197141
2018 The EphA2 fibronectin type-III domain 2 (FN2) interacts with anionic lipids (especially PIP2) via a specific site (K441, R443, R465, Q462, S464, S491, W467, F490, P459-461), anchoring the ectodomain at the membrane surface and constraining EphA2 ectodomain conformation. Multiscale molecular dynamics simulations, lipid vesicle binding assay, FN2 domain mutagenesis Structure Medium 26724997
2019 EPHA2 signaling through TGFβ induces PTGS2 (COX-2) expression in tumor cells; EPHA2-PTGS2 signaling drives T cell exclusion from the tumor microenvironment; Epha2 or Ptgs2 deletion sensitizes pancreatic tumors to immunotherapy. Genetic deletion (Epha2-/-, Ptgs2-/-), pharmacological inhibition, immunotherapy combination, tumor immune profiling The Journal of clinical investigation High 31162144
2019 Crystal structures of YSA peptide and derivatives bound to EphA2 ligand-binding domain (LBD) show that YSA targets the ephrin-binding pocket and mimics ephrin-A ligand binding features; C-terminal features can convert YSA from antagonist to agonist by promoting receptor oligomerization and autophosphorylation. Crystal structures (1.53-2.20 Å resolution), FRET measurements in live cells, functional signaling assays The Journal of biological chemistry High 31015204
2020 EphA2 directly phosphorylates NLRP3 at Tyr132, interfering with ASC speck formation and blocking NLRP3 inflammasome activation in airway epithelial cells; EphA2 deficiency enhances IL-1β and IL-18 production and exacerbates asthma. Co-immunoprecipitation, phosphorylation site mutagenesis (Tyr132), EphA2-/- mouse model, ASC speck assay EMBO reports High 32352641
2020 RSK1/2 phosphorylates EphA2 at Ser897 (oncogenic non-canonical signaling); RSK inhibition prevents EphA2-S897 phosphorylation and promotes a shift to canonical tumor-suppressive tyrosine phosphorylation; EphA2 and GPRC5A are co-regulated in a cisplatin resistance pathway. Pharmacological RSK inhibition, patient tumor analysis, cell line models, phospho-Western blot EMBO molecular medicine Medium 32165640
2020 EphA2 forms a protein complex with pendrin (SLC26A4), controlling pendrin localization; EphA2 mutants from Pendred syndrome patients attenuate ephrin-B2-induced but not ephrin-A1-induced EphA2 internalization with pendrin; ephrin-B2 binding to EphA2 triggers internalization with pendrin. Co-immunoprecipitation, protein localization assay, receptor internalization assay, patient mutation analysis Nature communications High 32165640
2020 PIP2 promotes EphA2 transmembrane domain dimerization specifically in the small crossing-angle (ligand-independent) conformation; the TM and juxtamembrane regions are conformationally coupled and PIP2 may alleviate electrostatic repulsion between positively charged JM segments. Hydrophobic matching peptide system, single-molecule SMA lipid particle dimerization assay The Journal of biological chemistry Medium 33277361
2020 ANXA1 competes with Cbl for binding EphA2 and inhibits Cbl-mediated EphA2 ubiquitination and degradation, thereby increasing EphA2 protein stability and oncogenic pS897-EphA2 signaling in nasopharyngeal carcinoma. Co-immunoprecipitation, ubiquitination assay, ANXA1/Cbl competition assay, in vitro and in vivo tumor models Cancer research High 32737118
2020 Phosphorylation of EphA2 at Y772 (ligand-independent) activates the Shp2/Erk-1/2 signaling pathway through Gab1 and Grb2, promoting NPC cell proliferation; Y772A mutation blocks this signaling. Phosphorylation-null mutant (Y772A) stable cell lines, Western blot, proliferation assay, xenograft model Cell death & disease Medium 32848131
2020 Crystal structures of KSHV gHgL and EBV gHgL in complex with the EphA2 ligand-binding domain (LBD) reveal that both viral glycoproteins bind the channel and peripheral regions of EphA2 LBD primarily using gL; mutations in key EphA2 residues verified in cell-based fusion assays. Crystal structure determination, cell-based fusion assays, EphA2 binding mutagenesis Nature communications High 33235207
2021 EphA2 interacts with and phosphorylates YAP protein, leading to YAP stabilization, nuclear translocation, and activation in gastric cancer cells; EphA2-induced chemoresistance is mediated by increasing YAP stability. Co-immunoprecipitation, phosphorylation assay, KD of YAP with xenograft rescue, Western blot International journal of cancer Medium 31376289
2021 EphA2 activates YES1 (non-receptor tyrosine kinase), which phosphorylates ANXA2 at Tyr24, leading to ANXA2 nuclear distribution and gastric cancer invasion; Y24F ANXA2 mutant cannot restore YES1-induced invasion. Co-immunoprecipitation, phosphorylation site mutagenesis (Tyr24F), KD/rescue experiments, mouse xenograft models Oncogene High 33941853
2021 EphA2 localizes to integrin adhesions where FAK mediates ligand-independent Y772 phosphorylation; EphA2 is required for fibrillar adhesion elongation and fibronectin fibrillogenesis by maintaining RhoA activity through p190RhoGAP regulation; Y772 mutation significantly blunts fibrillar adhesion length. EphA2 KO cells, Y772 phosphorylation site mutant, RhoA/p190RhoGAP activity assays, fibrillar adhesion imaging Matrix biology Medium 34537369
2021 Accumulation of multiple negative charges in the kinase-SAM linker (mimicking phosphorylation) induces cooperative conformational changes in EphA2 intracellular region from closed to extended states, perturbs the juxtamembrane segment and kinase domain, and promotes EphA2 oligomerization in cells; multiple kinases catalyze this linker phosphorylation. Integrative structural biology (SAXS, NMR, crystallography), FRET in cells, phosphomimetic mutant analysis Nature communications High 34857764
2021 USP3 deubiquitinase binds EPHA2 (through its F2 domain residue 203) and reduces EPHA2 protein degradation, activating PI3K/AKT signaling in osteosarcoma; EPHA2 knockdown reverses USP3-mediated pro-tumor effects. Co-immunoprecipitation, USP3 truncation mutants, ubiquitination assay, EPHA2 KD rescue Cell death & disease Medium 38531846
2022 CLDN1 directly interacts with EphA2 via its PDZ-binding motif, inhibiting EphA2 degradation and enhancing downstream AKT signaling and CD44 expression to promote cancer stemness and chemoresistance in colorectal cancer. Co-immunoprecipitation, biophysical binding assays, proteomics, PDZ-binding motif mutant analysis, patient-derived organoids Cancer letters Medium 37924938
2023 Ligand-free EphA2 assembles into multimers through two types of intermolecular ectodomain interactions: (1) extended symmetric interactions driving ligand-induced clustering and tumor-suppressive signaling (inhibiting ERK/AKT); (2) asymmetric interactions between amino terminus and membrane-proximal domain supporting oncogenic signaling and promoting migration and tumor invasiveness. Time-resolved live-cell fluorescence spectroscopy, EphA2 interaction mutants, in vitro migration assay, in vivo tumor invasion model Science High 37972196
2023 EphA2 is a functional entry receptor for HCMV in glioblastoma cells; EphA2 binds to the HCMV gH/gL complex to mediate membrane fusion, and EphA2 inhibitor impairs HCMV infection in glioblastoma organoids. EphA2 silencing/overexpression, HCMV infection assay, co-immunoprecipitation (EphA2-gH/gL), inhibitor treatment, organoid model PLoS pathogens Medium 37146061

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Role of B61, the ligand for the Eck receptor tyrosine kinase, in TNF-alpha-induced angiogenesis. Science (New York, N.Y.) 340 7536959
2000 The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization. Oncogene 324 11146556
2011 Emerging strategies for EphA2 receptor targeting for cancer therapeutics. Expert opinion on therapeutic targets 212 21142802
2002 Antibody targeting of the EphA2 tyrosine kinase inhibits malignant cell behavior. Cancer research 179 12019162
2020 Targeting EphA2 in cancer. Journal of hematology & oncology 173 32811512
2009 Elevation of receptor tyrosine kinase EphA2 mediates resistance to trastuzumab therapy. Cancer research 170 20028874
2005 EphA2 receptor tyrosine kinase as a promising target for cancer therapeutics. Current cancer drug targets 158 15892616
2017 EphA2 is an epithelial cell pattern recognition receptor for fungal β-glucans. Nature microbiology 144 29133884
2004 Antiangiogenic and antitumor efficacy of EphA2 receptor antagonist. Cancer research 142 14871820
2008 The EPHA2 gene is associated with cataracts linked to chromosome 1p. Molecular vision 130 19005574
2019 Tumor cell-intrinsic EPHA2 suppresses anti-tumor immunity by regulating PTGS2 (COX-2). The Journal of clinical investigation 129 31162144
2009 EPHA2 is associated with age-related cortical cataract in mice and humans. PLoS genetics 129 19649315
2010 Ephexin4 and EphA2 mediate cell migration through a RhoG-dependent mechanism. The Journal of cell biology 126 20679435
2021 Oncogenic functions and therapeutic targeting of EphA2 in cancer. Oncogene 125 33686241
2002 Activation of the EphA2 tyrosine kinase stimulates the MAP/ERK kinase signaling cascade. Oncogene 117 12400011
2018 Chemoresistance Transmission via Exosome-Mediated EphA2 Transfer in Pancreatic Cancer. Theranostics 116 30613276
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
2016 EphA2 is a functional receptor for the growth factor progranulin. The Journal of cell biology 107 27903606
2014 Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC. The Journal of clinical investigation 99 24713656
2014 EPHA2 is a mediator of vemurafenib resistance and a novel therapeutic target in melanoma. Cancer discovery 99 25542448
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
2013 EphA2 cleavage by MT1-MMP triggers single cancer cell invasion via homotypic cell repulsion. The Journal of cell biology 79 23629968
2004 Expression of EphA2 and E-cadherin in colorectal cancer: correlation with cancer metastasis. Oncology reports 79 14767510
2017 Emerging and Diverse Functions of the EphA2 Noncanonical Pathway in Cancer Progression. Biological & pharmaceutical bulletin 77 28966234
2018 The EphA2 receptor is activated through induction of distinct, ligand-dependent oligomeric structures. Communications biology 74 30271902
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 67 33941853
2013 EphA2 and Src regulate equatorial cell morphogenesis during lens development. Development (Cambridge, England) 66 24026120
2022 Exosomal EPHA2 derived from highly metastatic breast cancer cells promotes angiogenesis by activating the AMPK signaling pathway through Ephrin A1-EPHA2 forward signaling. Theranostics 63 35673569
2017 EphA2 Expression Regulates Inflammation and Fibroproliferative Remodeling in Atherosclerosis. Circulation 61 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
2016 EphA2 is a key effector of the MEK/ERK/RSK pathway regulating glioblastoma cell proliferation. Cellular signalling 60 27132626
1997 ECK, a human EPH-related gene, maps to 1p36.1, a common region of alteration in human cancers. Genomics 60 9119409
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
2009 Regulation of mammary gland branching morphogenesis by EphA2 receptor tyrosine kinase. Molecular biology of the cell 55 19321667
2012 A role for epha2 in cell migration and refractive organization of the ocular lens. Investigative ophthalmology & visual science 53 22167091
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
2019 Morphological characteristics of vasculogenic mimicry and its correlation with EphA2 expression in gastric adenocarcinoma. Scientific reports 49 30833656
2020 Adaptive RSK-EphA2-GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer. EMBO molecular medicine 48 32115889
2016 The SAM domain inhibits EphA2 interactions in the plasma membrane. Biochimica et biophysica acta. Molecular cell research 48 27776928
2020 ANXA1 Binds and Stabilizes EphA2 to Promote Nasopharyngeal Carcinoma Growth and Metastasis. Cancer research 47 32737118
2021 Drug-resistant cancer cell-derived exosomal EphA2 promotes breast cancer metastasis via the EphA2-Ephrin A1 reverse signaling. Cell death & disease 46 33879771
2006 Silencing the receptor EphA2 suppresses the growth and haptotaxis of malignant mesothelioma cells. Cancer 46 17041885
2022 A novel TanCAR targeting IL13Rα2 and EphA2 for enhanced glioblastoma therapy. Molecular therapy oncolytics 45 35317513
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
2012 EphA2/Ephrin-A1 signaling complexes restrict corneal epithelial cell migration. Investigative ophthalmology & visual science 41 22247486
2023 Claudin-1 interacts with EPHA2 to promote cancer stemness and chemoresistance in colorectal cancer. Cancer letters 39 37924938
2020 Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome. Nature communications 39 32165640
2016 Novel anti-EPHA2 antibody, DS-8895a for cancer treatment. Cancer biology & therapy 39 27653549
2018 A novel pH-dependent membrane peptide that binds to EphA2 and inhibits cell migration. eLife 38 30222105
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
2010 Dual targeting of EphA2 and ER restores tamoxifen sensitivity in ER/EphA2-positive breast cancer. Breast cancer research and treatment 37 20602165
2020 Molecular basis of EphA2 recognition by gHgL from gammaherpesviruses. Nature communications 36 33235207
2014 Design, synthesis and bioevaluation of an EphA2 receptor-based targeted delivery system. ChemMedChem 35 24677792
2023 Time-resolved live-cell spectroscopy reveals EphA2 multimeric assembly. Science (New York, N.Y.) 34 37972196
2015 Structures of the EphA2 Receptor at the Membrane: Role of Lipid Interactions. Structure (London, England : 1993) 34 26724997
2020 PIP2 promotes conformation-specific dimerization of the EphA2 membrane region. The Journal of biological chemistry 32 33277361
2014 EphB6 promotes anoikis by modulating EphA2 signaling. Cellular signalling 32 25239188
2020 Y772 phosphorylation of EphA2 is responsible for EphA2-dependent NPC nasopharyngeal carcinoma growth by Shp2/Erk-1/2 signaling pathway. Cell death & disease 30 32848131
2019 Engineering nanomolar peptide ligands that differentially modulate EphA2 receptor signaling. The Journal of biological chemistry 30 31015204
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
2018 EphA2/Ephrin-A1 Mediate Corneal Epithelial Cell Compartmentalization via ADAM10 Regulation of EGFR Signaling. Investigative ophthalmology & visual science 28 29351356
2017 Chemoproteomics-Aided Medicinal Chemistry for the Discovery of EPHA2 Inhibitors. ChemMedChem 28 28544567
2024 USP3 promotes osteosarcoma progression via deubiquitinating EPHA2 and activating the PI3K/AKT signaling pathway. Cell death & disease 27 38531846
2017 Design and synthesis of small molecule agonists of EphA2 receptor. European journal of medicinal chemistry 27 29128116
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 27 26940768
2020 Spatial organization-dependent EphA2 transcriptional responses revealed by ligand nanocalipers. Nucleic acids research 26 32352518
2021 EphA2 and EGFR: Friends in Life, Partners in Crime. Can EphA2 Be a Predictive Biomarker of Response to Anti-EGFR Agents? Cancers 25 33572284
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
2021 Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker. Nature communications 24 34857764
2018 miR‑141 inhibits glioma vasculogenic mimicry by controlling EphA2 expression. Molecular medicine reports 24 29901110
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
2014 (99m)Tc-labeled SWL specific peptide for targeting EphA2 receptor. Nuclear medicine and biology 24 24768147
2020 Serum Exo-EphA2 as a Potential Diagnostic Biomarker for Pancreatic Cancer. Pancreas 23 32898008
2019 EPHA2 mutations with oncogenic characteristics in squamous cell lung cancer and malignant pleural mesothelioma. Oncogenesis 23 31484920
2014 Cross-talk between EphA2 and BRaf/CRaf is a key determinant of response to Dasatinib. Clinical cancer research : an official journal of the American Association for Cancer Research 23 24486585
2022 EPHA2, EPHA4, and EPHA7 Expression in Triple-Negative Breast Cancer. Diagnostics (Basel, Switzerland) 22 35204461
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
2020 Effect of EphA2 knockdown on melanoma metastasis depends on intrinsic ephrinA1 level. Cellular oncology (Dordrecht, Netherlands) 21 32291572
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
2006 A novel mechanism for p53 to regulate its target gene ECK in signaling apoptosis. Molecular cancer research : MCR 21 17050670
2009 Loss of EphA2 receptor tyrosine kinase reduces ApcMin/+ tumorigenesis. International journal of cancer 20 19089910
2006 Analysis of EphA2 expression and mutant p53 in ovarian carcinoma. Cancer biology & therapy 20 16969087
2022 Ligands with different dimeric configurations potently activate the EphA2 receptor and reveal its potential for biased signaling. iScience 19 35243233
2021 EphA2 signaling within integrin adhesions regulates fibrillar adhesion elongation and fibronectin deposition. Matrix biology : journal of the International Society for Matrix Biology 19 34537369
2025 Enhancement of anti-sarcoma immunity by NK cells engineered with mRNA for expression of a EphA2-targeted CAR. Clinical and translational medicine 18 39763064
2022 MFSD4A inhibits the malignant progression of nasopharyngeal carcinoma by targeting EPHA2. Cell death & disease 18 35410462
2014 Tobacco smoke induces epithelial barrier dysfunction via receptor EphA2 signaling. American journal of physiology. Cell physiology 18 24717580
2014 Deletion of the EphA2 receptor exacerbates myocardial injury and the progression of ischemic cardiomyopathy. Frontiers in physiology 18 24795639