Affinage

EPHA4

Ephrin type-A receptor 4 · UniProt P54764

Length
986 aa
Mass
109.9 kDa
Annotated
2026-06-09
100 papers in source corpus 43 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

EphA4 is a receptor tyrosine kinase that, upon binding A- and B-class ephrins, clusters and activates a tyrosine-kinase cascade to control cell repulsion, adhesion, cytoskeletal remodeling, and synaptic function across the nervous system and beyond (PMID:12496762, PMID:9259557, PMID:19875447). Its unusual pan-ephrin promiscuity is structurally explained: ephrin-A5 binding drives conformational change and higher-order clustering reinforced by an LBD–fibronectin receptor-receptor contact, while LBD residues Gln12/Glu14 provide interclass ephrin-B binding (PMID:19875447, PMID:23959867). Activated EphA4 channels signaling principally into Rho-family GTPase regulation—recruiting Cdk5 to activate the RhoA-GEF ephexin1 (PMID:17143272), engaging the Rac-GAP alpha2-chimaerin via its SH2 domain (PMID:17785182, PMID:17785183, PMID:17911252), and acting through SPAR/Rap1 and PLCgamma1/cofilin—to drive growth-cone collapse, dendritic spine retraction, and actin reorganization (PMID:18094260, PMID:17494698). In parallel, ligand-activated EphA4 recruits the ubiquitin ligase APC(Cdh1) to degrade GluR1 and downregulates beta1-integrin signaling, linking it to AMPA-receptor homeostasis and synaptic plasticity (PMID:21186356, PMID:17875741). At the circuit level EphA4 directs axon guidance of corticospinal, limb-motor, and commissural tracts—requiring kinase activity for some tracts but acting kinase-independently (as a ligand) for the anterior commissure—and patterns neural crest and rhombomere/somite boundaries downstream of Krox-20 and Mesp2 (PMID:9789074, PMID:10887087, PMID:11182082, PMID:9425139, PMID:16728472). EphA4 additionally regulates astrocytic gliosis after injury, glial glutamate transport during LTP, oligodendrocyte myelination via ephexin1/RhoA/ROCK, and is a mediator of amyloid-beta oligomer-induced synaptic dysfunction through c-Abl, antagonized by SORLA (PMID:15537875, PMID:19734893, PMID:24958880, PMID:24658113, PMID:29350423, PMID:29114064). Outside the nervous system it negatively regulates osteoclast bone resorption, endothelial collateral remodeling, glucagon secretion, and macrophage efferocytosis (PMID:26251403, PMID:31689239, PMID:23983218, PMID:37941008).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Established EphA4 as a repulsive guidance receptor governing positional sorting, answering how migrating cells reach correct destinations.

    Evidence Dominant-negative receptor and ectopic ephrin-B2 in Xenopus neural crest

    PMID:9259557

    Open questions at the time
    • Downstream signaling not defined
    • Mammalian relevance not tested in this study
  2. 1998 High

    Genetic knockout defined EphA4 as essential for corticospinal tract formation and revealed direct transcriptional control by Krox-20 in rhombomeres, linking patterning to receptor expression.

    Evidence EphA4 null mice with anterograde tracing; Krox-20 binding-site mutagenesis and transgenic reporters

    PMID:9425139 PMID:9789074

    Open questions at the time
    • Did not separate kinase-dependent from kinase-independent function
    • Effector pathways unresolved
  3. 2000 High

    Showed EphA4 dosage encodes binary axon pathfinding decisions, explaining dorsal/ventral limb motor selection.

    Evidence EphA4 knockout limb innervation analysis with differential protein expression

    PMID:10887087

    Open questions at the time
    • Co-acting guidance systems not yet integrated
    • Mechanism of dorsal-specific enrichment unknown
  4. 2001 High

    Demonstrated EphA4 can signal both as a kinase-active receptor and as a kinase-independent ligand, resolving how one molecule guides distinct tracts.

    Evidence Kinase-dead and SAM-deletion knock-in mice with tract tracing

    PMID:11182082

    Open questions at the time
    • Reverse-signaling partner for AC not identified
    • Structural basis of kinase-independent mode unclear
  5. 2003 High

    Connected EphA4 to dendritic spine morphology via neuroglial cross-talk, establishing a postsynaptic role and a Rho-GEF mechanism in vascular cells.

    Evidence Hippocampal slices with KO mice and kinase-dead mutant; Co-IP and GEF assays of Vsm-RhoGEF in VSMCs

    PMID:12496762 PMID:12775584

    Open questions at the time
    • Full effector chain to actin not yet mapped
    • VSMC and neuronal mechanisms not unified
  6. 2006 High

    Identified Cdk5 recruitment to EphA4 as the trigger for ephexin1/RhoA activation and spine retraction, defining a core kinase-effector module; Mesp2 added a second direct transcriptional input.

    Evidence Reciprocal Co-IP, Cdk5-/- brains, phosphorylation and electrophysiology; Mesp2 binding and reporter assays

    PMID:16728472 PMID:17143272

    Open questions at the time
    • Spatial control of Cdk5 recruitment unknown
    • Crosstalk between ephexin1 and other GEFs unresolved
  7. 2007 High

    Mapped parallel downstream effectors—alpha2-chimaerin/Rac1, PLCgamma1/cofilin, SPAR/Rap, and beta1-integrin inactivation—that mediate growth-cone collapse and spine remodeling, and showed FGFR trans-activation.

    Evidence SH2-domain interaction, GAP/GEF activity assays, KO mice phenocopying, juxtamembrane mutagenesis, yeast two-hybrid and trans-phosphorylation

    PMID:16365308 PMID:17494698 PMID:17785182 PMID:17785183 PMID:17875741 PMID:17911252 PMID:18094260

    Open questions at the time
    • Hierarchy among parallel effectors not established
    • Context-dependent effector selection unexplained
  8. 2009 High

    Defined the structural basis of pan-ephrin promiscuity and linked EphA4 to LTP via glial glutamate transport and cortical progenitor proliferation.

    Evidence EphA4-ephrin-B2 crystal structure with mutagenesis; ephrin-A3/EphA4 mutant LTP recordings; cortical progenitor gain/loss of function

    PMID:19542359 PMID:19734893 PMID:19875447

    Open questions at the time
    • Cluster assembly mechanism still incomplete in 2009
    • Progenitor effector pathway not defined
  9. 2010 High

    Revealed that EphA4 drives AMPA-receptor homeostasis by recruiting APC(Cdh1) to degrade GluR1, connecting receptor activation to proteostatic control of synaptic strength.

    Evidence Reciprocal Co-IP, in vitro proteasomal degradation, Cdh1 knockdown with mEPSC recordings

    PMID:21186356

    Open questions at the time
    • How phosphorylated EphA4 selects APC(Cdh1) unknown
    • Other proteasomal substrates not identified
  10. 2013 High

    Resolved the full ectodomain architecture and clustering mechanism, and used conditional and forward-signaling-specific models to assign cell-autonomous guidance roles in cochlea and spinal cord.

    Evidence Full ectodomain and ephrin-A5 complex crystallography with mutagenesis; conditional EphA4 mutants with tract/innervation tracing

    PMID:23385583 PMID:23959867 PMID:24360544

    Open questions at the time
    • Stoichiometry of physiological clusters in vivo unknown
    • Link between cluster size and effector output unmapped
  11. 2014 High

    Implicated EphA4 as a mediator of amyloid-beta oligomer synaptic toxicity via c-Abl, identified small-molecule and peptide antagonists, and showed ectodomain shedding tunes ligand availability.

    Evidence EphA4-KO neurons and APP/PS1 mice with LTP; molecular docking and rhynchophylline; cyclic peptide co-crystal structures; cleavage-resistant knock-in mice

    PMID:24658113 PMID:24958880 PMID:25264256 PMID:25268696

    Open questions at the time
    • In vivo therapeutic efficacy of antagonists not established
    • Sheddase identity and regulation unresolved
  12. 2017 Medium

    Extended EphA4 function to dependence-receptor apoptosis in glioblastoma, SORLA-mediated negative regulation in AD, and Sipa1l3/Wnt control in eye development.

    Evidence Ephrin-B3 silencing with GBM xenografts; SORLA Co-IP, transgenic mice and human AD brain; Xenopus epistasis with Wnt reporters

    PMID:27993984 PMID:28423606 PMID:29114064

    Open questions at the time
    • Dependence-receptor death effectors not defined
    • SORLA regulatory mechanism on clustering incompletely resolved
  13. 2020 High

    Defined non-neuronal physiological roles: endothelial EphA4 suppresses collateral remodeling via Tie2/Akt, alpha-cell EphA4 tonically inhibits glucagon through F-actin, osteoclast EphA4 restrains bone resorption via beta3-integrin, and macrophage EphA4 limits efferocytosis through ERK/Stat6/MERTK.

    Evidence Cell-type-specific conditional KO mice with functional and biochemical pathway assays across vascular, pancreatic, bone, and immune systems

    PMID:23983218 PMID:26251403 PMID:31689239 PMID:37941008

    Open questions at the time
    • Ligands driving each peripheral context not fully defined
    • Shared versus distinct effector logic across tissues unclear
  14. 2022 High

    Established that EphA4 in oligodendrocyte lineage cells restrains maturation and myelination via ephexin1/RhoA/ROCK, identifying it as a remyelination target after stroke.

    Evidence OPC-specific conditional KO, knockdown/overexpression in MCAO/R and OGD/R models with pathway epistasis

    PMID:29350423 PMID:35762396

    Open questions at the time
    • Axonal versus glial ligand source not isolated
    • Translation to chronic demyelination untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct ephrin ligands and cluster geometries are decoded into selection among the many parallel effector pathways (Cdk5/ephexin1, alpha2-chimaerin, PLCgamma1, SPAR/Rap, APC(Cdh1), integrin) in a cell-type-specific manner remains unresolved.
  • No unified model linking cluster state to effector choice
  • Quantitative effector competition not measured
  • Context determinants of kinase-dependent versus dependence-receptor outputs unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 3 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3 GO:0098631 cell adhesion mediator activity 2
Localization
GO:0005634 nucleus 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 1
Partners
CDK5CHN1EFNA3FCHSDFGFR1NGEFPLCG1SORL1

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 EphA4 is enriched on dendritic spines of pyramidal neurons; activation by astrocytic ephrin-A3 induces spine retraction, while inhibiting ephrin/EphA4 interactions or using kinase-inactive EphA4 distorts spine shape, establishing that ephrin-A3/EphA4 signaling controls dendritic spine morphology through neuroglial cross-talk. Hippocampal slice experiments, EphA4 knockout mice, kinase-inactive EphA4 transfection, ephrin-A3 activation assays Nature neuroscience High 12496762
1997 EphA4 and EphB1 expressed in migrating neural crest cells mediate repulsive interactions with ephrin-B2 to restrict intermingling of third arch neural crest cells and target them to the correct branchial arch destination; inhibition of EphA4/EphB1 function via truncated receptors causes aberrant migration, and ectopic ephrin-B2 scatters third arch neural crest. Truncated dominant-negative receptor expression in Xenopus, ectopic ephrin-B2 overexpression, neural crest migration tracking Current biology : CB High 9259557
1998 EphA4 (Sek1) is required for corticospinal tract formation; EphA4 null mice show major disruptions of the corticospinal tract in the medulla and spinal cord, demonstrating a critical role in establishing corticospinal projections. EphA4 null mutant mouse generation, anterograde tracing experiments, anatomical analysis Proceedings of the National Academy of Sciences of the United States of America High 9789074
2004 EphA4 expression is upregulated on astrocytes at spinal cord lesion sites; EphA4-/- mice show reduced astrocytic gliosis and glial scar formation, and EphA4-/- astrocytes fail to respond to inflammatory cytokines (IFN-γ or LIF). Neurons grown on wild-type astrocytes extend shorter neurites than on EphA4-/- astrocytes, but grow longer neurites when astrocyte EphA4 is blocked by monomeric EphrinA5-Fc, establishing EphA4 as a regulator of astrocytic gliosis and axonal inhibition after spinal cord injury. EphA4 knockout mice, spinal cord hemisection, anterograde and retrograde tracing, in vitro astrocyte/neuron co-culture assays, cytokine stimulation, monomeric EphrinA5-Fc blockade The Journal of neuroscience High 15537875
2006 Cdk5 is recruited to EphA4 upon ephrin-A1 activation, leading to tyrosine phosphorylation and activation of Cdk5. Activated EphA4/Cdk5 then enhances activation of ephexin1 (a RhoA GEF) via Cdk5-dependent phosphorylation of ephexin1, leading to RhoA activation and dendritic spine retraction. Cdk5 activity is required for ephrin-A1-triggered spine retraction and mEPSC frequency reduction. Cdk5 inhibition assays, Co-immunoprecipitation of EphA4 and Cdk5, tyrosine phosphorylation assays, Cdk5-/- brains, ephrin-A1 stimulation, mEPSC recordings, spine density analysis Nature neuroscience High 17143272
2009 EphA4 in postsynaptic CA1 neurons and ephrin-A3 in astrocytes modulate LTP at the CA3-CA1 synapse by regulating glial glutamate transporter abundance; lack of EphA4 increases glial glutamate transporters, and ephrin-A3 modulates transporter currents in astrocytes. Pharmacological inhibition of glial glutamate transporters rescues LTP defects in EphA4 and ephrin-A3 mutant mice. EphA4 and ephrin-A3 mutant mice, LTP recordings, glutamate transporter current measurements, pharmacological transporter inhibition, transgenic ephrin-A3 overexpression Nature neuroscience High 19734893
2000 EphA4 expressed at higher levels in dorsal versus ventral limb motor axons is required for dorsal/ventral pathway selection; in EphA4 mutant mice, presumptive dorsal motor axons fail to enter the dorsal compartment of the limb and instead join the ventral nerve, resulting in absence of the peroneal nerve. EphA4 gene inactivation (knockout mouse), limb innervation analysis, immunolabeling of EphA4 protein in dorsal vs. ventral axons Development (Cambridge, England) High 10887087
2001 EphA4 kinase activity is required for corticospinal tract (CST) formation (receptor function), whereas anterior commissure (AC) formation is rescued by kinase-dead EphA4, indicating EphA4 acts as a ligand (kinase-independent) for AC. The cytoplasmic SAM domain is not required for either function. Knock-in mice expressing kinase-dead or reduced-kinase EphA4 mutants, SAM domain deletion mutants, axon tract tracing Neuron High 11182082
2007 Alpha2-chimaerin, a Rac-specific GTPase-activating protein, binds activated EphA4 via its SH2 domain and mediates EphA4-triggered axonal growth cone collapse by enhancing its GAP activity toward Rac1. Alpha2-chimaerin mutant mice phenocopy EphA4 kinase-dead mice with hopping gait and aberrant midline axon guidance, establishing alpha2-chimaerin as an essential downstream effector of EphA4. Co-immunoprecipitation, SH2 domain interaction assay, in vitro GAP activity assay, tyrosine phosphorylation assay, alpha2-chimaerin knockout mice, growth cone collapse assay, locomotor analysis Neuron / PNAS High 17785182 17785183 17911252
2009 Crystal structure of EphA4 ligand-binding domain (LBD) in complex with ephrin-B2 reveals a loose fit of the ephrin-B2 G-H loop in the EphA4 binding channel. Residues Gln12 and Glu14 of EphA4 make surface contacts critical for ephrin-B class (interclass) binding but not ephrin-A binding; mutation of these residues reduces affinity for ephrin-B ligands ~10-fold without affecting ephrin-A affinity, explaining EphA4's unique pan-ephrin binding promiscuity. X-ray crystallography, site-directed mutagenesis, binding affinity measurements, NMR characterization The Journal of biological chemistry High 19875447
2013 High-resolution structures of the complete EphA4 ectodomain and its complex with ephrin-A5 reveal how ligand binding promotes conformational changes in the EphA4 LBD to form higher-order signaling clusters. A previously undescribed receptor-receptor interaction between the EphA4 LBD and membrane-proximal fibronectin domains is functionally important for efficient receptor activation, demonstrated by structure-based mutagenesis. X-ray crystallography of full EphA4 ectodomain and ephrin-A5 complex, structure-based mutagenesis, receptor activation assays Proceedings of the National Academy of Sciences of the United States of America High 23959867
2010 EphA4 activation results in decrease of synaptic and surface GluR1 (AMPA receptor subunit) via the ubiquitin-proteasome system (UPS). EphA4, upon ligand-dependent activation and tyrosine phosphorylation, associates with the ubiquitin ligase APC(Cdh1); APC(Cdh1) directly targets GluR1 for proteasomal degradation. Cdh1 depletion abolishes EphA4-dependent GluR1 downregulation and prevents mEPSC amplitude reduction during homeostatic plasticity. Co-immunoprecipitation of EphA4 with APC/Cdh1, in vitro proteasomal degradation assay, Cdh1 knockdown in neurons, mEPSC recordings, surface GluR1 imaging Nature neuroscience High 21186356
2007 EphA4 activation by ephrin-A3 in hippocampal slices inhibits beta1-integrin signaling: decreases tyrosine phosphorylation of FAK, Pyk2, and Cas, and reduces Cas association with Fyn and Crk. Inhibition of beta1-integrin or Cas function mimics EphA4-induced spine morphological changes, and preventing beta1-integrin inactivation blocks EphA4 effects on spines. Hippocampal slice ephrin-A3 stimulation, phosphorylation assays, Co-immunoprecipitation, integrin activity assay in neuronal cells, dominant-negative constructs The Journal of cell biology High 17875741
2003 EphA4 associates with Vsm-RhoGEF (a VSMC-specific RhoA GEF) in quiescent vascular smooth muscle cells. Upon ephrin-A1 stimulation, EphA4 phosphorylates Vsm-RhoGEF on tyrosine, enhancing its GEF activity toward RhoA. Dominant-negative Vsm-RhoGEF or RNAi depletion blocks ephrin-A1-induced actin stress fiber assembly in VSMCs. Co-immunoprecipitation (EphA4-Vsm-RhoGEF), tyrosine phosphorylation assays, GEF activity assay, dominant-negative overexpression, siRNA knockdown, actin staining Circulation research High 12775584
2007 EphA4 interacts with the PDZ domain of spine-associated RapGAP (SPAR) via its C-terminus, mediating EphA4-dependent inactivation of Rap1 and Rap2. SPAR-mediated Rap1 inactivation (but not Rap2) is critical for ephrin-A-dependent growth cone collapse and decreased integrin-mediated adhesion in neuronal cells. Co-immunoprecipitation of EphA4-SPAR, Rap GTPase activity assays, dominant-negative SPAR, growth cone collapse assay, integrin adhesion assay The Journal of neuroscience Medium 18094260
2007 EphA4 activation by ephrin stimulation recruits and activates PLCgamma1 through an SH2 domain interaction requiring EphA4 juxtamembrane tyrosines. PLC activity is required for ephrin-induced spine retraction, and EphA4/PLC signaling modulates the association of cofilin with the plasma membrane, linking EphA4 signaling to actin depolymerization and spine restructuring. PLCgamma1 recruitment assay, SH2 domain interaction, juxtamembrane tyrosine mutagenesis, PLC inhibitors, cofilin membrane fractionation, hippocampal slice spine morphology The Journal of neuroscience High 17494698
2005 EphA4 promotes cell adhesion within rhombomeres (in addition to mediating repulsion between rhombomeres); in mosaic zebrafish embryos, EphA4-depleted cells sort away from EphA4-expressing cells, supporting a differential cell adhesion mechanism parallel to repulsion in driving rhombomere boundary formation. Antisense morpholino knockdown in zebrafish, mosaic embryo analysis, cell sorting assays Current biology : CB Medium 15797022
1998 Krox-20 transcription factor directly activates EphA4 transcription in rhombomeres 3 and 5 through eight Krox-20 binding sites within a 470 bp enhancer element; mutation of these sites abolishes r3/r5-specific enhancer activity, and ectopic Krox-20 drives ectopic enhancer activation. Transgenic mouse enhancer analysis, Krox-20 binding site mutagenesis, ectopic Krox-20 expression, luciferase reporter assays Development (Cambridge, England) High 9425139
2006 GDNF/Ret and ephrin-A/EphA4 signaling cooperate in the same binary motor axon guidance decision (dorsal vs ventral limb); Ret and EphA4 double-mutant mice show enhanced misrouting of LMC(l) axons compared to single mutants, demonstrating epistatic cooperation between these two guidance systems. Gdnf, Ret, and EphA4 single and double mutant mouse analysis, limb motor axon tracing Neuron High 16600854
2005 Trans-activation between EphA4 and FGFRs is mediated by direct protein-protein interactions between the juxtamembrane domain of FGFR1-4 and the N-terminal kinase domain of EphA4. FGFR activation leads to tyrosine phosphorylation of kinase-negative EphA4, and EphA4 activation phosphorylates kinase-negative FGFR1; both receptors mutually potentiate FRS2alpha phosphorylation and MAPK activation. Yeast two-hybrid, Co-immunoprecipitation, kinase-negative receptor trans-phosphorylation assays, MAPK activation assays, ephrin-A1/FGF co-stimulation Proceedings of the National Academy of Sciences of the United States of America High 16365308
2014 Soluble amyloid-beta oligomers (AβOs) activate EphA4 in hippocampal neurons and synaptoneurosomes; EphA4 depletion or a small-molecule inhibitor (rhynchophylline, identified by molecular docking to the EphA4 LBD) blocks AβO-induced EphA4 activation and reverses suppression of LTP in APP/PS1 transgenic mice, establishing EphA4 as a mediator of Aβ-induced synaptic dysfunction. EphA4 knockdown in CA1, APP/PS1 transgenic mice, LTP recordings, molecular docking, rhynchophylline administration, EphA4 phosphorylation assays Proceedings of the National Academy of Sciences of the United States of America High 24958880
2014 EphA4 is upstream of c-Abl kinase activation by amyloid-beta oligomers in hippocampal neurons; AβO-induced EphA4 tyrosine phosphorylation is required for c-Abl activation (no c-Abl activation detected in EphA4-KO neurons exposed to AβOs). EphA4/c-Abl signaling mediates dendritic spine reduction, LTP blockade, and neuronal apoptosis caused by AβOs. EphA4 knockout neurons, sh-EphA4 transfection, c-Abl activity assays, EphA4 antagonist peptide (KYL), c-Abl inhibitor (STI), LTP recordings, spine density analysis PloS one High 24658113
2006 Mesp2 transcription factor directly binds to E-box-containing enhancer sequences of Epha4 and activates its transcription in the anterior presomitic mesoderm; forced Mesp2 expression activates EphA4 expression and represses caudal gene Uncx4.1 in somitic cells. Enhancer deletion analysis, luciferase reporter assays, transgenic mice, Mesp2 chromatin immunoprecipitation / direct binding assay, ectopic Mesp2 expression Development (Cambridge, England) High 16728472
2007 EphA4 is localized predominantly on the plasma membrane of axon terminals and dendritic spines (25-40% of terminals and 9-19% of spines labeled) at asymmetric/excitatory synapses in adult rat hippocampus, with dual pre- and postsynaptic localization supporting roles in synaptic plasticity. Electron microscopic immunocytochemistry (immunoperoxidase and immunogold labeling) in adult rat hippocampus The Journal of comparative neurology Medium 17299751
2013 EphA4 forward signaling (ephrin-A5/EphA4) is required for targeting type I spiral ganglion neuron afferents to inner hair cells in the cochlea; in EphA4 forward signaling-deficient mice, type I projections aberrantly invade the outer hair cell area. Downstream effectors ephexin-1, cofilin, and myosin light chain kinase act downstream of EphA4 to induce type I neuron growth cone collapse. EphA4 and ephrin-A5 knockout mice, conditional EphA4 mutants, growth cone collapse assay with ephexin-1/cofilin/MLCK pathway analysis, cochlear innervation analysis Nature communications High 23385583
2015 EphA4 forward signaling in pancreatic alpha-cells maintains a dense F-actin network that tonically inhibits glucagon secretion; alpha-cell-specific EphA4-/- mice exhibit abnormal glucagon dynamics and less dense F-actin. Stimulation of EphA4 inhibits glucagon secretion while inhibition enhances it, and restoration of EphA4 forward signaling in sorted alpha-cells rescues normal basal glucagon secretion and glucose inhibition of secretion. Alpha-cell-specific EphA4 knockout mice, glucagon secretion assays, EphA4 stimulation/inhibition in islets, sorted alpha-cells, F-actin density measurements Diabetes High 26251403
2008 EphA4 forms a heteroreceptor complex with FGFR1 in glioma cells; EphA4 overexpression enhances FGF2-mediated MAPK and Akt phosphorylation, and increases active Rac1 and Cdc42, promoting cell proliferation and migration. Co-immunoprecipitation (EphA4-FGFR1), MAPK/Akt phosphorylation assays, Rac1/Cdc42 pull-down (GTP-bound), overexpression in U251 glioma cells Molecular cancer therapeutics Medium 18790757
2018 Axonal ephrin-A1 activates EphA4 on oligodendrocytes to trigger the ephexin1-RhoA-ROCK-myosin 2 signaling cascade, causing inhibition of oligodendrocyte process extension and reduced myelination. EphA4 knockdown or inhibition at multiple levels of this pathway increases the number of myelin sheaths per oligodendrocyte. Axon-mimicking microfibers, zebrafish myelination model, EphA4 knockdown, pathway inhibitors (ROCK, myosin 2), ephexin1 assays, myelin sheath counting Glia High 29350423
2017 SORLA (SORL1) directly interacts with EphA4 and attenuates ephrinA1-induced EphA4 clustering and activation; SORLA transgenic mice show decreased EphA4 activation and redistribution to postsynaptic densities, with milder LTP and memory deficits induced by Aβ oligomers. Active EphA4 levels are elevated in human AD brains inversely correlated with SORLA/EphA4 association. Co-immunoprecipitation (SORLA-EphA4), SORLA transgenic mice, EphA4 clustering assay, LTP recordings, human AD brain analysis The Journal of experimental medicine High 29114064
2014 EphA4 shedding (ectodomain cleavage) in limb mesenchyme regulates spinal motor axon guidance: blocking EphA4 cleavage increases full-length EphA4 in limb mesenchyme, which via cis-attenuation reduces effective ephrin-A concentration available to trigger EphA4 forward signaling in motor axons, causing guidance defects. Cleavage-resistant EphA4 on neurons is as effective as wild-type for redirecting motor axons. Cleavage-resistant EphA4 knock-in mice, in vitro cell detachment assays, motor axon tracing, conditional EphA4 cleavage ablation in limb mesenchyme Current biology : CB High 25264256
2020 EphA4 in vascular endothelial cells suppresses pial collateral remodeling and cerebral blood flow recovery after ischemic stroke; endothelial-specific EphA4 deletion (EphA4fl/fl/Tie2-Cre and EphA4fl/fl/VeCadherin-CreERT2) enhances arteriogenic response. EphA4 negatively regulates Tie2 receptor signaling in endothelial cells through p-Akt modulation. Endothelial-specific EphA4 conditional knockout mice (two Cre lines), vessel painting, CBF measurement, Akt phosphorylation assays, peptide inhibition of EphA4 The Journal of clinical investigation High 31689239
2009 EphA4 forward signaling, specifically requiring EphA4 kinase activity, promotes proliferation of cortical progenitor cells during corticogenesis; EphA4-/- cortex has fewer cells and less cell division. EphA4 and ephrin-B1 (expressed in cortical progenitors) bind and initiate signaling, and ephrin-B1 overexpression stimulates division of neighboring cells via EphA4 forward signaling. EphA4-/- mice, in vivo EphA4 overexpression/knockdown in progenitors, cell division assays, binding assay (EphA4-ephrin-B1), cortical area measurements Development (Cambridge, England) Medium 19542359
2013 EphrinB3-induced EphA4 forward signaling guides both ascending Zic2+/EphA4+ spinal neuron axons and descending corticospinal tract axons using the same molecular mechanism; conditional EphA4 mutant analysis reveals that dorsal funiculus development depends on EphA4 in Zic2+ spinal neurons, not in descending CST axons. Conditional EphA4 knockout mice (Zic2-Cre and other Cre lines), axon tract tracing, anatomical analysis Neuron High 24360544
2007 EphA4 signaling in Xenopus blastulae induces reversible, cell-autonomous loss of adhesion; this is rescued by Nckbeta (Grb4) interaction with EphA4. EphA4 activates xPAK1 in an Nck-dependent manner; xPAK1 GTPase-binding domain sequesters active Cdc42, causing RhoA-GTP downregulation and loss of cell-cell adhesion. Xenopus blastula injection, dominant-negative and constitutively active GTPase constructs, xPAK1 activation assay, epistasis analysis, Cdc42/Rac/RhoA activity assays Molecular biology of the cell Medium 17215521
2002 In early Xenopus embryos, EphA4 catalytic activity inhibits RhoA GTPase (in contrast to activation in neuronal cells); constitutively active XRhoA rescues EphA4-induced loss of cell-cell adhesion, and overexpression of ephexin blocks EphA4-induced dissociation, suggesting an ephexin-dependent or independent pathway to Rho depending on cell context. Chimeric EPP receptor expression in Xenopus embryos, constitutively active XRhoA rescue, Rho GTPase inhibitor injection, ephexin overexpression Differentiation; research in biological diversity Medium 11963655
2014 Crystal structure of a cyclic peptide antagonist (APY) bound to the EphA4 ligand-binding domain shows efficient occupation of the ephrin-binding pocket with a 'closed' loop conformation. Structure-guided optimization yielded APY-βAla8.am with nanomolar EphA4 affinity; this peptide potently inhibits ephrin-induced EphA4 activation in cells and EphA4-dependent neuronal growth cone collapse with high EphA4 selectivity. X-ray crystallography of peptide-EphA4 LBD complex, structure-guided mutagenesis, binding affinity assay, cell-based EphA4 activation assay, growth cone collapse assay ACS chemical biology High 25268696
2014 EphA4 deficiency in osteoclasts activates beta3-integrin signaling through reduced phosphorylation of tyr-747, which increases binding of stimulatory talin and reduces binding of inhibitory Dok1 to beta3-integrin, in turn activating Vav3 and osteoclast bone resorption activity. EphA4 is thus a negative regulator of osteoclastic activity via this integrin-signaling pathway. EphA4 null mice (bone analysis), siRNA knockdown in RAW/C4 cells, EfnA4-Fc stimulation, beta3-integrin phosphorylation assays, talin/Dok1 Co-IP with beta3-integrin, Vav3 activation assay, bone resorption assay Journal of bone and mineral research High 23983218
2016 EphA4 is an upstream negative regulator of efferocytosis in macrophages/microglia after brain injury; EphA4 loss enhances efferocytosis by increasing p-ERK and p-Stat6 activity, which upregulates MERTK and Gas6 expression. ERK and Stat6 inhibitors abrogate the efferocytosis enhancement in EphA4 KO cells, establishing an EphA4→ERK/Stat6→MERTK signaling axis. Bone marrow chimeric EphA4 KO mice, TBI model, in vitro efferocytosis assay, phosphoarray, ERK/Stat6 selective inhibitors, MERTK/Gas6 mRNA analysis, single-cell RNAseq Journal of neuroinflammation High 37941008
2017 EphA4 acts upstream of Sipa1l3 during eye development in Xenopus; EphA4 deficiency phenocopies Sipa1l3 loss, and rescue experiments show EphA4 is upstream of Sipa1l3. Both proteins inhibit canonical Wnt/beta-catenin signaling (EphA4/Sipa1l3 loss upregulates axin2); inhibiting Wnt/beta-catenin or activating non-canonical Wnt rescues the EphA4-depletion eye phenotype. Xenopus morpholino knockdown, direct interaction assay (EphA4-Sipa1l3), genetic epistasis (rescue experiments), Wnt pathway reporter (axin2), pathway inhibition/activation rescue Development (Cambridge, England) Medium 27993984
2022 EphA4 promotes proliferation of oligodendrocyte precursor cells (OPCs) but reduces maturation to oligodendrocytes and decreases myelin-associated proteins after ischemic stroke; conditional OPC-specific EphA4 knockout improves remyelination and functional recovery. This effect is mediated by the Ephexin-1/RhoA/ROCK signaling pathway. PDGFRα-EphA4-shRNA, LV-EphA4 overexpression, EphA4fl/fl/AAV-PDGFRα-Cre conditional KO, MCAO/R ischemia model, OGD/R in vitro, myelin protein analysis, Ephexin-1/RhoA/ROCK pathway assays Glia High 35762396
2017 EphA4 acts as a dependence receptor: in the absence of its ligand ephrin-B3, EphA4 triggers apoptosis in glioblastoma cells. Ephrin-B3 overexpression in GBM inhibits EphA4 pro-apoptotic activity; Ephrin-B3 silencing reduces tumor vascularization and growth in xenograft mice. Ephrin-B3 silencing (siRNA), xenograft GBM mouse model, apoptosis assays, in vitro endothelial cell survival assay, human GBM biopsy analysis Oncotarget Medium 28423606

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling. Nature neuroscience 420 12496762
1997 The EphA4 and EphB1 receptor tyrosine kinases and ephrin-B2 ligand regulate targeted migration of branchial neural crest cells. Current biology : CB 282 9259557
2004 Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 260 15537875
2006 Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nature neuroscience 259 17143272
1998 EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract. Proceedings of the National Academy of Sciences of the United States of America 259 9789074
2012 EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. Nature medicine 241 22922411
2009 Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport. Nature neuroscience 236 19734893
2000 Targeting of the EphA4 tyrosine kinase receptor affects dorsal/ventral pathfinding of limb motor axons. Development (Cambridge, England) 227 10887087
2001 Kinase-dependent and kinase-independent functions of EphA4 receptors in major axon tract formation in vivo. Neuron 213 11182082
2014 Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America 174 24958880
2006 Cooperation between GDNF/Ret and ephrinA/EphA4 signals for motor-axon pathway selection in the limb. Neuron 160 16600854
2010 APC(Cdh1) mediates EphA4-dependent downregulation of AMPA receptors in homeostatic plasticity. Nature neuroscience 151 21186356
2005 EphA4 is required for cell adhesion and rhombomere-boundary formation in the zebrafish. Current biology : CB 135 15797022
1998 Segmental expression of the EphA4 (Sek-1) receptor tyrosine kinase in the hindbrain is under direct transcriptional control of Krox-20. Development (Cambridge, England) 127 9425139
2007 EphA4-dependent axon guidance is mediated by the RacGAP alpha2-chimaerin. Neuron 124 17785182
2007 The EphA4 receptor regulates dendritic spine remodeling by affecting beta1-integrin signaling pathways. The Journal of cell biology 122 17875741
2008 EphA4 promotes cell proliferation and migration through a novel EphA4-FGFR1 signaling pathway in the human glioma U251 cell line. Molecular cancer therapeutics 109 18790757
2007 alpha2-Chimaerin is an essential EphA4 effector in the assembly of neuronal locomotor circuits. Neuron 100 17785183
2003 EphA4-mediated Rho activation via Vsm-RhoGEF expressed specifically in vascular smooth muscle cells. Circulation research 100 12775584
2011 EphA4 blockers promote axonal regeneration and functional recovery following spinal cord injury in mice. PloS one 97 21931787
2003 Targeting the EphA4 receptor in the nervous system with biologically active peptides. Molecular and cellular neurosciences 93 14697664
2007 Alpha2-chimaerin interacts with EphA4 and regulates EphA4-dependent growth cone collapse. Proceedings of the National Academy of Sciences of the United States of America 90 17911252
2005 Trans-activation of EphA4 and FGF receptors mediated by direct interactions between their cytoplasmic domains. Proceedings of the National Academy of Sciences of the United States of America 82 16365308
2000 Expression of EphA4, ephrin-A2 and ephrin-A5 during axon outgrowth to the hindlimb indicates potential roles in pathfinding. Developmental neuroscience 79 10894987
2014 EphA4 activation of c-Abl mediates synaptic loss and LTP blockade caused by amyloid-β oligomers. PloS one 78 24658113
2009 Structural characterization of the EphA4-Ephrin-B2 complex reveals new features enabling Eph-ephrin binding promiscuity. The Journal of biological chemistry 77 19875447
2006 Behavioral and electromyographic characterization of mice lacking EphA4 receptors. Journal of neurophysiology 77 16641385
1997 Immunolocalization of the receptor tyrosine kinase EphA4 in the adult rat central nervous system. Brain research 77 9401744
2013 Insights into Eph receptor tyrosine kinase activation from crystal structures of the EphA4 ectodomain and its complex with ephrin-A5. Proceedings of the National Academy of Sciences of the United States of America 75 23959867
2007 The EphA4 receptor regulates neuronal morphology through SPAR-mediated inactivation of Rap GTPases. The Journal of neuroscience : the official journal of the Society for Neuroscience 73 18094260
2007 EphA4 signaling regulates phospholipase Cgamma1 activation, cofilin membrane association, and dendritic spine morphology. The Journal of neuroscience : the official journal of the Society for Neuroscience 71 17494698
2013 Ephrin-A5/EphA4 signalling controls specific afferent targeting to cochlear hair cells. Nature communications 67 23385583
2001 Development and reorganization of corticospinal projections in EphA4 deficient mice. The Journal of comparative neurology 67 11438928
2006 Identification of Epha4 enhancer required for segmental expression and the regulation by Mesp2. Development (Cambridge, England) 61 16728472
2018 Amyloid-β oligomers synaptotoxicity: The emerging role of EphA4/c-Abl signaling in Alzheimer's disease. Biochimica et biophysica acta. Molecular basis of disease 59 29378302
2009 Promotion of proliferation in the developing cerebral cortex by EphA4 forward signaling. Development (Cambridge, England) 58 19542359
2008 Overexpression of EphA4 gene and reduced expression of EphB2 gene correlates with liver metastasis in colorectal cancer. International journal of oncology 58 18695888
2007 Localization of EphA4 in axon terminals and dendritic spines of adult rat hippocampus. The Journal of comparative neurology 56 17299751
2013 EphrinB3/EphA4-mediated guidance of ascending and descending spinal tracts. Neuron 55 24360544
2012 Global evaluation of Eph receptors and ephrins in lung adenocarcinomas identifies EphA4 as an inhibitor of cell migration and invasion. Molecular cancer therapeutics 55 22807579
2008 Overexpression of the receptor tyrosine kinase EphA4 in human gastric cancers. World journal of gastroenterology 55 18837080
2006 EphA4 receptor, overexpressed in pancreatic ductal adenocarcinoma, promotes cancer cell growth. Cancer science 54 16965393
2005 EphA4 defines a class of excitatory locomotor-related interneurons. Proceedings of the National Academy of Sciences of the United States of America 54 16172411
2014 The Ephrin-A5/EphA4 Interaction Modulates Neurogenesis and Angiogenesis by the p-Akt and p-ERK Pathways in a Mouse Model of TLE. Molecular neurobiology 51 25502292
2022 Exosomal miR-532-5p induced by long-term exercise rescues blood-brain barrier function in 5XFAD mice via downregulation of EPHA4. Aging cell 49 36494892
2006 Thymic alterations in EphA4-deficient mice. Journal of immunology (Baltimore, Md. : 1950) 48 16818734
2018 Ephrin-A1-EphA4 signaling negatively regulates myelination in the central nervous system. Glia 46 29350423
2013 Modifying expression of EphA4 and its downstream targets improves functional recovery after stroke. Human molecular genetics 45 23418304
2013 Ephrin-A1/EphA4-mediated adhesion of monocytes to endothelial cells. Biochimica et biophysica acta 44 23707953
2012 Expression and activation of EphA4 in the human brain after traumatic injury. Journal of neuropathology and experimental neurology 44 22318127
2015 EphA4 Receptor Forward Signaling Inhibits Glucagon Secretion From α-Cells. Diabetes 43 26251403
2021 Exosomal miR-106b-5p derived from melanoma cell promotes primary melanocytes epithelial-mesenchymal transition through targeting EphA4. Journal of experimental & clinical cancer research : CR 41 33741023
2016 Transcriptomic Biomarkers for Tuberculosis: Evaluation of DOCK9. EPHA4, and NPC2 mRNA Expression in Peripheral Blood. Frontiers in microbiology 40 27826286
2020 EphA4/Tie2 crosstalk regulates leptomeningeal collateral remodeling following ischemic stroke. The Journal of clinical investigation 38 31689239
2006 EphA4 regulates central nervous system vascular formation. The Journal of comparative neurology 38 16802330
2004 EphA4 signaling promotes axon segregation in the developing auditory system. Developmental biology 38 15081355
2017 SORLA attenuates EphA4 signaling and amyloid β-induced neurodegeneration. The Journal of experimental medicine 37 29114064
2006 Temporal regulation of EphA4 in astroglia during murine retinal and optic nerve development. Molecular and cellular neurosciences 37 16574431
2017 Potent and Selective EphA4 Agonists for the Treatment of ALS. Cell chemical biology 36 28196613
2016 Activation of EphA4 and EphB2 Reverse Signaling Restores the Age-Associated Reduction of Self-Renewal, Migration, and Actin Turnover in Human Tendon Stem/Progenitor Cells. Frontiers in aging neuroscience 36 26779014
2007 EphA4 misexpression alters tonotopic projections in the auditory brainstem. Developmental neurobiology 35 17577206
2007 Auditory brainstem neural activation patterns are altered in EphA4- and ephrin-B2-deficient mice. The Journal of comparative neurology 35 17948875
2000 Developmental regulation of EphA4 expression in the chick auditory brainstem. The Journal of comparative neurology 35 10982468
2023 Efferocytosis is restricted by axon guidance molecule EphA4 via ERK/Stat6/MERTK signaling following brain injury. Journal of neuroinflammation 33 37941008
2009 Developmental course of EphA4 cellular and subcellular localization in the postnatal rat hippocampus. The Journal of comparative neurology 33 19086003
2004 Ectopic EphA4 receptor induces posterior protrusions via FGF signaling in Xenopus embryos. Molecular biology of the cell 33 14742708
2019 Peripheral loss of EphA4 ameliorates TBI-induced neuroinflammation and tissue damage. Journal of neuroinflammation 32 31711546
2014 EphA4 receptor is a novel negative regulator of osteoclast activity. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 32 23983218
2014 Development and structural analysis of a nanomolar cyclic peptide antagonist for the EphA4 receptor. ACS chemical biology 32 25268696
2001 Regulation of Epha4 expression in paraxial and lateral plate mesoderm by ectoderm-derived signals. Developmental dynamics : an official publication of the American Association of Anatomists 32 11307170
2017 Increased EphA4-ephexin1 signaling in the medial prefrontal cortex plays a role in depression-like phenotype. Scientific reports 31 28769056
2007 EphA4 signaling regulates blastomere adhesion in the Xenopus embryo by recruiting Pak1 to suppress Cdc42 function. Molecular biology of the cell 31 17215521
2016 EphA4 is Involved in Sleep Regulation but Not in the Electrophysiological Response to Sleep Deprivation. Sleep 30 26612390
2014 EphA4 receptor shedding regulates spinal motor axon guidance. Current biology : CB 30 25264256
2016 An Epha4/Sipa1l3/Wnt pathway regulates eye development and lens maturation. Development (Cambridge, England) 27 27993984
2014 Thalamic afferents influence cortical progenitors via ephrin A5-EphA4 interactions. Development (Cambridge, England) 27 25480914
2016 MiR-93 Targeting EphA4 Promotes Neurite Outgrowth from Spinal Cord Neurons. Journal of molecular neuroscience : MN 26 26798048
2017 EphA4 Regulates Neuroblast and Astrocyte Organization in a Neurogenic Niche. The Journal of neuroscience : the official journal of the Society for Neuroscience 25 28258169
2017 Identification and characterization of Nanobodies targeting the EphA4 receptor. The Journal of biological chemistry 25 28526745
2015 EphrinB2/EphA4-mediated activation of endothelial cells increases monocyte adhesion. Molecular immunology 25 26552760
2007 Reduction of EphA4 receptor expression after spinal cord injury does not induce axonal regeneration or return of tcMMEP response. Neuroscience letters 25 17418490
2002 Ephrin-as cooperate with EphA4 to promote trunk neural crest migration. Gene expression 25 12450221
2002 Developmental expression of EphA4-tyrosine kinase receptor in the mouse brain and spinal cord. Mechanisms of development 25 14516691
2000 Expression of EphA4 in developing inner ears of the mouse and guinea pig. Hearing research 25 10601711
2017 Critical role of EphA4 in early brain injury after subarachnoid hemorrhage in rat. Experimental neurology 24 28698029
2013 EphA4 receptor tyrosine kinase is a modulator of onset and disease severity of experimental autoimmune encephalomyelitis (EAE). PloS one 24 23390555
2008 Coordinated action of N-CAM, N-cadherin, EphA4, and ephrinB2 translates genetic prepatterns into structure during somitogenesis in chick. Current topics in developmental biology 24 18023729
2018 Decreased signalling of EphA4 improves functional performance and motor neuron survival in the SOD1G93A ALS mouse model. Scientific reports 23 30061574
2011 Attenuation of scratch-induced reactive astrogliosis by novel EphA4 kinase inhibitors. Journal of neurochemistry 23 21736568
2006 Eph tyrosine kinase receptor EphA4 is required for the topographic mapping of the corticospinal tract. Proceedings of the National Academy of Sciences of the United States of America 23 17030822
2022 EPHA2, EPHA4, and EPHA7 Expression in Triple-Negative Breast Cancer. Diagnostics (Basel, Switzerland) 22 35204461
2022 EphA4 regulates white matter remyelination after ischemic stroke through Ephexin-1/RhoA/ROCK signaling pathway. Glia 22 35762396
2017 Ephrin-B3 supports glioblastoma growth by inhibiting apoptosis induced by the dependence receptor EphA4. Oncotarget 22 28423606
2017 miR-519d Promotes Melanoma Progression by Downregulating EphA4. Cancer research 22 29093007
2016 EphA4-mediated signaling regulates the aggressive phenotype of irradiation survivor colorectal cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 22 27323967
2018 Identification of new EphA4 inhibitors by virtual screening of FDA-approved drugs. Scientific reports 21 29743517
2014 The Ephrin receptor EphA4 restricts axonal sprouting and enhances branching in the injured mouse optic nerve. The European journal of neuroscience 21 25041248
2014 Are we using the right pharmacological tools to target EphA4? ACS chemical neuroscience 21 25405504
2002 EphA4 catalytic activity causes inhibition of RhoA GTPase in Xenopus laevis embryos. Differentiation; research in biological diversity 21 11963655
2016 The Role of EphA4 Signaling in Radiation-Induced EMT-Like Phenotype in Colorectal Cancer Cells. Journal of cellular biochemistry 20 27632701

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