Affinage

EPHA4

Ephrin type-A receptor 4 · UniProt P54764

Length
986 aa
Mass
109.9 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EphA4 is a promiscuous receptor tyrosine kinase that functions as a central organizer of axon guidance, dendritic spine morphology, synaptic plasticity, and myelination in the nervous system. Structurally, conformational flexibility of the D-E and J-K loops in its ligand-binding domain enables binding to both ephrin-A and ephrin-B subclass ligands, and distinct loop conformations underlie agonist versus antagonist responses (PMID:18708347, PMID:20678482, PMID:25334011). Upon ephrin-induced activation, EphA4 recruits effectors including Cdk5/ephexin-1 to activate RhoA, alpha2-chimaerin to inactivate Rac1, PLCγ1 to regulate cofilin, and APC(Cdh1) to ubiquitinate the AMPA receptor subunit GluR1, thereby controlling actin remodeling, growth cone collapse, spine retraction, and homeostatic synaptic scaling (PMID:17143272, PMID:17785183, PMID:17494698, PMID:21186356). Beyond neurons, EphA4 signaling on astrocytes regulates gliosis and glial glutamate transporter levels to modulate LTP (PMID:15537875, PMID:19734893), on oligodendrocytes it inhibits myelination through an ephexin-1/RhoA/ROCK cascade (PMID:29350423, PMID:35762396), and in the spinal cord its expression in Vglut2-positive excitatory interneurons is required for left-right locomotor alternation (PMID:12649481, PMID:24623763).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1997 Medium

    Before any functional studies in vivo, the subcellular distribution of EphA4 at synaptic sites in the adult brain was unknown; immunogold EM demonstrated enrichment on dendritic spine plasma membranes and myelinated axons, establishing EphA4 as a synaptically positioned receptor.

    Evidence Immunoperoxidase and immunogold electron microscopy in adult rat brain

    PMID:9401744

    Open questions at the time
    • No functional consequence of synaptic localization demonstrated
    • Ligand identity at these synaptic sites not established
  2. 1998 High

    The in vivo requirement for EphA4 in CNS axon guidance was established when EphA4-null mice showed disrupted corticospinal tract trajectories and a hopping gait, demonstrating a non-redundant role in long-range axon pathfinding.

    Evidence EphA4-null mouse with anterograde tracing and behavioral analysis

    PMID:9789074

    Open questions at the time
    • Cell-type autonomy of the phenotype not resolved
    • Downstream signaling pathway unknown
  3. 2000 High

    EphA4's role was extended to peripheral axon guidance when EphA4-mutant dorsal limb motor axons were shown to misproject ventrally, establishing EphA4-mediated repulsion as the mechanism for dorsal-ventral trajectory selection.

    Evidence EphA4 KO mouse with motor axon tracing

    PMID:10887087

    Open questions at the time
    • Cooperation with other guidance systems not tested
    • Downstream effectors not identified
  4. 2003 High

    Two contemporaneous studies revealed that EphA4 operates in distinct neuronal circuits — dendritic spines of hippocampal pyramidal neurons (controlling spine shape via neuroglial cross-talk with ephrin-A3) and spinal excitatory interneurons (where ephrinB3/EphA4 organizes left-right locomotor alternation) — demonstrating broad functional deployment across brain regions and ligand subclasses.

    Evidence EphA4 KO mice with hippocampal slice ephrin-A3 activation and spinal cord electrophysiology/ephrinB3 KO

    PMID:12496762 PMID:12649481

    Open questions at the time
    • Intracellular signaling mediating spine retraction uncharacterized
    • Molecular identity of the spinal midline barrier mechanism not known
  5. 2004 High

    EphA4's role was shown to extend beyond neurons to reactive astrocytes, where it drives gliosis and axon growth inhibition after spinal cord injury, broadening the receptor's function to neuroinflammatory contexts.

    Evidence EphA4 KO mice with spinal cord hemisection, in vitro astrocyte neurite outgrowth assays, monomeric ephrinA5-Fc blocker

    PMID:15537875

    Open questions at the time
    • Downstream signaling in astrocytes not defined
    • Whether blocking EphA4 promotes functional recovery in vivo not tested
  6. 2006 High

    The first downstream signaling cascade was delineated: Cdk5 is recruited to activated EphA4, phosphorylates ephexin-1, which activates RhoA to drive spine retraction — establishing the Cdk5/ephexin-1/RhoA module as the core effector for EphA4 in dendritic spine remodeling.

    Evidence Co-IP of EphA4/Cdk5/ephexin-1, Cdk5-null neurons, phospho-mutant ephexin-1, mEPSC recordings

    PMID:17143272

    Open questions at the time
    • Relationship of this pathway to other EphA4 effectors (Rac, integrins) not integrated
    • Whether the same cascade operates in axon guidance not tested
  7. 2007 High

    Multiple parallel EphA4 effector arms were discovered simultaneously: alpha2-chimaerin (RacGAP for Rac1, phenocopying EphA4 KO in vivo), PLCγ1/cofilin (actin remodeling in spines), SPAR/Rap1 (integrin inactivation for growth cone collapse), and integrin inhibition via Cas/FAK dephosphorylation — revealing a branched signaling architecture downstream of EphA4.

    Evidence Alpha2-chimaerin KO mice (two independent labs), Co-IPs and GAP assays, PLCγ1 SH2 binding and PLC inhibitor studies, SPAR/Rap activity assays, integrin/Cas/FAK phospho-immunoblotting

    PMID:17494698 PMID:17785183 PMID:17875741 PMID:17911252 PMID:18094260

    Open questions at the time
    • How these parallel arms are coordinated or selectively activated remains unknown
    • SPAR and PLCγ1 pathways validated in single labs only
  8. 2008 High

    Structural biology began resolving how EphA4 achieves ligand promiscuity: crystal structures revealed a jellyfish β-sandwich with flexible D-E and J-K loops forming the ephrin-binding channel, and small-molecule antagonists were shown to bind competitively within this channel.

    Evidence X-ray crystallography, NMR HSQC titration, ITC, ephrin competition ELISA

    PMID:18708347

    Open questions at the time
    • No full-length EphA4 structure
    • Mechanism of ligand-induced kinase activation not structurally resolved
  9. 2009 High

    Three discoveries expanded EphA4's functional scope: gamma-secretase cleavage of EphA4 generates an ICD that promotes spine formation via Rac; EphA4 controls LTP by regulating astrocytic glutamate transporter levels through ephrin-A3 reverse signaling; and EphA4/ephrin-B1 interaction drives cortical progenitor proliferation — demonstrating signaling roles in proteolytic processing, trans-synaptic glial regulation, and neurogenesis.

    Evidence Gamma-secretase cleavage biochemistry and Rac reporter; EphA4/ephrinA3 KO mice with LTP rescue by glutamate transporter inhibitors; EphA4 KO cortex BrdU analysis and in vivo electroporation

    PMID:19414612 PMID:19542359 PMID:19734893

    Open questions at the time
    • Physiological relevance of gamma-secretase cleavage not confirmed in vivo
    • Relative contribution of forward versus reverse signaling in LTP not fully resolved
  10. 2009 High

    Crystallographic analysis of EphA4 in complex with the cross-subclass ligand ephrin-B2 identified specific residues (Gln12, Glu14) that confer ephrin-B binding without affecting ephrin-A interaction, defining the structural basis for EphA4's unusual cross-subclass promiscuity.

    Evidence X-ray crystallography of EphA4-LBD/ephrin-B2 complex, mutagenesis with ITC/ELISA binding measurements

    PMID:19875447

    Open questions at the time
    • Functional consequences of selectively disrupting ephrin-B binding in vivo not tested
  11. 2010 High

    EphA4 was linked to homeostatic synaptic scaling through its association with the ubiquitin ligase APC(Cdh1), which targets the AMPA receptor subunit GluR1 for proteasomal degradation — extending EphA4 signaling from structural spine remodeling to receptor trafficking.

    Evidence Co-IP of EphA4/APC/Cdh1, in vitro ubiquitination, Cdh1 knockdown, mEPSC recordings

    PMID:21186356

    Open questions at the time
    • How EphA4 activation triggers APC(Cdh1) recruitment mechanistically is unclear
    • Whether this pathway operates in pathological conditions not examined
  12. 2013 High

    Conditional and cell-type-specific knockouts refined the circuit-level requirement: EphA4 in Vglut2+ spinal excitatory interneurons is both necessary and sufficient for locomotor alternation, and ephrinB3/EphA4 guides both ascending spinal and descending CST axons through midline barriers, with the CST defect arising non-autonomously from EphA4 in Zic2+ spinal neurons.

    Evidence Cell-type-specific conditional EphA4 KO (Vglut2-Cre, Zic2-Cre), locomotor analysis, anterograde/retrograde tracing

    PMID:24360544 PMID:24623763

    Open questions at the time
    • How EphA4 in spinal neurons non-autonomously affects CST axon trajectory is mechanistically unresolved
  13. 2014 Medium

    EphA4 was identified as a mediator of amyloid-β oligomer synaptotoxicity: Aβ oligomers activate EphA4, which signals through c-Abl to cause spine loss, LTP blockade, and apoptosis; genetic or pharmacological EphA4 inhibition rescues these deficits in AD mouse models, positioning EphA4 as a candidate therapeutic target in Alzheimer's disease.

    Evidence EphA4 KO neurons, shRNA, KYL antagonist peptide, rhynchophylline (small molecule), APP/PS1 mice, LTP electrophysiology

    PMID:24658113 PMID:24958880

    Open questions at the time
    • Whether EphA4 is a direct Aβ receptor or is activated indirectly remains unresolved
    • Therapeutic efficacy in human AD not established
    • Findings from single labs; independent replication needed
  14. 2014 High

    NMR dynamics studies and co-crystal structures with cyclic peptide antagonists established that agonism versus antagonism of EphA4 correlates with opposite modulation of backbone dynamics in the ligand-binding domain, providing a dynamic framework for drug design.

    Evidence Solution NMR structure with dynamics measurements; X-ray crystallography of EphA4-LBD/APY peptide complex with structure-guided optimization

    PMID:25268696 PMID:25334011

    Open questions at the time
    • Whether dynamics-based rules generalize to other Eph receptors untested
    • In vivo efficacy of optimized peptide antagonists not demonstrated
  15. 2017 Medium

    EphA4's role in neuroinflammation was expanded: SORLA physically interacts with EphA4 to attenuate its activation (relevant to AD), the ephexin-1/RhoA/ROCK2 cascade mediates blood-brain barrier disruption after subarachnoid hemorrhage, and EphA4 acts as a dependence receptor triggering apoptosis in the absence of ephrin-B3 in glioblastoma.

    Evidence SORLA-EphA4 Co-IP and SORLA transgenic mice with LTP; EphA4 siRNA in SAH rat model with ROCK inhibitor rescue; ephrin-B3 knockdown in glioblastoma xenografts

    PMID:28423606 PMID:28698029 PMID:29114064

    Open questions at the time
    • SORLA mechanism of EphA4 inhibition not structurally defined
    • Dependence receptor function confirmed only for glioblastoma context
    • BBB disruption pathway from single lab
  16. 2018 Medium

    EphA4 was shown to inhibit oligodendrocyte myelination through the ephexin-1/RhoA/ROCK/myosin-2 cascade, extending the canonical spine retraction pathway to a glial cell myelination context.

    Evidence Microfiber myelination assay, zebrafish model, EphA4 knockdown, ROCK/RhoA pharmacological inhibition

    PMID:29350423

    Open questions at the time
    • In vivo mammalian validation limited at this time
    • Whether same pathway operates in remyelination after injury not established
  17. 2022 Medium

    OPC-conditional EphA4 deletion after ischemic stroke confirmed EphA4 inhibits OPC maturation and myelination via ephexin-1/RhoA/ROCK, and its removal improves functional recovery, validating EphA4 as a negative regulator of remyelination.

    Evidence PDGFRα-Cre conditional EphA4 KO, MCAO stroke model, myelin protein Western blots, pathway analysis

    PMID:35762396

    Open questions at the time
    • Long-term functional outcome and specificity of benefit not assessed
    • Single lab
  18. 2023 Medium

    EphA4 on peripheral myeloid-derived cells was found to suppress efferocytosis after brain injury by inhibiting the ERK/Stat6/MERTK pathway, revealing a non-neuronal, immune-regulatory function of EphA4 in post-injury debris clearance.

    Evidence Bone marrow chimeric EphA4 KO mice, single-cell RNAseq, in vitro efferocytosis, ERK/Stat6 inhibitors

    PMID:37941008

    Open questions at the time
    • Whether this is a direct kinase-mediated effect or involves ligand engagement unclear
    • Single lab; independent replication needed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how EphA4 coordinates its multiple parallel effector arms in a context-dependent manner; whether Aβ oligomers directly bind EphA4 or activate it indirectly; a full-length EphA4 structure showing kinase activation mechanism; and the translational potential of EphA4 inhibition in Alzheimer's disease or demyelinating conditions.
  • No full-length EphA4 structure available
  • No direct binding data for Aβ oligomers to EphA4
  • No clinical translation data for any EphA4-targeted therapy

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0098772 molecular function regulator activity 4
Localization
GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-1266738 Developmental Biology 7 R-HSA-112316 Neuronal System 5 R-HSA-5357801 Programmed Cell Death 2 R-HSA-392499 Metabolism of proteins 1
Partners
ARHGEF5CDK5CHN2EFNA3EFNB3PLCG1SIPA1L2SORL1

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 EphA4 is enriched on dendritic spines of hippocampal pyramidal neurons; activation by astrocyte-expressed ephrin-A3 induces spine retraction, and kinase-inactive EphA4 or EphA4 knockout causes distorted spine morphology, demonstrating that ephrin-A3/EphA4 signaling controls dendritic spine shape through neuroglial cross-talk. EphA4 knockout mice, kinase-inactive EphA4 transfection in hippocampal slices, ephrin-A3 activation assays, immunolocalization Nature neuroscience High 12496762
2003 EphA4-positive excitatory spinal interneurons and ephrinB3 are required for left-right limb alternation during locomotion; loss of EphA4 or ephrinB3 converts alternating gait to synchronous hopping, establishing EphA4 as an essential organizer of the spinal central pattern generator. EphA4 and ephrinB3 knockout mice, isolated spinal cord electrophysiology, anatomical tracing Science High 12649481
1998 EphA4 is required for the development of the corticospinal tract; EphA4 null mice show major disruptions in corticospinal axon trajectories within the medulla and spinal cord, resulting in a hopping gait. EphA4 null mutant mouse, anterograde tracing of corticospinal tract, behavioral analysis Proceedings of the National Academy of Sciences of the United States of America High 9789074
2006 Cdk5 is recruited to activated EphA4, undergoes tyrosine phosphorylation and activation, then phosphorylates ephexin1 to enhance RhoA activation, driving ephrin-A1-induced dendritic spine retraction and reduction of mEPSC frequency; blocking Cdk5 or its phosphorylation of ephexin1 abolishes EphA4-dependent spine retraction. Pharmacological Cdk5 inhibition, Cdk5-/- neurons, Co-IP of EphA4/Cdk5/ephexin1, phospho-mutant ephexin1 constructs, mEPSC recordings Nature neuroscience High 17143272
2004 EphA4 is upregulated on reactive astrocytes after spinal cord injury; EphA4-/- astrocytes fail to respond to inflammatory cytokines, show reduced gliosis, and support longer neurite outgrowth; blocking astrocyte EphA4 with monomeric ephrinA5-Fc promotes neurite extension, identifying EphA4 as a regulator of astrocytic gliosis and axonal inhibition after injury. EphA4 KO mice, spinal cord hemisection, anterograde/retrograde tracing, in vitro neurite outgrowth on astrocytes, monomeric EphA4 blocker, cytokine stimulation assay The Journal of neuroscience High 15537875
2009 EphA4 in the postsynaptic CA1 neuron modulates LTP by controlling astrocytic ephrin-A3 reverse signaling, which in turn regulates glial glutamate transporter levels; lack of EphA4 increases glial glutamate transporter abundance, and pharmacological inhibition of glial glutamate transporters rescues LTP defects in EphA4 and ephrin-A3 mutant mice. EphA4 and ephrin-A3 knockout mice, LTP electrophysiology, pharmacological glutamate transporter inhibition, astrocyte transporter current recording, transgenic ephrin-A3 overexpression Nature neuroscience High 19734893
2000 EphA4 expressed on dorsal limb motor axons mediates dorsal-versus-ventral trajectory selection; in EphA4 mutant mice, presumptive dorsal motor axons fail to enter the dorsal compartment and join the ventral nerve, demonstrating EphA4-dependent repulsion by ephrin ligands in ventral mesoderm. EphA4 knockout mouse, axon tracing, protein expression analysis in motor axon subpopulations Development High 10887087
2007 Alpha2-chimaerin interacts with activated EphA4 via its SH2 domain, undergoes tyrosine phosphorylation, and enhances its RacGAP activity toward Rac1, mediating ephrin-induced growth cone collapse; alpha2-chimaerin mutant mice phenocopy EphA4 kinase-inactive mice with a hopping gait and defective corticospinal/spinal interneuron projections. Co-IP, SH2-domain binding, in vitro GAP activity assay, alpha2-chimaerin KO mice, locomotor analysis, axon tracing; confirmed by two independent labs (PMIDs 17785183 and 17911252) Neuron High 17785183 17911252
2010 EphA4 activation leads to association with the ubiquitin ligase APC(Cdh1), which targets GluR1 (AMPA receptor subunit) for proteasomal degradation; depletion of Cdh1 abolishes EphA4-dependent GluR1 downregulation and prevents homeostatic reduction of mEPSC amplitude caused by chronic elevated synaptic activity. Co-IP of EphA4 with APC/Cdh1, in vitro ubiquitination assay, Cdh1 knockdown, mEPSC recordings, surface GluR1 assay Nature neuroscience High 21186356
2009 Gamma-secretase cleaves EphA4 in an activity-dependent manner at synapses; the resulting EphA4 intracellular domain (ICD) promotes dendritic spine formation by activating Rac signaling, linking gamma-secretase processing of EphA4 to spine morphogenesis. Identification of EphA4 as gamma-secretase substrate by biochemical cleavage assay, overexpression of EphA4-ICD, Rac signaling reporter assay, spine counting The Journal of cell biology Medium 19414612
2007 EphA4 activation by ephrin-A3 inhibits beta1-integrin activity in hippocampal neurons by decreasing phosphorylation of Cas, FAK, and Pyk2 and reducing Cas-Fyn and Cas-Crk associations; inhibition of integrin or Cas function mimics EphA4-induced spine retraction, and blocking beta1-integrin inactivation prevents EphA4 effects on spines. Ephrin-A3 stimulation in hippocampal slices, phospho-immunoblotting of FAK/Pyk2/Cas, co-IP of Cas with Fyn/Crk, integrin activity assay, spine morphology analysis The Journal of cell biology High 17875741
2007 EphA4 interacts via its C-terminus PDZ-binding motif with the PDZ domain of SPAR (spine-associated RapGAP), leading to Cdk5-dependent inactivation of Rap1 and Rap2; SPAR-mediated Rap1 inactivation is required for ephrin-A-dependent growth cone collapse and decreased integrin-mediated adhesion in neuronal cells. Co-IP of EphA4 with SPAR, Rap1/Rap2 activity assays, Rap GTPase-activating assay, growth cone collapse assay with dominant-active Rap mutants The Journal of neuroscience Medium 18094260
2007 EphA4 activation recruits and activates PLCgamma1 via an SH2 domain interaction requiring EphA4 juxtamembrane tyrosines; PLC activity is required for ephrin-induced spine retraction and modulates cofilin membrane association, linking EphA4 to actin remodeling in dendritic spines. Co-IP of EphA4 with PLCgamma1, SH2 domain binding, PLC inhibitor studies in hippocampal slices, cofilin fractionation assay, spine morphology imaging The Journal of neuroscience Medium 17494698
2005 EphA4 cytoplasmic domain directly interacts with the juxtamembrane domain of FGFR1-4 (identified by yeast two-hybrid and confirmed biochemically); activated FGFR1 trans-phosphorylates kinase-dead EphA4 and vice versa, and ephrin-A1 co-stimulation potentiates FGF-induced MAPK signaling through FRS2alpha. Yeast two-hybrid, Co-IP, kinase-dead receptor trans-phosphorylation, MAPK assay with ligand co-stimulation Proceedings of the National Academy of Sciences of the United States of America Medium 16365308
2006 GDNF/Ret and EphA4 signals cooperate in the same binary dorsal-ventral motor axon guidance decision; LMC(l) axons require EphA4-mediated repulsion from ephrin-A-expressing ventral mesoderm, and loss of both Ret and EphA4 synergistically worsens aberrant ventral trajectory, placing the two systems in a cooperative pathway. Gdnf, Ret, and EphA4 single and compound knockout mice, motor axon tracing, genetic epistasis Neuron High 16600854
2008 Rin1, a postnatal brain-specific Rab5-GEF, co-localizes with EphA4 in synaptosomal fractions, interacts with EphA4 via its SH2 domain (requiring EphA4 tyrosine phosphorylation), and mediates ligand-induced EphA4 endocytosis in amygdala neurons; EphA4 is required for synaptic plasticity in the amygdala, and Rin1 suppresses this plasticity by promoting EphA4 internalization. Co-IP of Rin1 and EphA4 from synaptosomes, SH2 domain requirement, internalization assay in neurons, EphA4 KO LTP assay Proceedings of the National Academy of Sciences of the United States of America Medium 18723684
2005 Alpha-syntrophin interacts with ARMS (ankyrin repeat-rich membrane spanning protein) via a PDZ domain interaction, clustering ARMS at the neuromuscular junction (NMJ); ARMS enhances EphA4 signaling, and alpha-syntrophin further augments this; alpha-syntrophin null mice show disrupted ARMS and EphA4 localization at the NMJ. Yeast two-hybrid, Co-IP, PDZ domain-dependent clustering assay, siRNA knockdown in C2C12 myotubes, alpha-syntrophin KO mouse immunolocalization The Journal of cell biology Medium 15939763
2008 Meltrin beta/ADAM19 interacts physically with EphA4 in developing motor neurons; co-expression of ADAM19 and EphA4 blocks endocytosis of ephrin-A5-EphA4 complexes independently of ADAM19 protease activity, stabilizing ephrin-A5 signaling and regulating NMJ formation. Co-IP of ADAM19 and EphA4, internalization assay, protease-dead ADAM19 mutant, ADAM19 KO mouse NMJ analysis PloS one Medium 18830404
2009 Crystal structure of the EphA4 ligand-binding domain in complex with ephrin-B2 reveals a loose fit of the ephrin-B2 G-H loop in the EphA4 ligand-binding channel; mutation of EphA4 residues Gln12 and Glu14 selectively reduces ephrin-B affinity ~10-fold without affecting ephrin-A binding, defining separate molecular determinants for EphA4's cross-subclass (ephrin-B) binding. X-ray crystallography, mutagenesis, binding affinity measurements (ITC/ELISA), NMR The Journal of biological chemistry High 19875447
2008 Crystal structure of the EphA4 ligand-binding domain (first for an EphA subclass receptor) shows a jellyfish beta-sandwich with variable D-E and J-K loop regions forming the ephrin-binding channel; two small-molecule antagonists bind within this channel contacting Ile31-Met32, Gln43, and Ile131-Gly132, competitively displacing ephrin ligands with Kd ~20-26 µM. X-ray crystallography, NMR HSQC titration, ITC, molecular docking, ephrin competition ELISA The Journal of biological chemistry High 18708347
2010 Crystal structure of the EphA4 ligand-binding domain reveals two distinct, well-ordered conformations in the unbound state, suggesting that EphA4's structural flexibility in the ligand-binding surface underlies its promiscuous binding to both ephrin-A and ephrin-B ligands. X-ray crystallography at 2.3 Å resolution Biochemical and biophysical research communications High 20678482
2014 Solution NMR structure of the EphA4 LBD shows that two small molecules trigger opposite signaling outputs by oppositely modulating EphA4 backbone dynamics: one enhances dynamics (agonist) and the other suppresses dynamics (antagonist), establishing a dynamic principle for EphA4 agonism versus antagonism. Solution NMR (first for 16 Eph receptors), NMR dynamics measurements, small-molecule binding studies ACS chemical biology High 25334011
2014 Crystal structure of the cyclic peptide antagonist APY bound to the EphA4 LBD shows that the peptide occupies the ephrin ligand-binding pocket and induces a 'closed' loop conformation; structure-guided optimization yielded APY-βAla8.am with nanomolar EphA4 affinity that inhibits ephrin-induced EphA4 activation and growth cone collapse. X-ray crystallography of EphA4-LBD/peptide complex, structure-guided mutagenesis, binding affinity measurements, cell-based EphA4 activation assay, growth cone collapse assay ACS chemical biology High 25268696
2014 Amyloid-β oligomers (AβOs) activate EphA4 in hippocampal neurons, leading to downstream activation of c-Abl kinase in dendritic spines; EphA4 KO or EphA4 antagonist prevents AβO-induced c-Abl activation, dendritic spine loss, LTP blockade, and neuronal apoptosis, placing EphA4 upstream of c-Abl in AβO-mediated synaptotoxicity. EphA4 KO neurons, EphA4 shRNA, EphA4 antagonist peptide KYL, c-Abl inhibitor STI, phospho-EphA4 and phospho-c-Abl immunoblotting, spine counting, LTP electrophysiology PloS one Medium 24658113
2014 Enhanced EphA4 signaling in the hippocampus of APP/PS1 AD mice mediates synaptic LTP impairment; soluble Aβ oligomers activate EphA4, EphA4 depletion in CA1 reverses LTP suppression, and the small molecule rhynchophylline (identified by molecular docking as an EphA4 inhibitor) blocks EphA4 activity and restores LTP in AD mice. APP/PS1 transgenic mouse, EphA4 shRNA in CA1, molecular docking, in vitro kinase inhibition, oral drug administration, LTP electrophysiology Proceedings of the National Academy of Sciences of the United States of America Medium 24958880
2017 SORLA physically interacts with EphA4 and attenuates ephrinA1-induced EphA4 clustering and activation; SORLA transgenic mice show decreased EphA4 activation and redistribution to postsynaptic densities, with reduced Aβ-induced LTP deficits; active EphA4 is elevated in human AD brains and inversely correlates with SORLA/EphA4 association. Co-IP of SORLA and EphA4, SORLA transgenic mouse, EphA4 phosphorylation assay, LTP electrophysiology, postsynaptic density fractionation, human AD brain analysis The Journal of experimental medicine Medium 29114064
2013 Ephrin-A5 in cochlear hair cells signals through EphA4 on spiral ganglion neurons to repel type I afferent fibers from the outer hair cell area; in the absence of ephrin-A5 or EphA4, type I projections aberrantly invade the outer hair cell layer; downstream of EphA4, ephexin-1, cofilin, and MLCK mediate growth cone collapse of type I spiral ganglion neurons. Ephrin-A5 and EphA4 KO mice, anterograde tracing, growth cone collapse assay, ephexin-1/cofilin/MLCK pharmacological inhibition Nature communications High 23385583
2011 EphrinB3/EphA4 bidirectional signaling mediates segregation of MGE- and POA-derived cortical interneurons into deep and superficial migratory streams: EphA4 forward signaling repels deeply migrating MGE interneurons from POA-derived cells expressing ephrinB3, while EphA4-induced ephrinB3 reverse signaling restricts POA interneurons to the superficial path. In vitro migration assays with ephrinB3/EphA4 perturbation, in utero electroporation, EphA4 conditional KO mice, DiI labeling The Journal of neuroscience Medium 22171039
2013 EphrinB3/EphA4 forward signaling guides both ascending Zic2+/EphA4+ spinal interneuron axons (ipsilateral, embryonic) and descending corticospinal tract axons (postnatal) through the same molecular mechanism; conditional EphA4 KO shows CST guidance defects are linked to EphA4 in Zic2+ spinal neurons, not CST axons themselves. Conditional EphA4 KO mice (cell-type specific), anterograde and retrograde tracing, in situ hybridization, immunohistochemistry Neuron High 24360544
2014 Spinal cord-specific deletion of EphA4 signaling in excitatory Vglut2+ neurons is sufficient to generate the hopping gait, accompanied by increased midline crossing of Vglut2+ axons; forebrain-specific deletion does not affect locomotor pattern, functionally localizing the EphA4 circuit requirement to spinal excitatory interneurons. Intersectional genetics (cell-type-specific conditional KO), overground locomotion analysis, anterograde tracing of midline-crossing axons The Journal of neuroscience High 24623763
2018 Axonal ephrin-A1 interacts with EphA4 on oligodendrocytes to activate an ephexin1-RhoA-ROCK-myosin 2 signaling cascade that inhibits oligodendrocyte process extension and myelination; inhibition of EphA4 or downstream pathway components increases the number of myelin sheaths per oligodendrocyte. Axon-mimicking microfibers, zebrafish myelination model, EphA4 knockdown, pharmacological ROCK and RhoA inhibition, Co-IP/signaling pathway analysis Glia Medium 29350423
2013 Ephrin-A1/EphA4 signaling in endothelial cells promotes monocyte adhesion via activation of the Rho signaling pathway and subsequent actin stress fiber polymerization, without requiring active transcription; EphA4 mediates this pro-adhesive effect downstream of ephrin-A1. Ephrin-A1-Fc stimulation of endothelial cells, monocyte adhesion assay, Rho activation assay, actin polymerization imaging, EphA4 blocking antibody, transcription inhibitor control Biochimica et biophysica acta Medium 23707953
2017 EphA4 acts as a dependence receptor: in the absence of its ligand ephrin-B3, EphA4 triggers cell apoptosis; ephrin-B3 overexpression in glioblastoma inhibits EphA4 pro-apoptotic activity, supports tumor and endothelial cell survival, and silencing ephrin-B3 decreases tumor vascularization and growth in xenograft models. Ephrin-B3 siRNA knockdown, EphA4 dependence receptor apoptosis assay, xenograft mouse model, in vitro endothelial cell survival assay Oncotarget Medium 28423606
2009 EphA4 is required for cortical progenitor cell proliferation; EphA4-/- cortex has reduced area, fewer cells, and less cell division; overexpression of EphA4 expands the progenitor pool; EphA4 interacts with and is activated by ephrin-B1 expressed on neighboring progenitors, driving forward signaling-mediated proliferation. EphA4 KO mice, in vivo electroporation of dominant-negative/wild-type EphA4, Co-IP of EphA4 with ephrin-B1, BrdU incorporation assay Development Medium 19542359
2022 EphA4 in oligodendrocyte precursor cells (OPCs) promotes OPC proliferation but inhibits their maturation and myelination after ischemic stroke; the pro-myelination effect of EphA4 deletion is mediated by the Ephexin-1/RhoA/ROCK signaling pathway; OPC-conditional EphA4 KO improves myelin-associated protein levels and functional recovery. OPC-specific conditional EphA4 KO (PDGFRα-Cre), MCAO stroke model, shRNA, LV-EphA4 overexpression, Western blot for myelin proteins, Ephexin-1/RhoA/ROCK pathway analysis Glia Medium 35762396
2017 EphA4 in subarachnoid hemorrhage activates the Ephexin-1/RhoA/ROCK2 pathway to promote blood-brain barrier disruption, brain edema, and apoptotic neuronal death; EphA4 siRNA reduces these effects, while recombinant Ephexin-1 reverses the siRNA effect and Fasudil (ROCK2 inhibitor) restores the phenotype. EphA4 siRNA (i.c.v.), recombinant Ephexin-1, Fasudil, SAH rat model, Evans blue permeability assay, brain water content, Western blot, tight junction protein analysis Experimental neurology Medium 28698029
2023 EphA4 on peripheral myeloid-derived immune cells restricts efferocytosis after brain injury by suppressing the ERK/Stat6/MERTK pathway; loss of EphA4 on infiltrating macrophages/microglia enhances MERTK expression and activity, increases phagocytosis of apoptotic debris, and improves functional outcome. Bone marrow chimeric EphA4 KO mice, single-cell RNAseq, in vitro efferocytosis assay, ERK/Stat6 selective inhibitors, p-MERTK/p-ERK/p-Stat6 co-localization Journal of neuroinflammation Medium 37941008
1997 EphA4 immunoreactivity in the adult rat brain is enriched in dendrites and dendritic spines (associated with the plasma membrane) and in myelinated axons, establishing the subcellular localization of EphA4 at synaptic sites in the mature CNS. Immunoperoxidase and immunogold electron microscopy with region/cell-type fractionation in adult rat brain Brain research Medium 9401744
2016 EBV latent membrane protein 1 (LMP1) suppresses EphA4 expression by activating the ERK pathway, leading to Sp1-mediated repression of the EphA4 promoter; overexpression of EphA4 prevents LCL proliferation, identifying EphA4 as a growth suppressor downstream of LMP1-ERK-Sp1 signaling in B lymphoma cells. EphA4 overexpression/knockdown in LCLs, LMP1 overexpression/knockdown, luciferase promoter assay, ERK pathway inhibitors, Sp1 ChIP Blood Medium 27338098
2016 An EphA4/Sipa1l3/Wnt pathway regulates eye development: EphA4 acts upstream of Sipa1l3 (direct physical interaction), and both inhibit canonical Wnt/β-catenin signaling; depletion of either EphA4 or Sipa1l3 in Xenopus causes smaller eyes with lens fiber cell maturation defects and upregulation of the Wnt target axin2. Co-IP of EphA4 and Sipa1l3, morpholino loss-of-function in Xenopus, epistasis rescue experiments, axin2 reporter (canonical Wnt readout), Wnt pathway inhibitors Development Medium 27993984

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 416 12496762
2003 Role of EphA4 and EphrinB3 in local neuronal circuits that control walking. Science (New York, N.Y.) 275 12649481
2004 Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 259 15537875
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
2006 Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nature neuroscience 258 17143272
2012 EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. Nature medicine 239 22922411
2009 Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport. Nature neuroscience 234 19734893
2000 Targeting of the EphA4 tyrosine kinase receptor affects dorsal/ventral pathfinding of limb motor axons. Development (Cambridge, England) 227 10887087
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 172 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 150 21186356
2005 EphA4 is required for cell adhesion and rhombomere-boundary formation in the zebrafish. Current biology : CB 134 15797022
2001 EphA4/ephrin-A5 interactions in muscle precursor cell migration in the avian forelimb. Development (Cambridge, England) 129 11731448
2007 The EphA4 receptor regulates dendritic spine remodeling by affecting beta1-integrin signaling pathways. The Journal of cell biology 122 17875741
2009 EphA4 as an effector of Twist1 in the guidance of osteogenic precursor cells during calvarial bone growth and in craniosynostosis. Development (Cambridge, England) 120 19201948
2008 Small molecules can selectively inhibit ephrin binding to the EphA4 and EphA2 receptors. The Journal of biological chemistry 118 18728010
2007 alpha2-Chimaerin is an essential EphA4 effector in the assembly of neuronal locomotor circuits. Neuron 98 17785183
2011 EphA4 blockers promote axonal regeneration and functional recovery following spinal cord injury in mice. PloS one 97 21931787
2009 Synaptic activity prompts gamma-secretase-mediated cleavage of EphA4 and dendritic spine formation. The Journal of cell biology 95 19414612
2003 Targeting the EphA4 receptor in the nervous system with biologically active peptides. Molecular and cellular neurosciences 91 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
2004 Ephrin-A5 exerts positive or inhibitory effects on distinct subsets of EphA4-positive motor neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 85 14762125
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 81 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
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
2014 EphA4 activation of c-Abl mediates synaptic loss and LTP blockade caused by amyloid-β oligomers. PloS one 75 24658113
2009 Structural characterization of the EphA4-Ephrin-B2 complex reveals new features enabling Eph-ephrin binding promiscuity. The Journal of biological chemistry 75 19875447
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
2008 The Rab5 guanylate exchange factor Rin1 regulates endocytosis of the EphA4 receptor in mature excitatory neurons. Proceedings of the National Academy of Sciences of the United States of America 64 18723684
2006 Identification of Epha4 enhancer required for segmental expression and the regulation by Mesp2. Development (Cambridge, England) 61 16728472
2009 Promotion of proliferation in the developing cerebral cortex by EphA4 forward signaling. Development (Cambridge, England) 58 19542359
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 57 29378302
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
2008 Crystal structure and NMR binding reveal that two small molecule antagonists target the high affinity ephrin-binding channel of the EphA4 receptor. The Journal of biological chemistry 55 18708347
2008 Overexpression of the receptor tyrosine kinase EphA4 in human gastric cancers. World journal of gastroenterology 54 18837080
2006 EphA4 receptor, overexpressed in pancreatic ductal adenocarcinoma, promotes cancer cell growth. Cancer science 54 16965393
2003 EphA4 provides repulsive signals to developing cochlear ganglion neurites mediated through ephrin-B2 and -B3. The Journal of comparative neurology 53 12761826
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
2011 EphA4 preserves postnatal and adult neural stem cells in an undifferentiated state in vivo. Journal of cell science 51 21444754
2011 Bidirectional ephrinB3/EphA4 signaling mediates the segregation of medial ganglionic eminence- and preoptic area-derived interneurons in the deep and superficial migratory stream. The Journal of neuroscience : the official journal of the Society for Neuroscience 51 22171039
2006 Thymic alterations in EphA4-deficient mice. Journal of immunology (Baltimore, Md. : 1950) 48 16818734
2022 Exosomal miR-532-5p induced by long-term exercise rescues blood-brain barrier function in 5XFAD mice via downregulation of EPHA4. Aging cell 46 36494892
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
2005 {alpha}-Syntrophin regulates ARMS localization at the neuromuscular junction and enhances EphA4 signaling in an ARMS-dependent manner. The Journal of cell biology 44 15939763
2014 Spinal glutamatergic neurons defined by EphA4 signaling are essential components of normal locomotor circuits. The Journal of neuroscience : the official journal of the Society for Neuroscience 43 24623763
2012 Distinctive binding of three antagonistic peptides to the ephrin-binding pocket of the EphA4 receptor. The Biochemical journal 43 22489865
2010 Upregulation of EphA4 on astrocytes potentially mediates astrocytic gliosis after cortical lesion in the marmoset monkey. Journal of neurotrauma 42 20486805
2016 Transcriptomic Biomarkers for Tuberculosis: Evaluation of DOCK9. EPHA4, and NPC2 mRNA Expression in Peripheral Blood. Frontiers in microbiology 39 27826286
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 38 33741023
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
2017 MicroRNA-335 suppresses the proliferation, migration, and invasion of breast cancer cells by targeting EphA4. Molecular and cellular biochemistry 36 28795314
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
2008 Meltrin beta/ADAM19 interacting with EphA4 in developing neural cells participates in formation of the neuromuscular junction. PloS one 36 18830404
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
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 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
2023 Efferocytosis is restricted by axon guidance molecule EphA4 via ERK/Stat6/MERTK signaling following brain injury. Journal of neuroinflammation 30 37941008
2014 Altered distribution of the EphA4 kinase in hippocampal brain tissue of patients with Alzheimer's disease correlates with pathology. Acta neuropathologica communications 30 25027113
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) 26 25480914
2010 Crystal structure of the ligand-binding domain of the promiscuous EphA4 receptor reveals two distinct conformations. Biochemical and biophysical research communications 26 20678482
2019 EphA4 loss improves social memory performance and alters dendritic spine morphology without changes in amyloid pathology in a mouse model of Alzheimer's disease. Alzheimer's research & therapy 25 31831046
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
2016 MiR-93 Targeting EphA4 Promotes Neurite Outgrowth from Spinal Cord Neurons. Journal of molecular neuroscience : MN 25 26798048
2012 Inhibition of EphA4 signaling after ischemia-reperfusion reduces apoptosis of CA1 pyramidal neurons. Neuroscience letters 25 22580205
2007 Auditory brainstem responses are impaired in EphA4 and ephrin-B2 deficient mice. Hearing research 25 17967521
2002 Ephrin-as cooperate with EphA4 to promote trunk neural crest migration. Gene expression 25 12450221
2000 Expression of EphA4 in developing inner ears of the mouse and guinea pig. Hearing research 25 10601711
2016 Regulation of EBV LMP1-triggered EphA4 downregulation in EBV-associated B lymphoma and its impact on patients' survival. Blood 24 27338098
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
2017 Critical role of EphA4 in early brain injury after subarachnoid hemorrhage in rat. Experimental neurology 23 28698029
2014 Dynamic principle for designing antagonistic/agonistic molecules for EphA4 receptor, the only known ALS modifier. ACS chemical biology 23 25334011
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
2004 Analysis of EphA4 in the lesser spotted catshark identifies a primitive gnathostome expression pattern and reveals co-option during evolution of shark-specific morphology. Development genes and evolution 23 15300436
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
2018 Decreased signalling of EphA4 improves functional performance and motor neuron survival in the SOD1G93A ALS mouse model. Scientific reports 22 30061574
2017 Ephrin-B3 supports glioblastoma growth by inhibiting apoptosis induced by the dependence receptor EphA4. Oncotarget 22 28423606
2010 Generation of an EphA4 conditional allele in mice. Genesis (New York, N.Y. : 2000) 22 20014422
2007 Deletion of EphA4 enhances deafferentation-induced ipsilateral sprouting in auditory brainstem projections. The Journal of comparative neurology 22 17702003
2003 Role of EphA4 in defining the position of a motoneuron pool within the spinal cord. The Journal of comparative neurology 22 12577325
2017 miR-519d Promotes Melanoma Progression by Downregulating EphA4. Cancer research 21 29093007
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