EPHA4 Gene

HGNC Family	Fibronectin type III domain containing, Receptor kinases, Sterile alpha motif (SAM) domain containing (SAMD)
Name	EPH receptor A4
Description	This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n EPHA4 is a receptor tyrosine kinase with versatile roles in the developing and mature nervous system. In several studies, EPHA4 has been shown to regulate synapse formation and remodeling by modulating dendritic spine morphology and excitatory connectivity. For example, EPHA4 is enriched on dendritic spines where its interaction with astrocyte‐expressed ephrin ligands (ephrin‐A3) mediates spine retraction and regulates the arrangement of synaptic contacts, in part by influencing integrin‐dependent adhesion and altering glial glutamate transporter activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Consistent with this, EPHA4‐dependent signaling has been implicated in long‐term potentiation and thereby in the processes underlying learning and memory."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the spinal cord, EPHA4 is critical for establishing proper locomotor circuitry. Gene knockout studies reveal that loss of EPHA4 disrupts the normal left–right alternation of limb movement—yielding a synchronous “hopping” gait—and affects the organization of central pattern generators by influencing the differentiation and positioning of specific interneuron populations."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Moreover, during axon guidance, EPHA4 activation triggers repulsive signals via downstream effectors such as alpha‐chimaerin; this signaling cascade is essential for appropriate growth cone collapse and proper targeting of corticospinal axons."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n EPHA4 function also appears to influence neural regeneration and neurodegeneration. In models of spinal cord injury, disruption of EPHA4 leads to enhanced axonal regrowth and diminished astrocytic gliosis, suggesting that EPHA4 normally contributes to an inhibitory environment for regeneration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Likewise, in amyotrophic lateral sclerosis (ALS) models, downregulation or inhibition of EPHA4 signaling correlates with improved motor neuron survival and prolonged lifespan, pointing to its role as a modulator of neuronal vulnerability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Additional evidence from genome‐wide imaging studies suggests that genetic variants near EPHA4 are associated with regional differences in gray matter density, further highlighting its importance in maintaining brain structure and function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, although EPHA4 is best known for its neural functions, its expression in malignant T lymphocytes has been observed in Sézary syndrome, where it may serve as a potential biomarker and therapeutic target."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Together, these findings demonstrate that EPHA4 functions as a key mediator of neuron–glia interactions, synaptic organization, and axon guidance, while also influencing regenerative responses and neurodegenerative vulnerability.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Keith K Murai, Louis N Nguyen, Fumitoshi Irie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Neurosci (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nn994"}], "href": "https://doi.org/10.1038/nn994"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12496762"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12496762"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Maria A Carmona, Keith K Murai, Lei Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0903328106"}], "href": "https://doi.org/10.1073/pnas.0903328106"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19592509"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19592509"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Caroline Bourgin, Keith K Murai, Melanie Richter, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The EphA4 receptor regulates dendritic spine remodeling by affecting beta1-integrin signaling pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.200610139"}], "href": "https://doi.org/10.1083/jcb.200610139"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17875741"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17875741"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Alessandro Filosa, Sónia Paixão, Silke D Honsek, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Neurosci (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nn.2394"}], "href": "https://doi.org/10.1038/nn.2394"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19734893"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19734893"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Klas Kullander, Simon J B Butt, James M Lebret, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of EphA4 and EphrinB3 in local neuronal circuits that control walking."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1079641"}], "href": "https://doi.org/10.1126/science.1079641"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12649481"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12649481"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Line Lundfald, C Ernesto Restrepo, Simon J B Butt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phenotype of V2-derived interneurons and their relationship to the axon guidance molecule EphA4 in the developing mouse spinal cord."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Neurosci (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1460-9568.2007.05906.x"}], "href": "https://doi.org/10.1111/j.1460-9568.2007.05906.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18028107"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18028107"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Takuji Iwasato, Hironori Katoh, Hiroshi Nishimaru, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Rac-GAP alpha-chimerin regulates motor-circuit formation as a key mediator of EphrinB3/EphA4 forward signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2007.07.022"}], "href": "https://doi.org/10.1016/j.cell.2007.07.022"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17719550"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17719550"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Heike Wegmeyer, Joaquim Egea, Nadine Rabe, et al. "}, {"type": "b", "children": [{"type": "t", "text": "EphA4-dependent axon guidance is mediated by the RacGAP alpha2-chimaerin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuron (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neuron.2007.07.038"}], "href": "https://doi.org/10.1016/j.neuron.2007.07.038"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17785182"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17785182"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Yona Goldshmit, Mary P Galea, Graham Wise, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.2981-04.2004"}], "href": "https://doi.org/10.1523/JNEUROSCI.2981-04.2004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15537875"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15537875"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Annelies Van Hoecke, Lies Schoonaert, Robin Lemmens, et al. "}, {"type": "b", "children": [{"type": "t", "text": "EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm.2901"}], "href": "https://doi.org/10.1038/nm.2901"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22922411"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22922411"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Li Shen, Sungeun Kim, Shannon L Risacher, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Whole genome association study of brain-wide imaging phenotypes for identifying quantitative trait loci in MCI and AD: A study of the ADNI cohort."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuroimage (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neuroimage.2010.01.042"}], "href": "https://doi.org/10.1016/j.neuroimage.2010.01.042"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20100581"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20100581"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Remco van Doorn, Remco Dijkman, Maarten H Vermeer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aberrant expression of the tyrosine kinase receptor EphA4 and the transcription factor twist in Sézary syndrome identified by gene expression analysis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-04-1253"}], "href": "https://doi.org/10.1158/0008-5472.CAN-04-1253"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15313894"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15313894"}]}]}]}
Synonyms	SEK, EK8, HEK8, TYRO1
Proteins	EPHA4_HUMAN
NCBI Gene ID	2043
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

EPHA4 has 9,692 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, functional term, phrase or reference, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 132 datasets.

Click the + buttons to view associations for EPHA4 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

EPHA4 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by EPHA4 gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of EPHA4 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of EPHA4 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of EPHA4 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of EPHA4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of EPHA4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of EPHA4 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of EPHA4 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of EPHA4 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of EPHA4 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of EPHA4 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of EPHA4 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Gene Mutation Profiles	cell lines with EPHA4 gene mutations from the CCLE Cell Line Gene Mutation Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with EPHA4 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with EPHA4 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of EPHA4 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of EPHA4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of EPHA4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of EPHA4 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing EPHA4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing EPHA4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with EPHA4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with EPHA4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with EPHA4 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with EPHA4 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with EPHA4 gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with EPHA4 gene in GWAS and other genetic association datasets from the dbGAP Gene-Trait Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of EPHA4 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by EPHA4 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DEPOD Substrates of Phosphatases	phosphatases that dephosphorylate EPHA4 protein from the curated DEPOD Substrates of Phosphatases dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores	diseases associated with EPHA4 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with EPHA4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with EPHA4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with EPHA4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with EPHA4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at EPHA4 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of EPHA4 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of EPHA4 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing EPHA4 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with EPHA4 gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.