EPHA4 EPH receptor A4 [Homo sapiens (human)] - Gene

Summary

Official Symbol: EPHA4provided by HGNC
Official Full Name: EPH receptor A4provided by HGNC
Primary source: HGNC:HGNC:3388
See related: Ensembl:ENSG00000116106 MIM:602188
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: EK8; SEK; HEK8; TYRO1
Summary: 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]
Expression: Broad expression in brain (RPKM 16.1), testis (RPKM 9.3) and 17 other tissues See more
Orthologs: mouse all

Genomic context

Location:: 2q36.1

Exon count:: 19

Annotation release	Status	Assembly	Chr	Location
109	current	GRCh38.p12 (GCF_000001405.38)	2	NC_000002.12 (221418027..221574202, complement)
105	previous assembly	GRCh37.p13 (GCF_000001405.25)	2	NC_000002.11 (222282747..222437010, complement)

Chromosome 2 - NC_000002.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

MiR-519d down-regulates EphA4 expression in melanoma.
Title: miR-519d Promotes Melanoma Progression by Downregulating EphA4.
These findings confirmed that EphA4 is a direct target gene of miR-335 and that miR-335 suppresses breast cancer cell proliferation and motility in part by directly inhibiting EphA4 expression.
Title: MicroRNA-335 suppresses the proliferation, migration, and invasion of breast cancer cells by targeting EphA4.
Therefore EphA4 is an emerging AbetaOs receptor and the activation of the EphA4/c-Abl axis would explain the synaptic spine alterations found in Alzheimer's disease.
Title: Amyloid-β oligomers synaptotoxicity: The emerging role of EphA4/c-Abl signaling in Alzheimer's disease.
High erythropoietin-producing hepatocellular carcinoma receptor A (EphA) 1, 2, and 4 expression levels were significantly related to recurrence.
Title: Prognostic Significance of High EphA1-4 Expression Levels in Locally Advanced Gastric Cancer.
These results demonstrate a novel role for SORLA as a physiological and pathological EphA4 modulator.
Title: SORLA attenuates EphA4 signaling and amyloid β-induced neurodegeneration.
The expression of both EphA4-FL and EphA4-N was significantly higher in the nervous tissue of SOD1(G93A) compared to wild-type mice suggesting that both forms are modulated during the disease process.
Title: The identification of a novel isoform of EphA4 and ITS expression in SOD1<sup>G93A</sup> mice.
the PI3K/AKT, Wnt/beta-catenin signaling pathways as well as ERK1/2 downstream of EPHA4 receptor activation, play an important role in the regulation of events related with the EMT development, which may be associated with the therapeutic failure in rectal cancer after radiotherapy.
Title: The Role of EphA4 Signaling in Radiation-Induced EMT-Like Phenotype in Colorectal Cancer Cells.
Molecular interactions of EphA4, growth hormone receptor, Jak2, and STAT5B have been described.
Title: Molecular interactions of EphA4, growth hormone receptor, Janus kinase 2, and signal transducer and activator of transcription 5B.
Findings demonstrated that mutant alpha2-chimaerin and EphA4 have different genetic interactions in distinct motor neuron pools: abducens neurons use bidirectional ephrin signaling via mutant alpha2-chimaerin to direct growth, while cervical spinal neurons use only ephrin forward signaling
Title: Mutant α2-chimaerin signals via bidirectional ephrin pathways in Duane retraction syndrome.
Reduced EphA4 expression is associated with EBV-associated B lymphoma.
Title: Regulation of EBV LMP1-triggered EphA4 downregulation in EBV-associated B lymphoma and its impact on patients' survival.

Submit: New GeneRIF Correction See all GeneRIFs (40)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

NHGRI GWAS Catalog

Description
Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy. NHGRI GWA Catalog NHGRI GWA CatalogPubMed
Genome-wide SNP associations with rubella-specific cytokine responses in measles-mumps-rubella vaccine recipients. NHGRI GWA Catalog NHGRI GWA CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Pathways from BioSystems

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Axon guidance, organism-specific biosystem (from KEGG)
Axon guidance, organism-specific biosystemAxon guidance represents a key stage in the formation of neuronal network. Axons are guided by a variety of guidance factors, such as netrins, ephrins, Slits, and semaphorins. These guidance cues are...
Axon guidance, conserved biosystem (from KEGG)
Axon guidance, conserved biosystemAxon guidance represents a key stage in the formation of neuronal network. Axons are guided by a variety of guidance factors, such as netrins, ephrins, Slits, and semaphorins. These guidance cues are...
Axon guidance, organism-specific biosystem (from REACTOME)
Axon guidance, organism-specific biosystemAxon guidance / axon pathfinding is the process by which neurons send out axons to reach the correct targets. Growing axons have a highly motile structure at the growing tip called the growth cone, w...
Developmental Biology, organism-specific biosystem (from REACTOME)
Developmental Biology, organism-specific biosystemAs a first step towards capturing the array of processes by which a fertilized egg gives rise to the diverse tissues of the body, examples of three kinds of processes have been annotated. These are a...
EPH-Ephrin signaling, organism-specific biosystem (from REACTOME)
EPH-Ephrin signaling, organism-specific biosystemDuring the development process cell migration and adhesion are the main forces involved in morphing the cells into critical anatomical structures. The ability of a cell to migrate to its correct dest...
EPH-ephrin mediated repulsion of cells, organism-specific biosystem (from REACTOME)
EPH-ephrin mediated repulsion of cells, organism-specific biosystemDespite high-affinity multimeric interaction between EPHs and ephrins (EFNs), the cellular response to EPH-EFN engagement is usually repulsion between the two cells and signal termination. These repu...
EPHA forward signaling, organism-specific biosystem (from Pathway Interaction Database)
EPHA forward signaling, organism-specific biosystem
EPHA forward signaling
EPHA-mediated growth cone collapse, organism-specific biosystem (from REACTOME)
EPHA-mediated growth cone collapse, organism-specific biosystemEPH/Ephrin signaling is coupled to Rho family GTPases such as Rac, Rho and Cdc42 that connect bidirectional receptor-ligand interactions to changes in the actin cytoskeleton (Noren & Pasquale 2004, G...
EphrinA-EPHA pathway, organism-specific biosystem (from Pathway Interaction Database)
EphrinA-EPHA pathway, organism-specific biosystem
EphrinA-EPHA pathway
Gene regulatory network modelling somitogenesis, organism-specific biosystem (from WikiPathways)
Gene regulatory network modelling somitogenesis, organism-specific biosystemReaction scheme of the proposed gene regulatory network (GRN). The scheme details the full GRN for one cell and part of a neighboring cell for those reactions that involve ligand-receptor interactio...
Spinal Cord Injury, organism-specific biosystem (from WikiPathways)
Spinal Cord Injury, organism-specific biosystemThis pathway provides an overview of cell types, therapeutic targets, drugs, new proposed targets and pathways implicated in spinal cord injury. Spinal cord injury is a complex multistep process that...

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

SHGC-24374 (e-PCR)
- UniSTS:99864

RH70277 (e-PCR)
- UniSTS:32538

RH78262 (e-PCR)
- UniSTS:18225

MARC_49122-49123:1117732036:1 (e-PCR)
- UniSTS:477489

EPHA4_1970 (e-PCR)
- UniSTS:280656

RH12531 (e-PCR)
- UniSTS:76116

RH93447 (e-PCR)
- UniSTS:84331

A004S26 (e-PCR)
- UniSTS:73092

RH46518 (e-PCR)
- UniSTS:62385

NoName (e-PCR)
- UniSTS:484284

STS-T47772 (e-PCR)
- UniSTS:54495

Homology

Homologs of the EPHA4 gene: The EPHA4 gene is conserved in chimpanzee, Rhesus monkey, dog, mouse, rat, chicken, zebrafish, C.elegans, and frog.
Orthologs from Annotation Pipeline: 236 organisms have orthologs with human gene EPHA4
Orthologs

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
ATP binding	IEA Inferred from Electronic Annotation more info
DH domain binding	IDA Inferred from Direct Assay more info	PubMed
GPI-linked ephrin receptor activity	ISS Inferred from Sequence or Structural Similarity more info
PH domain binding	IPI Inferred from Physical Interaction more info	PubMed
amyloid-beta binding	TAS Traceable Author Statement more info	PubMed
ephrin receptor binding	IEA Inferred from Electronic Annotation more info
identical protein binding	IEA Inferred from Electronic Annotation more info
kinase activity	IGI Inferred from Genetic Interaction more info	PubMed
protein binding	IPI Inferred from Physical Interaction more info	PubMed
protein kinase activity	IDA Inferred from Direct Assay more info	PubMed
protein tyrosine kinase binding	IPI Inferred from Physical Interaction more info	PubMed
transmembrane receptor protein tyrosine kinase activity	IBA Inferred from Biological aspect of Ancestor more info	PubMed
transmembrane-ephrin receptor activity	IBA Inferred from Biological aspect of Ancestor more info	PubMed
transmembrane-ephrin receptor activity	ISS Inferred from Sequence or Structural Similarity more info

Process	Evidence Code	Pubs
adult walking behavior	IEA Inferred from Electronic Annotation more info
axon guidance	IBA Inferred from Biological aspect of Ancestor more info	PubMed
cell adhesion	IEA Inferred from Electronic Annotation more info
cellular response to amyloid-beta	ISS Inferred from Sequence or Structural Similarity more info
corticospinal tract morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
ephrin receptor signaling pathway	IGI Inferred from Genetic Interaction more info	PubMed
ephrin receptor signaling pathway	TAS Traceable Author Statement more info
fasciculation of motor neuron axon	ISS Inferred from Sequence or Structural Similarity more info
fasciculation of sensory neuron axon	ISS Inferred from Sequence or Structural Similarity more info
glial cell migration	IEA Inferred from Electronic Annotation more info
motor neuron axon guidance	ISS Inferred from Sequence or Structural Similarity more info
negative regulation of axon regeneration	ISS Inferred from Sequence or Structural Similarity more info
negative regulation of long-term synaptic potentiation	ISS Inferred from Sequence or Structural Similarity more info
negative regulation of neuron projection development	ISS Inferred from Sequence or Structural Similarity more info
negative regulation of proteolysis involved in cellular protein catabolic process	IGI Inferred from Genetic Interaction more info	PubMed
nephric duct morphogenesis	IEA Inferred from Electronic Annotation more info
neuron projection fasciculation	ISS Inferred from Sequence or Structural Similarity more info
neuron projection guidance	ISS Inferred from Sequence or Structural Similarity more info
peptidyl-tyrosine phosphorylation	IDA Inferred from Direct Assay more info	PubMed
positive regulation of JUN kinase activity	IEA Inferred from Electronic Annotation more info
positive regulation of Rho guanyl-nucleotide exchange factor activity	IDA Inferred from Direct Assay more info	PubMed
positive regulation of amyloid-beta formation	IGI Inferred from Genetic Interaction more info	PubMed
positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process	IGI Inferred from Genetic Interaction more info	PubMed
positive regulation of dendrite morphogenesis	IEA Inferred from Electronic Annotation more info
positive regulation of protein tyrosine kinase activity	ISS Inferred from Sequence or Structural Similarity more info
protein autophosphorylation	IDA Inferred from Direct Assay more info	PubMed
protein stabilization	IGI Inferred from Genetic Interaction more info	PubMed
regulation of GTPase activity	ISS Inferred from Sequence or Structural Similarity more info
regulation of astrocyte differentiation	ISS Inferred from Sequence or Structural Similarity more info
regulation of axonogenesis	ISS Inferred from Sequence or Structural Similarity more info
regulation of dendritic spine morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
regulation of modification of synaptic structure	ISS Inferred from Sequence or Structural Similarity more info
synapse pruning	IEA Inferred from Electronic Annotation more info
transmembrane receptor protein tyrosine kinase signaling pathway	IBA Inferred from Biological aspect of Ancestor more info	PubMed

Component	Evidence Code	Pubs
Golgi apparatus	IEA Inferred from Electronic Annotation more info
Schaffer collateral - CA1 synapse	IEA Inferred from Electronic Annotation more info
axon	ISS Inferred from Sequence or Structural Similarity more info
axon terminus	IEA Inferred from Electronic Annotation more info
axonal growth cone	IEA Inferred from Electronic Annotation more info
cell junction	IEA Inferred from Electronic Annotation more info
cell surface	IEA Inferred from Electronic Annotation more info
cytoplasm	ISS Inferred from Sequence or Structural Similarity more info
dendrite	ISS Inferred from Sequence or Structural Similarity more info
dendritic shaft	ISS Inferred from Sequence or Structural Similarity more info
dendritic spine	IBA Inferred from Biological aspect of Ancestor more info	PubMed
dendritic spine	ISS Inferred from Sequence or Structural Similarity more info
early endosome membrane	ISS Inferred from Sequence or Structural Similarity more info
endoplasmic reticulum	IEA Inferred from Electronic Annotation more info
filopodium	IEA Inferred from Electronic Annotation more info
glutamatergic synapse	IEA Inferred from Electronic Annotation more info
integral component of plasma membrane	IBA Inferred from Biological aspect of Ancestor more info	PubMed
integral component of plasma membrane	ISS Inferred from Sequence or Structural Similarity more info
integral component of postsynaptic membrane	IEA Inferred from Electronic Annotation more info
integral component of presynaptic membrane	IEA Inferred from Electronic Annotation more info
mitochondrial outer membrane	IEA Inferred from Electronic Annotation more info
neuromuscular junction	IEA Inferred from Electronic Annotation more info
neuron projection	IBA Inferred from Biological aspect of Ancestor more info	PubMed
perikaryon	IEA Inferred from Electronic Annotation more info
plasma membrane	NAS Non-traceable Author Statement more info	PubMed
plasma membrane	TAS Traceable Author Statement more info
postsynaptic density	IEA Inferred from Electronic Annotation more info
receptor complex	IBA Inferred from Biological aspect of Ancestor more info	PubMed

General protein information

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Preferred Names: ephrin type-A receptor 4

Names: EPH-like kinase 8; TYRO1 protein tyrosine kinase; receptor protein-tyrosine kinase HEK8; tyrosine-protein kinase TYRO1; tyrosine-protein kinase receptor SEK

NP_001291465.1

EC 2.7.10.1

NP_001291466.1

EC 2.7.10.1

NP_004429.1

EC 2.7.10.1

XP_005246431.1

EC 2.7.10.1

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

mRNA and Protein(s)

NM_001304536.1 → NP_001291465.1 ephrin type-A receptor 4 isoform a precursor

See identical proteins and their annotated locations for NP_001291465.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the longest transcript and encodes the longest isoform (a). Variants 1 and 2 both encode the same isoform (a).

Source sequence(s)

AC010899, AK290306, BC105000, BM676153

Consensus CDS

CCDS2447.1

UniProtKB/Swiss-Prot

P54764

UniProtKB/TrEMBL

A0A024R452

Related

ENSP00000386829.1, ENST00000409938.5

Conserved Domains (5) summary

cd09545
Location:911 → 981

SAM_EPH-A4; SAM domain of EPH-A4 subfamily of tyrosine kinase receptors

cd10482
Location:30 → 203

EphR_LBD_A4; Ligand Binding Domain of Ephrin type-A Receptor 4

cd00063
Location:441 → 532

FN3; Fibronectin type 3 domain; One of three types of internal repeats found in the plasma protein fibronectin. Its tenth fibronectin type III repeat contains an RGD cell recognition sequence in a flexible loop between 2 strands. Approximately 2% of all ...

cd05066
Location:616 → 882

PTKc_EphR_A; Catalytic domain of the Protein Tyrosine Kinases, Class EphA Ephrin Receptors

pfam14575
Location:562 → 616

EphA2_TM; Ephrin type-A receptor 2 transmembrane domain
NM_001304537.1 → NP_001291466.1 ephrin type-A receptor 4 isoform b

See identical proteins and their annotated locations for NP_001291466.1

Status: REVIEWED

Description

Transcript Variant: This variant (3) differs in the 5' UTR and coding sequence compared to variant (1). The resulting isoform (b) has a shorter and distinct N-terminus compared to isoform a.

Source sequence(s)

AC010899, AK300772, BC105000, BM676153, DA451606

UniProtKB/Swiss-Prot

P54764

Conserved Domains (7) summary

cd09545
Location:860 → 930

SAM_EPH-A4; SAM domain of EPH-A4 subfamily of tyrosine kinase receptors

smart00454
Location:864 → 924

SAM; Sterile alpha motif

cd10473
Location:3 → 152

EphR_LBD_A; Ligand Binding Domain of Ephrin type-A Receptors

cd00063
Location:390 → 481

FN3; Fibronectin type 3 domain; One of three types of internal repeats found in the plasma protein fibronectin. Its tenth fibronectin type III repeat contains an RGD cell recognition sequence in a flexible loop between 2 strands. Approximately 2% of all ...

cd05066
Location:565 → 831

PTKc_EphR_A; Catalytic domain of the Protein Tyrosine Kinases, Class EphA Ephrin Receptors

pfam07714
Location:570 → 827

Pkinase_Tyr; Protein tyrosine kinase

pfam14575
Location:511 → 565

EphA2_TM; Ephrin type-A receptor 2 transmembrane domain
NM_001363748.1 → NP_001350677.1 ephrin type-A receptor 4 isoform c precursor

Status: REVIEWED

Description

Transcript Variant: This variant (4) differs in the 5' UTR and 3' coding sequence compared to variant (1). The resulting isoform (c) has a shorter and distinct C-terminus compared to isoform a.

Source sequence(s)

AC010899, AC079834

Consensus CDS

CCDS86924.1

Conserved Domains (5) summary

cd10482
Location:30 → 203

EphR_LBD_A4; Ligand Binding Domain of Ephrin type-A Receptor 4

cd00063
Location:441 → 532

FN3; Fibronectin type 3 domain; One of three types of internal repeats found in the plasma protein fibronectin. Its tenth fibronectin type III repeat contains an RGD cell recognition sequence in a flexible loop between 2 strands. Approximately 2% of all ...

cd05066
Location:616 → 882

PTKc_EphR_A; Catalytic domain of the Protein Tyrosine Kinases, Class EphA Ephrin Receptors

pfam14575
Location:562 → 616

EphA2_TM; Ephrin type-A receptor 2 transmembrane domain

cl15755
Location:911 → 949

SAM_superfamily; SAM (Sterile alpha motif )
NM_004438.5 → NP_004429.1 ephrin type-A receptor 4 isoform a precursor

See identical proteins and their annotated locations for NP_004429.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) differs in the 5' UTR compared to variant 1. Variants 1 and 2 both encode the same isoform (a).

Source sequence(s)

AC010899, BC105000, BM676153, DA451606

Consensus CDS

CCDS2447.1

UniProtKB/Swiss-Prot

P54764

UniProtKB/TrEMBL

A0A024R452

Related

ENSP00000281821.2, ENST00000281821.6

Conserved Domains (5) summary

cd09545
Location:911 → 981

SAM_EPH-A4; SAM domain of EPH-A4 subfamily of tyrosine kinase receptors

cd10482
Location:30 → 203

EphR_LBD_A4; Ligand Binding Domain of Ephrin type-A Receptor 4

cd00063
Location:441 → 532

FN3; Fibronectin type 3 domain; One of three types of internal repeats found in the plasma protein fibronectin. Its tenth fibronectin type III repeat contains an RGD cell recognition sequence in a flexible loop between 2 strands. Approximately 2% of all ...

cd05066
Location:616 → 882

PTKc_EphR_A; Catalytic domain of the Protein Tyrosine Kinases, Class EphA Ephrin Receptors

pfam14575
Location:562 → 616

EphA2_TM; Ephrin type-A receptor 2 transmembrane domain

RefSeqs of Annotated Genomes: Homo sapiens Annotation Release 109

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p12 Primary Assembly

Genomic

NC_000002.12 Reference GRCh38.p12 Primary Assembly

Range

221418027..221574202 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_005246374.3 → XP_005246431.1 ephrin type-A receptor 4 isoform X1

UniProtKB/TrEMBL

E9PG71

Related

ENSP00000386276.1, ENST00000409854.5

Conserved Domains (5) summary

cd10482
Location:30 → 203

EphR_LBD_A4; Ligand Binding Domain of Ephrin type-A Receptor 4

cd00063
Location:441 → 532

FN3; Fibronectin type 3 domain; One of three types of internal repeats found in the plasma protein fibronectin. Its tenth fibronectin type III repeat contains an RGD cell recognition sequence in a flexible loop between 2 strands. Approximately 2% of all ...

cd05066
Location:616 → 882

PTKc_EphR_A; Catalytic domain of the Protein Tyrosine Kinases, Class EphA Ephrin Receptors

pfam14575
Location:562 → 616

EphA2_TM; Ephrin type-A receptor 2 transmembrane domain

cl15755
Location:911 → 949

SAM_superfamily; SAM (Sterile alpha motif )