EPH receptor A4

EPHA4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2LW8, 2WO1, 2WO2, 2WO3, 3CKH, 3GXU, 4BK4, 4BK5, 4BKA, 4BKF, 4M4P, 4M4R, 4W4Z, 4W50, 5JR2
Identifiers
Aliases	EPHA4 , Epha4, 2900005C20Rik, AI385584, Cek8, Hek8, Sek, Sek1, Tyro1, rb, EPH receptor A4, HEK8, SEK, TYRO1, EK8
External IDs	OMIM: 602188; MGI: 98277; HomoloGene: 20933; GeneCards: EPHA4; OMA:EPHA4 - orthologs
Gene location (Human) Chr. Chromosome 2 (human) [1] Band 2q36.1 Start 221,418,027 bp [1] End 221,574,202 bp [1]
Gene location (Mouse) Chr. Chromosome 1 (mouse) [2] Band 1 C4|1 39.55 cM Start 77,343,822 bp [2] End 77,491,725 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Brodmann area 23 frontal pole middle temporal gyrus lateral nuclear group of thalamus endothelial cell primary visual cortex superior frontal gyrus parietal lobe postcentral gyrus palpebral conjunctiva Top expressed in Rostral migratory stream medial ganglionic eminence ventricular zone dorsal striatum genital tubercle dentate gyrus of hippocampal formation granule cell medial dorsal nucleus lateral geniculate nucleus nucleus accumbens tail of embryo More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity protein kinase activity nucleotide binding GPI-linked ephrin receptor activity ephrin receptor binding DH domain binding transmembrane-ephrin receptor activity kinase activity protein binding identical protein binding transmembrane receptor protein tyrosine kinase activity PH domain binding protein tyrosine kinase activity ATP binding ephrin receptor activity amyloid-beta binding protein tyrosine kinase binding Cellular component cytoplasm axon terminus integral component of membrane cell body perikaryon postsynaptic membrane Golgi apparatus endosome cell projection early endosome membrane membrane postsynaptic density filopodium neuromuscular junction plasma membrane dendritic spine axonal growth cone integral component of plasma membrane synapse cell surface mitochondrial outer membrane cell junction axon dendrite early endosome endoplasmic reticulum neuron projection dendritic shaft receptor complex Schaffer collateral - CA1 synapse glutamatergic synapse integral component of postsynaptic membrane integral component of presynaptic membrane Biological process negative regulation of axon regeneration fasciculation of motor neuron axon phosphorylation transmembrane receptor protein tyrosine kinase signaling pathway positive regulation of JUN kinase activity regulation of GTPase activity nervous system development regulation of axonogenesis multicellular organism development protein phosphorylation regulation of astrocyte differentiation cell adhesion positive regulation of dendrite morphogenesis nephric duct morphogenesis protein autophosphorylation corticospinal tract morphogenesis peptidyl-tyrosine phosphorylation fasciculation of sensory neuron axon motor neuron axon guidance positive regulation of Rho guanyl-nucleotide exchange factor activity regulation of dendritic spine morphogenesis glial cell migration adult walking behavior axon guidance ephrin receptor signaling pathway negative regulation of neuron projection development protein stabilization positive regulation of protein tyrosine kinase activity neuron projection guidance synapse pruning neuron projection fasciculation negative regulation of long-term synaptic potentiation positive regulation of amyloid-beta formation positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process negative regulation of proteolysis involved in cellular protein catabolic process cellular response to amyloid-beta regulation of modification of synaptic structure Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2043 13838 Ensembl ENSG00000116106 ENSMUSG00000026235 UniProt P54764 Q03137 RefSeq (mRNA) NM_001304536 NM_001304537 NM_004438 NM_001363748 NM_007936 RefSeq (protein) NP_001291465 NP_001291466 NP_004429 NP_001350677 NP_031962 Location (UCSC) Chr 2: 221.42 – 221.57 Mb Chr 1: 77.34 – 77.49 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

EPH receptor A4 (ephrin type-A receptor 4) is a protein that in humans is encoded by the EPHA4 gene. ^{[5] [6]}

Structure

This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. 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. ^[6]

Function

EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system.

EphA4 is a ubiquitously expressed receptor tyrosine kinase of the Eph family that mediates bidirectional cell signaling through interactions with both ephrin-A and ephrin-B ligands, orchestrating axonal guidance, synaptic plasticity, and glial responses in the central nervous system. EphA4 is a versatile modulator of neuronal development and pathology, integrating cytoskeletal remodeling, axon guidance, and glial scar formation via RhoA/ROCK-dependent signaling, while its overactivation impedes axonal regeneration after spinal cord or brain injury. ^[7] EphA4 sustains inhibitory cues that limit neuronal repair, and its inhibition has been shown to enhance motor function recovery and myelination. EphA4 disrupts synaptic integrity and potentiating amyloid-driven neurotoxicity; conversely, genetic or pharmacological attenuation of EphA4 signaling restores synaptic function and ameliorates cognitive decline. ^[8] EphA4 directly triggers motor neuron death in models of motor neuron disease through caspase activation and excitotoxic pathways. ^[9]

Clinical significance

EphA4 is a multifunctional receptor tyrosine kinase whose altered signaling is implicated in numerous neurological diseases. ^[7] It regulates axonal guidance, synaptic plasticity, and myelination during central nervous system development, but its over activation contributes to neurodegenerative processes including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease, traumatic brain injury, and spinal cord injury. Dysregulated signaling promotes astrocytic gliosis, glial scar formation, and impaired axonal regeneration, thereby limiting neuronal recovery. ^[7] In AD, enhanced EphA4 activity drives synaptic loss and cognitive decline through mechanisms such as β-amyloid–induced dendritic spine retraction, while receptor inhibition restores synaptic integrity. ^[8] In ALS, EphA4 expression level acts as a modifier of disease severity, with reduced receptor activity correlating with slower progression and enhanced motor neuron survival. ^[9] Overall, EphA4 serves as a critical mediator of neuroinflammation, synaptic dysfunction, and regenerative inhibition, positioning it as a promising therapeutic target across degenerative and traumatic brain disorders. ^{[7] [8] [9]}

References

1. GRCh38: Ensembl release 89: ENSG00000116106 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000026235 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Eph Nomenclature Committee (August 1997). "Unified nomenclature for Eph family receptors and their ligands, the ephrins". Cell. 90 (3): 403–404. doi: 10.1016/S0092-8674(00)80500-0 . PMID   9267020. S2CID   26773768.
6. "Entrez Gene: EPHA4 EPH receptor A4".
7. Verma M, Chopra M, Kumar H (October 2023). "Unraveling the Potential of EphA4: A Breakthrough Target and Beacon of Hope for Neurological Diseases". Cellular and Molecular Neurobiology. 43 (7): 3375–3391. doi:10.1007/s10571-023-01390-0. PMC   11409998 . PMID   37477786.
8. Ganguly D, Thomas JA, Ali A, Kumar R (November 2022). "Mechanistic and therapeutic implications of EphA-4 receptor tyrosine kinase in the pathogenesis of Alzheimer's disease". The European Journal of Neuroscience. 56 (9): 5532–5546. doi:10.1111/ejn.15591. PMID   34989046.
9. Zhao J, Stevens CH, Boyd AW, Ooi L, Bartlett PF (August 2021). "Role of EphA4 in Mediating Motor Neuron Death in MND". International Journal of Molecular Sciences. 22 (17): 9430. doi: 10.3390/ijms22179430 . PMC   8430883 . PMID   34502339.

Further reading

• Flanagan JG, Vanderhaeghen P (1998). "The ephrins and Eph receptors in neural development". Annual Review of Neuroscience. 21: 309–345. doi:10.1146/annurev.neuro.21.1.309. PMID   9530499.
• Zhou R (March 1998). "The Eph family receptors and ligands". Pharmacology & Therapeutics. 77 (3): 151–181. doi:10.1016/S0163-7258(97)00112-5. PMID   9576626.
• Holder N, Klein R (May 1999). "Eph receptors and ephrins: effectors of morphogenesis". Development. 126 (10): 2033–2044. doi:10.1242/dev.126.10.2033. PMID   10207129.
• DG W (2000). "Eph receptors and ephrins: Regulators of guidance and assembly". A Survey of Cell Biology. International Review of Cytology. Vol. 196. pp. 177–244. doi:10.1016/S0074-7696(00)96005-4. ISBN   978-0-12-364600-2. PMID   10730216.
• Xu Q, Mellitzer G, Wilkinson DG (July 2000). "Roles of Eph receptors and ephrins in segmental patterning". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 355 (1399): 993–1002. doi:10.1098/rstb.2000.0635. PMC   1692797 . PMID   11128993.
• Wilkinson DG (March 2001). "Multiple roles of EPH receptors and ephrins in neural development". Nature Reviews. Neuroscience. 2 (3): 155–164. doi:10.1038/35058515. PMID   11256076. S2CID   205014301.
• Fox GM, Holst PL, Chute HT, Lindberg RA, Janssen AM, Basu R, et al. (March 1995). "cDNA cloning and tissue distribution of five human EPH-like receptor protein-tyrosine kinases". Oncogene. 10 (5): 897–905. PMID   7898931.
• Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. doi:10.1016/0378-1119(94)90802-8. PMID   8125298.
• Ellis C, Kasmi F, Ganju P, Walls E, Panayotou G, Reith AD (April 1996). "A juxtamembrane autophosphorylation site in the Eph family receptor tyrosine kinase, Sek, mediates high affinity interaction with p59fyn". Oncogene. 12 (8): 1727–1736. PMID   8622893.
• Gale NW, Holland SJ, Valenzuela DM, Flenniken A, Pan L, Ryan TE, et al. (July 1996). "Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis". Neuron. 17 (1): 9–19. doi: 10.1016/S0896-6273(00)80276-7 . PMID   8755474. S2CID   1075856.
• Bonaldo MF, Lennon G, Soares MB (September 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi: 10.1101/gr.6.9.791 . PMID   8889548.
• Aasheim HC, Terstappen LW, Logtenberg T (November 1997). "Regulated expression of the Eph-related receptor tyrosine kinase Hek11 in early human B lymphopoiesis". Blood. 90 (9): 3613–3622. doi: 10.1182/blood.V90.9.3613 . PMID   9345045.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. doi:10.1016/S0378-1119(97)00411-3. PMID   9373149.
• Bergemann AD, Zhang L, Chiang MK, Brambilla R, Klein R, Flanagan JG (January 1998). "Ephrin-B3, a ligand for the receptor EphB3, expressed at the midline of the developing neural tube". Oncogene. 16 (4): 471–480. doi:10.1038/sj.onc.1201557. PMID   9484836. S2CID   2497788.
• Janis LS, Cassidy RM, Kromer LF (June 1999). "Ephrin-A binding and EphA receptor expression delineate the matrix compartment of the striatum". The Journal of Neuroscience. 19 (12): 4962–4971. doi: 10.1523/JNEUROSCI.19-12-04962.1999 . PMC   6782661 . PMID   10366629.