EPH receptor A4
EPH receptor A4 (ephrin type-A receptor 4) is a protein that in humans is encoded by the EPHA4 gene.
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.
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. 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. EphA4 directly triggers motor neuron death in models of motor neuron disease through caspase activation and excitotoxic pathways.
Clinical significance
EphA4 is a multifunctional receptor tyrosine kinase whose altered signaling is implicated in numerous neurological diseases. 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. 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. 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. 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.
References
- 1 2 3 GRCh38: Ensembl release 89: ENSG00000116106 – Ensembl, May 2017
- 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000026235 – Ensembl, May 2017
- ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ↑ 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.
- 1 2 "Entrez Gene: EPHA4 EPH receptor A4".
- 1 2 3 4 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.
- 1 2 3 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.
- 1 2 3 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.
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