EPH receptor A4


EPH receptor A4 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, Alzheimer’s disease, 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.