EPHA4
Description
The EPHA4 (EPH receptor A4) is a protein-coding gene located on chromosome 2.
EPH receptor A4 (ephrin type-A receptor 4) is a protein that in humans is encoded by the EPHA4 gene. 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. In 2012, a publication in Nature Medicine revealed a connection between EPHA4 and the neurodegenerative disease Amyotrophic lateral sclerosis (ALS), where a defective gene allows ALS patients to live considerably longer than patients with an intact gene. This opens up for development of treatment for this currently untreatable disease.
EPHA4 is a receptor tyrosine kinase that binds to membrane-bound ephrin family ligands on neighboring cells, initiating a bidirectional signaling process. This signaling is crucial for cell-cell communication and various developmental processes. EPHA4 uniquely binds and is activated by both GPI-anchored ephrin-A and transmembrane ephrin-B ligands, including EFNA1 and EFNB3, contributing to its broad influence. EPHA4 regulates cell morphology and integrin-dependent cell adhesion by controlling the activity of Rac, Rap, and Rho GTPases. It plays a critical role in nervous system development by guiding axons, establishing corticospinal projections, and segregating motor and sensory axons during neuromuscular circuit formation. EPHA4 also contributes to synaptic plasticity, particularly through its activation by EFNA1, which triggers phosphorylation of CDK5 and subsequent phosphorylation of NGEF, ultimately regulating RHOA and dendritic spine morphogenesis. In the nervous system, EPHA4 participates in injury repair by inhibiting axonal regeneration, and in angiogenesis by influencing central nervous system vascular formation. Beyond the nervous system, EPHA4's promiscuous binding properties enable it to participate in a variety of cell-cell signaling events, including the development of the thymic epithelium. During development of the cochlear organ of Corti, EPHA4 regulates pillar cell separation by forming a ternary complex with ADAM10 and CADH1, leading to the cleavage of CADH1 by ADAM10 and disruption of adherens junctions. EPHA4 also phosphorylates CAPRIN1, promoting the formation of a membraneless compartment.
EPHA4 is also known as EK8, HEK8, SEK, TYRO1.
