EPHA3 gene

The EPHA3 gene (EPHA3 stands for: EPH receptor A3) is a protein-coding gene localized on chromosome 3p11.1. An important paralog of this gene is EPHA5.

This gene belongs to the ephrin receptor subfamily of the protein tyrosine kinase family. EPH and EPH-related receptors are involved in mediating development, especially in the nervous system. EPH subfamily receptors typically have a single kinase domain and an extracellular region containing a Cys-rich domain and two fibronectin type III repeats. The ephrin receptors are divided into two groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin A and ephrin B ligands. This gene encodes a protein that binds ephrin A ligands. Two alternatively spliced transcript variants have been described for this gene.

The encoded EPHA3 protein is a receptor tyrosine kinase that promiscuously binds membrane-bound ligands of the ephrin family located on neighboring cells, resulting in contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling, while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling.

The receptor is highly promiscuous for ephrin A ligands and preferentially binds EFNA5. Upon activation by EFNA5, it regulates cell-cell adhesion, cytoskeletal organization and cell migration. Plays a role in the migration and differentiation of cardiac cells and regulates the formation of the atrioventricular canal and septum during development, probably through activation by EFNA1. Is involved in retinotectal mapping of neurons. May also control segregation, but not guidance, of motor and sensory axons during development of the neuromuscular circuit.

Eph receptors are the largest family of receptor tyrosine kinases (RTKs) and are divided into two subclasses, EphA and EphB. Eph receptors were originally identified as mediators of axon guidance and are involved in many processes, particularly cancer development and progression.

Eph receptors were originally identified as mediators of axon guidance. They are involved in many processes, including vascular development and carcinogenesis and progression.

The following causes of abnormal and dilated blood vessels can be summarized for the nevus flammeus (Liu L et al. 2022):

• Somatic GNAQ (R183Q) mutations that induce angiopoietin-2 lead to the formation of enlarged capillary-like vessels
• Decreased number of perivascular nerve elements
• Coexistence of Eph receptor B1 and ephrin B2
• Lack of expression of alpha-smooth muscle actin
• Mutations in the PIK3CA, SMARCA4, EPHA3, MYB and PDGFR-B genes

Eph receptor tyrosine kinases regulate cell-cell interactions during normal and oncogenic development and are involved in a number of processes, including angiogenesis, stem cell maintenance and metastasis. They are therefore of great interest as targets for cancer therapy. EphA3, which was originally isolated from leukemia and melanoma cells, is currently one of the most promising therapeutic targets as it plays a tumor-promoting role in a variety of cancers (Janes PW et al. 2014).

In melanoma , the EPH receptor A3 (EphA3) is deregulated . Its role has not yet been clarified in detail (Ming D et al. 2022).

Diseases associated with EPHA3 include:

• beriberi and wet beriberi (beriberi is a disease caused by a deficiency of thiamine (vitamin B1). There are two main types: wet beriberi, which affects the cardiovascular system, and dry beriberi, which affects the nervous system. Symptoms of wet beriberi include an increased heart rate, shortness of breath and swollen legs, while symptoms of dry beriberi include difficulty walking, numbness in the hands and feet, confusion and pain. In the United States, beriberi is rare thanks to vitamin-rich foods, but risk factors include alcohol abuse, dialysis and high doses of diuretics. Genetic beriberi is a rare inherited form associated with problems with thiamine absorption. In infants, acute beriberi can lead to severe symptoms and death within a few hours. The disease is classified as wet or dry based on fluid accumulation in the body, with a mixture of symptoms occurring in some cases. Thiamine deficiency responds well to thiamine supplementation.
• Nevus flammeus (Portwine stain/PWS)

1. Janes PW et al. (2014) EphA3 biology and cancer. Growth Factors 32:176-189.
2. Lange M et al. (2008) Regulation of muscle development by DPF3, a novel histone acetylation and methylation reader of the BAF chromatin remodeling complex. Genes Dev 22:2370-2384.
3. Ming D et al. (2022) EphA3 targeted by miR-3666 contributes to melanoma malignancy via activating ERK1/2 and p38 MAPK pathways. Open Med (Wars) 17:2098-2108.
4. Wang Y et al.(2019) EphA3 Downregulation by Hypermethylation Associated with Lymph Node Metastasis and TNM Stage in Colorectal Cancer. Dig Dis Sci 64:1514-1522.