EPHB4 gene

The EPHB4 gene (EPHB4 stands for: Ephrin Receptor B4) is a protein-coding gene located on chromosome 7q22.1. The protein encoded by this gene binds to ephrin-B2 and plays an essential role in vascular development. Associated signaling pathways include GPCR pathway and EPH-ephrin signaling. Molecular activities originating from the gene activity include transferase activity, transfer of phosphorus-containing groups and protein tyrosine kinase activity. An important paralog of this gene is EPHB3.

Ephrin receptors and their ligands, the ephrins, mediate numerous developmental processes, particularly in the nervous system. Based on their structures and sequence relationships, the ephrins are divided into the ephrin A class (EFNA), which are anchored to the membrane by a glycosylphosphatidylinositol bond, and the ephrin B class (EFNB), which are transmembrane proteins. The Eph family 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. Ephrin receptors form the largest subgroup of the receptor tyrosine kinase (RTK) family.

Diseases associated with EPHB4 include lymphatic malformation 7 and capillary malformation-arteriovenous malformation 2 (Rhodoides nevus syndrome). Whole-exome sequencing data show different deleterious variants in EPHB4 associated with in 5 families associated with CM-AVM. In a larger screening of 54 index patients, 47 different mutations were detected when screening EPHB4: 27 resulted in a premature stop codon or splice site alteration, indicating loss of function. The other 20 are non-synonymous variants leading to amino acid substitutions. The phenotype, CM-AVM2, is similar to the RASA1-related CM-AVM1 and also to hereditary hemorrhagic telangiectasia. The p120RASGAP encoded by RASA1 is a direct effector of EPHB4. Our data underline the pathogenetic importance of this interaction and point to the EPHB4-RAS-ERK signaling pathway as a major cause of AVMs.

The protein encoded by the EPHB4 gene is a receptor tyrosine kinase that promiscuously binds transmembrane ligands of the ephrin B family located on neighboring cells, resulting in contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is called forward signaling, while the signaling pathway downstream of the ephrin ligand is called reverse signaling. Together with its cognate ligand/functional ligand EFNB2, the receptor kinase is involved in the regulation of cell adhesion and migration and plays a central role in cardiac morphogenesis, angiogenesis and the remodeling and permeability of blood vessels.

1. Amyere M (2017) Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling. Circulation 136:1037-1048.
2. Brix ATH et al. (2022) Capillary Malformation-arteriovenous Malformation Type 2: A Case Report and Review. Acta Derm Venereol 102:adv00662.