Ephrin-B2 is a ligand for RTK Eph receptors, mediating cell adhesion and repulsion-segregation, thus influencing cell migration and tissue morphogenesis and angiogenesis. Ephrin-B2 is highly expressed in the nervous system during development and required for neuronal survival. Also expressed in the brain and lung endothelial cells (EC) for angiogenesis. It is overexpressed in various cancers.

The erythropoietin-producing hepatocellular (Eph) receptors represent the largest known family of receptor tyrosine kinases and are activated by interactions with cell-surface ligands, termed ephrins. Eph receptors have been classified into two subfamilies, EphA and EphB, according to their preference for either glycosylphosphatidylinositol (GPI)-anchored ephrin-A ligands (ephrin-A1 to -A5) or transmembrane ephrin-B ligands (ephrin-B1 to -B3). All ephrin ligands share a conserved core sequence of approximately 125 amino acids, including 4 invariant cysteine residues, probably corresponding to a receptor binding domain ¹.

Ephrin-B2 is a cell surface transmembrane ligand ². Ephrin-B2 binds Eph receptors residing on adjacent cells, leading to 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. Forward and reverse signaling through Eph receptors is a unique characteristic to this RTK since ephrins are physically linked to the plasma membrane ³. For example, in angiogenesis EphB4-mediated forward signaling controls cellular repulsion and segregation from ephrin-B2-expressing cells, resulting in distinction between EphB4-expressing veins and ephrin-B2-expressing arteries ⁴.

Eph receptors and ephrins are highly expressed in the brain and in the developing nervous system, where they are involved in fundamental developmental processes of the nervous system, including axon guidance, axon fasciculation, neural crest cell migration, acquisition of brain subregional identity, and neuronal cell survival. They are also implicated in Alzheimer’s disease, and other neurodegenerative disorders ⁵.

Nipah virus (NiV) infection has both respiratory and encephalitic components and several cell types are targets of NiV, dictated by the expression of the ephrin-B2/3 ligand on the cell’s outer membrane, which interact with the NiV surface proteins. ephrin-B2 and ephrin-B3 on cells, are the only identified receptors for NiV and Hendra virus (HeV) from the family Paramyxoviridae. Vascular endothelial cells (ECs) are the major targets of infection by NiV and HeV ⁶ .

In cancer cells, Eph receptors and ephrins are overexpressed. Eph receptor bidirectional signaling with both tumor-promoting and tumor-suppressing activities has been observed in different cancer types and their microenvironments. EphB2 is aberrantly expressed in many cancer types, such as colorectal cancer, gastric cancer and hepatocellular carcinoma, driving tumorigenesis and tumor progression ⁷.