The first Eph receptor, which was found to be overexpressed in erythropoietin-producing hepatocellular carcinoma cell line (hence, the name Eph), was identified by homology cloning using the kinase domain of the viral oncogene v-fps as a probe for low-stringency hybridization (Hirai et al. 1987). Since then, other homologous members were cloned by low-stringency cross-hybridization or PCR with primers based on conserved sequences in the kinase domain. There are a total of fourteen homologous Eph receptors identified in mammals to date, comprising the largest family of RTK. They are generally categorized as either EphA or EphB receptor based on ligand specificity (see below).
During the early days when their ligands had not yet been identified, Eph receptors were often described as “orphan receptors” with unknown function. The first Eph receptor ligand, named at that time B61, was cloned as a cytokine-inducible gene (Holzman et al. 1990), although it was not...