EphB3, also known as Cek10, Tyro6, Sek4, Hek2, and Mdk5, is a 130 kDa member of the transmembrane Eph receptor tyrosine kinase family. The A and B classes of Eph proteins are distinguished by Ephrin ligand binding preference but have a common structural organization. Eph-Ephrin interactions are widely involved in the regulation of cell migration, tissue morphogenesis, and cancer progression (1). The 525 amino acid (aa) extracellular domain (ECD) of mature mouse EphB3 contains a ligand binding domain followed by a cysteine rich region and two fibronectin type III domains. The 418 aa cytoplasmic domain contains a tyrosine kinase domain, a sterile alpha motif (SAM), and a PDZ binding motif (2). Within the ECD, mouse EphB3 shares 96% and 99% aa sequence identity with human and rat EphB3, respectively. Binding of EphB3 to its ligands Ephrin-B1, B2, and B3 triggers forward signaling through EphB3 as well as reverse signaling through the Ephrin (1, 3). EphB3 also interacts in cis with the receptor tyrosine kinase Ryk (4). Activation of its kinase is required for some but not all of the effects of EphB3 on cellular adhesion, motility, and morphology (5). EphB3 is widely expressed during development and in the adult; it shows a complementary tissue distribution to the Ephrin-B ligands (6‑9). EphB3 function is important in vascular, nervous system, thymocyte, and palate development (6, 7, 10‑12). It directs embyronic neuronal axon pathfinding, and its upregulation on local macrophages following neuronal injury promotes the growth of regenerating axons (10, 13). EphB3 inhibits colorectal carcinogenesis and invasion by preventing the migration of tumor cells out of the intestinal crypt (9, 14). EphB3 function is supported by the cooperative action of EphB2 in several of these processes (6, 10‑12, 15).