Ephrins and their Eph receptors: multitalented directors of embryonic development

Ephrins are membrane‐bound ligands for the Eph family of protein tyrosine kinase receptors. Recent genetic studies have indicated that these molecules play key roles in diverse biological processes such as the development of the nervous system and angiogenesis. In the nervous system, they provide positional information by employing mechanisms that involve repulsion of migrating cells and growing axons. Understanding the mechanisms that mediate these biological responses will help to establish the molecular basis of topographic positioning within the developing embryo. Eph receptors have been conserved in a variety of eukaryotic species from Caenorhabditis elegans to man. They constitute the largest subgroup within the tyrosine protein kinase receptor family, with 14 receptors in mammals known to date. These receptors interact with cell‐surface‐bound ligands known as ephrins. The Eph receptors and their ephrin ligands can be divided into two classes based on structural features and binding affinities (Eph Nomenclature Committee, 1997; Figure 1). Type A ephrins are attached to the outer leaflet of the plasma membrane by a glycosyl phosphatidylinositol (GPI) moiety and they bind to the type A class of structurally related Eph receptors (Eph Nomenclature Committee, 1997). Type B ephrins have, in addition to their extracellular domain, a single transmembrane domain and a cytoplasmic tail. They bind to type B Eph receptors (Eph Nomenclature Committee, 1997). With the exception of EphA4, which can bind members of class A and class B ephrins, there appears to be very limited cross‐talk between the A and B classes (Gale et al ., 1996). Although there is a high degree of promiscuity between ephrins and Eph receptors of the same class, they may not be functionally interchangeable. For instance, there are considerable differences in binding affinities between different ligand–receptor pairs within the same class, suggesting that there may be preferred ligands for certain receptors …

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