Eph Receptors and Ephrin Ligands in Axon Guidance

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Abstract

The Eph tyrosine kinase receptors (a receptor family named for the expression of Eph in an erythropoietin-producing human hepatocellular carcinoma cell line) make up the largest family of receptor tyrosine kinases. In vertebrates, 14 Eph receptor members have been identified, divided in two sub-groups, the EphAs (EphA1 to A8) and EphBs (EphB1 to B6). Their nine membrane-bound ligands, the ephrins, are also subdivided into the ephrin-As (ephrin-A1 to A6) and ephrin-Bs (ephrin-B1 to B3). The first Eph receptor (EphA1) was identified in 1987, whereas the ephrin ligands were cloned in the mid-90s 1. Eph receptors and ephrins have been found in all animal species analyzed so far, from C. elegans to humans, and are highly conserved through evolution 2. Ephs and ephrins are involved in numerous developmental processes, such as boundary formation, angiogenesis and cell migration. Within the nervous system, Eph signaling regulates the migration pattern of neural crest cells, the boundary formation between hindbrain segments (rhombomeres), the proper formation of the corticospinal tract, the establishment of neural topographic maps and the formation and functional properties of neuronal synapses 1, 36. It is therefore not surprising that nature built a complicated and detailed network of proteins interacting with each other to fine tune each of these important processes. The identity of the receptor or ligand molecule is as important as the structure of the receptor-ligand complex to activate a specific signaling pathway and ultimately elicit the right cell decision.