Eph, a protein family coming of age: more confusion, insight, or complexity?

Since the mid-1980s, Eph receptors have evolved from being regarded as orphan receptors with unknown functions and ligands to becoming one of the most complex "global positioning systems" that regulates cell traffic in multicellular organisms. During this time, there has been an exponentially growing interest in Ephs and ephrin ligands, coinciding with important advances in the way biological function is interrogated through mapping of genomes and manipulation of genes. As a result, many of the original concepts that used to define Eph signaling and function went overboard. Clearly, the need for progress in understanding Eph-ephrin biology and the underlying molecular principles involved has been compelling. Many cell-positioning programs during normal and oncogenic development-in particular, the patterning of skeletal, vascular, and nervous systems-are modulated in some way by Eph-ephrin function. Undeniably, the complexity of the underlying signaling networks is considerable, and it seems probable that systems biology approaches are required to further improve our understanding of Eph function.