Ephrin signaling: One raft to rule them all? One raft to sort them? One raft to spread their call and in signaling bind them?

The Eph receptor tyrosine kinases (RTK) and their membrane-bound ligands, the ephrins, mediate cell-contact-dependent signaling events that control multiple aspects of metazoan embryonic development. The ephrins and their receptors regulate cell movement that is essential for forming and stabilizing the spatial organization of tissues and cell types. This includes the guidance of migrating cells or neuronal growth cones to specific targets. Although the biological responses mediated by the ephrin-Eph system were thought to be imparted by the Eph receptor via 'classical' RTK signaling pathways, there is now accumulating evidence that the ephrins are not merely ligands but have biological activity independent of the kinase activity of their cognate Eph receptor. This activity is commonly referred to as 'reverse' or 'bi-directional' signaling. Furthermore, ephrin-mediated signaling is restricted to specific membrane microdomains known as 'lipid rafts', which we believe imparts specificity to the extracellular signal. This review highlights the current data to support a role for lipid rafts in regulating aspects of ephrin-mediated signaling.