Ephrins

Abstract

Ephrins are cell surface proteins which bind to the Eph family of receptor tyrosine kinases. Cell surface‐attached ephrin‐A ligands principally activate EphA receptors, and transmembrane ephrin‐B ligands primarily activate EphB receptors. Ephs and ephrins influence many developmental processes, including compartmentalisation, cellular migration, axon guidance and angiogenesis. These developmental functions arise as Ephrin–Eph interactions shape cellular behaviours, including adhesion, migration and synaptic plasticity. Eph receptors communicate with the cytoskeleton through differential activation of small GTPases downstream of their tyrosine kinase activity. In addition to stimulating Eph receptors, ephrins signal within the cell which expresses them, a phenomenon termed ‘reverse signalling’. Ephrin‐B reverse signalling relies in part on phosphorylation of the cytoplasmic tail and recruitment of cytoplasmic proteins. Both ephrins and Ephs can modify internalisation and trafficking of other cell surface effector molecules.

Key Concepts:

  • Ephrins are implicated in numerous developmental events centred around cell‐contact‐dependent signalling.

  • Ephrin ligands and Eph receptors participate in axon guidance, and graded expression of this system is implicated in the topographic mapping of the retinotectal projection.

  • Ephrins also critically control synaptic function.

  • In the vasculature, EphB4 and ephrin‐B2 are required for angiogenesic remodelling of the primitive vascular plexus.

  • Ephrins both stimulate Eph receptor tyrosine kinases and transduce ‘reverse’ signals in the cells which express them.

  • The specific outcome of Eph–ephrin engagement depends on cellular context and on the involvement of other signalling components.

Keywords: axon guidance; cell migration; Eph; ephrin; receptor tyrosine kinase; signal transduction

Figure 1.

Receptors and ligands. Ephrin‐A ligands are attached to the cell surface by a GPI‐anchor, whereas ephrin‐B ligands span the membrane and contain a cytoplasmic domain. Both subgroups of Eph receptors have the same overall structure. Domains: Cys, cysteine‐rich; Cyto, cytoplasmic; Ext, extracellular; FNIII, fibronectin type III; Glob, globular; GPI, glycosylphosphatidylinositol anchor; TK, tyrosine kinase.

Figure 2.

Ephrins and Eph receptors function in tissue compartmentalisation. (a) The developing hindbrain is organised into segments termed rhombomeres. Expression of Eph receptors on rhombomeres 3 and 5, and ephrins on even‐numbered rhombomeres, maintains segregation of rhombomeric cells. (b) As somites form from the paraxial mesoderm, EphA4 triggers a reorganisation of ephrin‐B2 in the posterior portion of the most recently formed somite. (c) In the gastrointestinal system, cells in the crypt express EphB2 and EphB3, whereas cells in the villus generally express ephrins. Mice lacking EphB2 and EphB3 show cells normally confined to the crypt aberrantly located in the villar regions. (d) Schematic of Jorgensen et al. reductionist model of compartmentalisation by Eph–ephrin signalling. Cells are separately transfected with EphB2 or ephrin‐B1, then mixed 1:1. Receptor‐ and ligand‐expressing cells separate into aggregates with sharp borders. This segregation effect is lost if either receptor or ligand is silenced by siRNA cotransfection.

Figure 3.

Complementary gradients of Eph receptors and their ligands in the developing chick retinotectal system. (a) Axons from anterior (nasal, N) retinal ganglion cells project to posterior (P) tectum, whereas axons from the posterior (temporal, T) retina terminate in the anterior (A) tectum. (b) In the tectum (blue gradients), ephrin‐A2 and ‐A5 show graded expression along the anteroposterior axis, with ephrin‐A5 mostly confined to the posterior half. In the retina (red gradients), EphA3 receptors are expressed in an ascending A–P gradient, EphA5 is expressed uniformly, and EphB2 is expressed in an ascending dorsoventral gradient. Reproduced from Orioli and Klein (). Copyright © Elsevier.

Figure 4.

Model of bidirectional signalling by Eph receptors and ephrin‐B ligands during axonal pathfinding. (a) Anterior commissure axons (and presumably their migrating growth cones) express ephrin‐B ligands, whereas surrounding neurons express EphB receptors. Axons are guided by contact repulsion involving bidirectional signalling downstream of ligands and receptors (arrows). Tyrosine phosphorylation (P) of both receptors and ligands are likely to contribute to or activate downstream signalling cascades. (b) Spinal motor neurons express Eph receptors and are guided by ephrin ligands in adjacent cells. Here, receptors transduce signals into the axon and ligands may signal into muscle cells. Reproduced from Orioli and Klein (). Copyright © Elsevier.

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Further Reading

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Pasquale EB (2005) Eph receptor signalling casts a wide net on cell behaviour. Nature Reviews Molecular Cell Biology 6: 462–475.

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Kilari, Sreenivasulu, and Wilkinson, George(Nov 2011) Ephrins. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000831.pub3]