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  • Review Article
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Mechanisms and functions of eph and ephrin signalling

Nature Reviews Molecular Cell Biology volume 3, pages 475–486 (2002)Cite this article

Key Points

  • Biological functions for Eph receptors and ephrins include vascular development, tissue-border formation, cell migration, axon guidance and synaptic plasticity.

  • Eph receptors can act as a ligand in the same way that an ephrin ligand can act as a receptor. Ephrins are also able to signal into their host cell, which is referred to as 'reverse signalling'

  • Recent examples of Eph-receptor signalling mechanisms are: (1) Ephexin and Abl and their role in regulating the actin cytoskeleton; (2) Eph receptors as negative regulators of the extracellular-signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway; and (3) Eph receptors as regulators of cell adhesion through integrin cell–substrate interactions.

  • Recent examples of ephrin signalling mechanisms are: (1) Src family kinases (SFK) as positive regulators of ephrinB phosphorylation; (2) the recruitment of PDZ-domain-containing protein-tyrosine phosphatase PTP-BL to ephrinB membrane clusters; (3) the SH2–SH3 domain adaptor protein Grb4 as a downstream effector of ephrinB ligands; and (4) phosphorylation-independent signalling by ephrinB ligands through the new cytoplasmic protein PDZ-RGS3.

  • Some of the functions that are dependent on receptor-mediated signalling are: (1) kinase-dependent functions in formation of the corticospinal tract mediated by EphA4; (2) EphB2 forward signalling in the regulation of fluid homeostasis in the inner ear by EphB2; and (3) EphrinB–EphB2–NMDA-receptor influenced signalling clusters at the synapse and modulation of synapse functions, although some of these events are dependent on Eph receptor kinase signalling, whereas others are not.

  • Functions that require the ephrinB cytoplasmic domain are: (1) the establishment of boundaries between segments of the vertebrate hindbrain; and (2) remodelling of the embryonic vasculature.

  • A function that does not require the ephrinB cytoplasmic domain is neural-crest-cell migration, and is instead probably mediated by forward signalling of Eph receptors.

Abstract

Eph receptors constitute the largest family of tyrosine kinase receptors and, together with their plasma-membrane-bound ephrin ligands, have many important functions during development and adulthood. In contrast with most receptor tyrosine kinases, unidirectional signalling can originate from the ephrin ligands as well as from the Eph receptors. Furthermore, the concept of bidirectional signalling has emerged as an important mechanism by which Ephs and ephrins control the output signal in processes of cell–cell communication.

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Figure 1: General features of Eph receptors and ephrins.
Figure 2: Regulation of Eph receptor catalytic activity.
Figure 3: Summary of adaptor interactions described in this review.
Figure 4: Molecular mechanisms of ephrinB reverse signalling.
Figure 5: Corticospinal-tract-fibre guidance.
Figure 6: Long-term potentiation.
Figure 7: Boundary sorting.
Figure 8: Angiogenesis and vasculogenesis.
Figure 9: Migration of neural-crest cells.

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Acknowledgements

We thank I. C. Grunwald, A. Palmer and G. A. Wilkinson for critically reading the manuscript and helpful discussions. Work in the laboratory was supported by grants from the Human Frontiers Science Programme Organization, the Deutsche Forschungsgemeinschaft and the Max Planck Society. K. K is a Marie Curie Fellow.

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Authors and Affiliations

  1. AstraZeneca Transgenics & Comparative Genomics (ATCG), Mölndal, S-431 83, Sweden

    Klas Kullander

  2. Department of Molecular Neurobiology, Max Planck Institute of Neurobiology, Am Klopferspitz 18A, Martinsried, D-82152, Germany

    Rüdiger Klein

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  1. Klas Kullander
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DATABASES

Flybase

dock

InterPro

Dbl

PDZ-binding motif

pleckstrin homology

SAM

SH2

SH3 domains

LocusLink

Abi-1

axin

BDNF

Cdc42

CXCR4

EGF

EphA1

EphA2

EphA3

EphA4

EphA8

EphB1

EphB2

EphB3

EphB4

EphB6

Grb4

GRIP1

GRIP2

Nck

Pick1

R-Ras

SDF-1

SOS

syndecan-2

syntenin

VEGF

Swiss-Prot

Arg

Ephexin

ephrinA1

ephrinA3

ephrinA4

ephrinA5

ephrinB1

ephrinB3

FAK

Fyn

Grb2

lacZ

PI3Kγ

PDGF receptorβ

Rac1

TrkB receptor

VAB-1

Glossary

GPI ANCHOR

The function of this post-translational modification is to attach proteins to the exoplasmic leaflet of membranes, and possibly to specific domains therein. The anchor is made of one molecule of phosphatidylinositol to which a carbohydrate chain is linked through the C-6 hydroxyl of the inositol, and is linked to the protein through an ethanolamine phosphate moiety.

FIBRONECTIN TYPE III REPEAT

A 90-amino-acid-long stretch that is repeated 15–17 times in the fibronectin molecule. It is a common motif in many cell-surface proteins.

STERILE α-MOTIF

(SAM). A domain of ∼70 amino acids that is roughly conserved in many proteins and thought to participate in protein–protein interactions.

PDZ-DOMAIN

(PSD-95, Dlg and ZO-1/2). A protein–protein interaction domain of around 90 amino acids that binds particularly to carboxy-terminal polypeptides.

SYNAPTIC PLASTICITY

A change in the functional properties of a synapse as a result of use.

AUTOPHOSPHORYLATION

The phosphorylation by a protein of one of its own residues.

SH2 DOMAIN

(Src-homology-2 domain). A protein motif that recognizes and binds tyrosine-phosphorylated sequences, and thereby has a key role in relaying cascades of signal transduction.

SH3 DOMAIN

(Src-homology-3 domain). A protein sequence of around 50 amino acids that recognizes and binds sequences that are rich in proline.

NEURAL TUBE

A hollow, dorsal tube of embryonic nerve tissue that is formed by the rolling up of the neural plate. At the front, the tube expands to form the brain, whereas the posterior part narrows to form the spinal cord.

RHO FAMILY GTPASES

Ras-related GTPases that are involved in controlling the polymerization of actin.

GROWTH CONE

A motile, exploratory tip of the axon or dendrite of a growing nerve cell, which spreads out into a large cone-shaped appendage.

FILOPODIA

Long, thin protrusions at the periphery of cells and growth cones. They are composed of F-actin bundles.

LAMELLIPODIA

Flattened, sheet-like projections of crosslinked F-actin from the surface of a cell, which are often associated with cell migration.

DOMINANT-NEGATIVE

A defective protein that retains interaction capabilities and so distorts or competes with normal proteins.

RETINAL GANGLION CELLS

Cells that form the third and last layer of the retina. They are a type of interneuron that convey information from the retinal bipolar, horizontal and amacrine cells of the eye to the brain. The axons of ganglion cells form the fibers of the optic nerve.

VOMERONASAL SYSTEM

A cluster of sensory neurons in the nasal arch that detects pheromones and transmits this information to higher cortical centres.

ENDOTHELIAL CELLS

Thin, flattened cells of mesoblastic origin that are arranged in a single layer that lines the blood vessels and some body cavities; for example, those of the heart.

FASCICULATION

The bundling of axonal processes of neurons.

FOCAL ADHESIONS

Cellular structures that link the extracellular matrix on the outside of the cell, through integrin receptors, to the actin cytoskeleton inside the cell.

STRESS FIBRES

Axial bundles of F-actin underlying the cell bodies.

OPTIC DISC

The exit point of retinal axons from the eye into the optic nerve (also called the optic nerve head).

VENTRAL ENCLOSURE

The ability of epithelial sheets with free edges to join together and fuse at the ventral midline.

NEOCORTEX

The 'newer cortex', which refers to the telencephalic cortex as opposed to the evolutionarily older primitive cortex (piriform cortex). It is found in higher vertebrates and is the site of higher mental processes.

SEMICIRCULAR CANAL

Liquid-filled archformed canal that is part of the inner-ear balance organ.

VESTIBULAR SYSTEM

The inner-ear balance organ that keeps track of the position and motion of the head in space. It consists of three perpendicularly oriented semicircular canals, which detect angular acceleration, and the utricle and saccule, which detect linear acceleration.

PROTEOGLYCANS

A class of acidic glycoproteins that are found in the extracellular matrix, especially in connective tissues. They contain more carbohydrate than protein.

LONG-TERM POTENTIATION

A long-lasting increase in the efficacy of synaptic transmission, which is commonly elicited by high-frequency neuron stimulation.

NEURAL-CREST CELL

An embryonic cell that separates from the embryonic neural plate and migrates, giving rise to the spinal and autonomic ganglia, peripheral glia, chromaffin cells, melanocytes and some haematopoietic cells.

BRANCHIAL ARCH

In the higher vertebrate embryo, this is one of a series of arches — populated by neural-crest cells — that develop into structures of the ear, neck and face. The corresponding structures in fish and amphibians, sometimes referred to as gill arches, are made of bone or cartilage and are located on either side of the pharynx.

AORTIC ARCHES

Paired arches in vertebrate embryos that connect the ventral aorta with dorsal aorta(e) by running up between gill slits or gill pouches on each side.

PROTEOME

The complete set of (predicted) proteins in an organism. The term is analogous to the genome (the complete genetic material).

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Kullander, K., Klein, R. Mechanisms and functions of eph and ephrin signalling. Nat Rev Mol Cell Biol 3, 475–486 (2002). https://doi.org/10.1038/nrm856

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