Key Points
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The Eph receptors are a large family of receptor tyrosine kinases that bind membrane-anchored ligands, called ephrins, and influence many cellular functions.
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Eph–ephrin complexes at sites of cell–cell contact can progressively assemble into tetramers that contain two receptor and two ephrin molecules and into larger aggregates. Clusters of different sizes might have different signalling properties.
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Clustered Eph-receptor–ephrin complexes become phosphorylated on the cytoplasmic domain of both the receptor and the ephrin, and can generate bidirectional signals that propagate in both the Eph- and ephrin-expressing cells. The Eph receptors mediate 'forward' signals through their kinase activity and associated signalling proteins, and the ephrins mediate 'reverse' signals through associated tyrosine kinases and other signalling proteins. The actin cytoskeleton is an important target of these signals.
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Because Eph receptors and ephrins are both membrane-anchored, their interaction — which is of high affinity — can mediate cell–cell adhesion. The ensuing signalling pathways can either mediate attractive effects, including increased cell–substrate adhesion, cell migration and axon extension, or cause repulsive effects, including separation of the two cell surfaces away from each other, retraction of cell processes and decreased cell–substrate adhesion. The different signalling outcomes probably depend in part on the intensity of the Eph signals that are generated and crosstalk that occurs with other signalling pathways.
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The best studied activity of Eph receptors and ephrins is in the establishment of topographically organized synaptic connections in many regions of the developing nervous system through effects on growth cone guidance, axon branching and fasciculation.
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Eph receptors and ephrins also influence cell shape within and outside the nervous system. For example, they regulate dendritic spine morphogenesis and remodelling, epithelial branching morphogenesis, and remodelling of embryonic blood and lymphatic vessels.
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Repulsive Eph signals drive the sorting, and prevent the intermingling, of cell subpopulations marked by differential Eph or ephrin expression. Eph signals can also regulate cell-fate determination, in some cases by regulating access to an appropriate embryonic environment.
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Given the large number of Eph and ephrin genes and their multiple effects on the behaviour of many cell types, mutations in these genes could be implicated in several human genetic diseases. Furthermore, increasing evidence indicates that Eph receptors and ephrins could be exploited as disease targets. These areas of research are only beginning to be explored.
Abstract
Eph receptor tyrosine kinases mould the behaviour of many cell types by binding membrane-anchored ligands, ephrins, at sites of cell–cell contact. Eph signals affect both of the contacting cells and can produce diverse biological responses. New models explain how quantitative variations in the densities and signalling abilities of Eph receptors and ephrins could account for the different effects that are elicited on axon guidance, cell adhesion and cell migration during development, homeostasis and disease.
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Marquardt, T. et al. Coexpressed EphA receptors and ephrin-A ligands mediate opposing actions on growth cone navigation from distinct membrane domains. Cell 121, 127–139 (2005). Shows that EphA receptors and ephrin-A ligands expressed on the same growth cone segregate laterally into distinct membrane subdomains and both contribute to axon guidance: the EphA receptors by mediating repulsive effects, and the ephrin-A molecules by mediating attractive effects.
Acknowledgements
The author thanks N. Noren for comments on the manuscript. Work in the author's laboratory is supported by the National Institutes of Health and the Department of Defense.
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Glossary
- ANGIOGENESIS
-
The growth and proliferation of new blood vessels from existing vasculature.
- FIBRONECTIN TYPE-III REPEAT
-
A 90-amino-acid section that is repeated 15–17 times in the fibronectin molecule. It is a common motif in many cell-surface proteins.
- STERILE α-MOTIF
-
A domain of ∼70 amino acids that is roughly conserved in many proteins and thought to participate in protein–protein interactions.
- GPI-ANCHOR
-
The function of this post-translational modification is to attach proteins to the exoplasmic leaflet of membranes, possibly to specific domains therein. The anchor is made of a molecule of phosphatidylinositol, a carbohydrate chain and an ethanolamine phosphate moiety attached to the C terminus of the protein.
- PDZ-DOMAIN
-
A protein–protein interaction domain of ∼90 amino acids that binds particularly to motifs in the C terminus of polypeptides.
- TRANSPHOSPHORYLATION
-
The transfer of a phosphate group by a protein kinase to a residue in a different kinase molecule.
- SRC-FAMILY KINASES
-
Members of the Src family of tyrosine kinases, the largest of the non-receptor-tyrosine-kinase families.
- SRC-HOMOLOGY-2 DOMAIN
-
A domain of ∼100 amino acids that binds to phosphorylated tyrosine sequences in proteins.
- GUANINE NUCLEOTIDE-EXCHANGE FACTOR
-
A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein.
- UBIQUITIN LIGASE
-
An enzyme that couples the small protein ubiquitin to lysine residues on a target protein, marking that protein for destruction by the proteasome or the lysosome.
- LIPID RAFTS
-
Microdomains of the plasma membrane enriched in cholesterol and glycosphingolipids, where signalling proteins tend to concentrate. Different subsets of lipid rafts have been identified, based on distinctive molecular compositions.
- NEURAL CREST CELLS
-
Cells that originate from the neural crest region of a vertebrate embryo. They migrate outward and are progenitors of many mature cell types, including peripheral neurons.
- GROWTH CONE
-
A specialized region at the tip of an axonal process that controls the direction of axon growth by responding to guidance cues.
- EXTRACELLULAR MATRIX
-
(ECM). The complex, multi-molecular material that surrounds cells. The ECM comprises a scaffold on which tissues are organized, it provides cellular microenvironments and it regulates various cellular functions.
- HAEMOSTATIC PLUG
-
Aggregate of platelets that forms at sites of vascular injury and blocks blood loss.
- TOPOGRAPHIC MAP
-
In the nervous system, a topographic map is a spatially organized array of synaptic connections that map one structure onto another. It precisely preserves the spatial relationships among neurons in one structure in their connections with neurons in the other structure.
- TERMINATION ZONE
-
Topographically appropriate location where axon collateral branches arborize and make synaptic connections with target cells.
- STRIPE ASSAY
-
In vitro assay used to study molecules involved in axon guidance. Neural tissue explants are positioned near a surface coated with alternating stripes of different substrates, such as anterior and posterior tectal membranes. The pattern of neurite outgrowth or branching on the stripes allows evaluation of the effects of different substrates.
- FILOPODIA
-
Thin cellular processes containing long, unbranched, parallel bundles of actin filaments.
- DENDRITIC SPINES
-
Knob-like extensions of the dendritic surface that can receive synaptic input. The actin cytoskeleton within dendritic spines undergoes constant remodelling, giving rise to dynamic shape changes.
- GLIAL CELLS
-
Non-neuronal cells of the central nervous system, which comprise astrocytes, oligodendrocytes, microglia and ependymal cells.
- RHO-FAMILY GTPases
-
A family of small (∼21 kDa) GTP-binding proteins that are related to Ras, and that regulate the cytoskeleton. The nucleotide-bound state is regulated by GTPase-activating proteins, which catalyse hydrolysis of the bound GTP, and guanine nucleotide-exchange factors, which catalyse GDPGTP exchange.
- ANIMAL CAPS
-
(Animal-cap assay). An experimental culture system that uses the animal cap of the blastula of amphibians and zebrafish. Historically used to study how early embryonic cells respond to inductive signals to produce differentiated tissues, it can also be used to study how surface molecules drive cell segregation in a three-dimensional model system.
- X-INACTIVATION
-
Random inactivation of one of the two X chromosomes in females to preserve an appropriate level of expression of the genes on the X chromosome.
- DIENCEPHALON
-
A subdivision of the vertebrate brain. The eye develops from a protrusion of the embryonic diencephalon, therefore the diencephalic region of the developing brain surrounds the region destined to become the eye, known as the eye field.
- PARAXIAL MESODERM
-
Mesodermal tissue that lies on either side of the neural tube and gives rise to somites, which organize the segmental pattern of vertebrate embryos.
- SOMITES
-
A series of paired blocks of cells that form during early vertebrate development and give rise to the backbone and body muscle.
- ADHERENS JUNCTION
-
A cell–cell adhesion complex that contains classical cadherins and catenins that are attached to cytoplasmic actin filaments.
- NONSENSE-MEDIATED DECAY
-
A surveillance mechanism that degrades mRNAs containing premature termination codons, thereby limiting the synthesis of abnormal proteins.
- GLIAL SCAR
-
Scar tissue composed of astrocytes and extracellular matrix molecules that forms in response to mechanical injury to the adult central nervous system. It represents a considerable obstacle to axonal regeneration.
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Pasquale, E. Eph receptor signalling casts a wide net on cell behaviour. Nat Rev Mol Cell Biol 6, 462–475 (2005). https://doi.org/10.1038/nrm1662
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DOI: https://doi.org/10.1038/nrm1662
