Eph–ephrin signalling in adult tissues and cancer
Introduction
Eph receptors constitute the largest subfamily of transmembrane tyrosine kinase receptors described to date, with 14 members identified in mammals. Their ligands, the ephrins, are membrane-anchored proteins which are grouped into two subclasses: type-A ephrins (ephrinA1–ephrinA6) which are attached to the cell surface through a glycosylphosphatidylinositol (GPI) anchor, and type-B ephrins (ephrinB1–ephrinB3) containing transmembrane and intracellular domains (Figure 1). Depending on their sequence similarity and on their affinity for ephrins, Eph receptors are also classified in two groups. In general, EphA receptors (EphA1–EphA10) bind ephrinAs and EphB receptors (EphB1–EphB6) bind ephrinBs, yet promiscuity in their binding specificities has been described for some members (reviewed in [1]). Upon cell-to-cell contact and ligand–receptor engagement, intracellular signalling is induced in a bidirectional fashion: ‘forward signalling’ starts in receptor-expressing cells, while ‘reverse signalling’ initiates in cells expressing the corresponding ligand (Figure 1) (reviewed in [2] and [3]).
Eph–ephrin signalling regulates a number of cellular events during embryonic development such as cell migration, repulsion versus adhesion, and cell-to-cell communication. Most of these responses are achieved through the ability of Eph–ephrin signalling to regulate actin cytoskeleton dynamics (reviewed in [2, 3, 4]). Here, we will discuss recent findings on the role that Eph–ephrin signalling plays in several adult tissues. Because of space constraints, we will not comment on its key functions in neural plasticity and regeneration of the adult nervous system (for comprehensive reviews on this topic please see refs. [4] and [5]).
Section snippets
Control of tissue architecture and cell positioning in the adult
The intestinal epithelium represents perhaps the best-known example of adult tissue architecture controlled by Eph–ephrin signalling. The innermost layer of the intestinal tube is a mono-stratified epithelium which is folded into millions of bag-shaped invaginations called crypts. At the base of each crypt reside a handful of exceptionally active stem cells which continuously regenerate the epithelium [6••]. Cell renewal is accomplished in a bottom-up fashion. Intestinal stem cells (ISCs)
Regulation of blood cell function
EphB signalling also plays an important role favouring thrombus growth and stability [17•]. Thrombus formation initiates as a response to vascular injury, and involves platelet activation and aggregation as well as fibrin clot formation. EphA4, EphB1 and ephrinB1 are expressed on the surface of freely circulating resting platelets. Upon activation, integrin-dependent aggregation allows Eph–ephrin interaction between contacting platelets. Eph–ephrin signals induce the phosphorylation of integrin
Control of pancreas physiology
Communication between endocrine β cells in the pancreas is required to inhibit basal insulin secretion during fasting periods, as well as to enhance glucose-stimulated insulin release after food intake. EphA5 and its cognate ligand ephrinA5 are coexpressed in β cells. When blood glucose levels are low, forward signalling through EphA5 receptor prevents insulin release from secretory granules. Upon an increase in glucose concentration, EphA5 receptor is dephosphorylated. Under these conditions,
Eph signalling in tumorigenesis
Somatic mutations and epigenetic silencing of Eph genes have been found in several types of cancer (Table 1). Recent evidences suggest that Eph–ephrin signalling suppresses tumor progression yet, in some cases, Eph–ephrin interactions may also promote cancer growth depending on tumor type and context.
Discussion
Distinct combinations of Eph receptors and ephrin ligands are expressed in virtually every single tissue of the adult body. The findings summarized here indicate that Eph–ephrin signalling has widespread roles in establishing the complex cellular architecture of adult tissues and in regulating certain physiological functions such as hormone secretion or platelet aggregation. Future research will pinpoint specific roles for each receptor–ligand pair in particular organs yet redundancy,
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We apologize to the authors of original manuscripts that have not been cited because of space limitations. We thank Elena Sancho for manuscript proof reading and suggestions. A.M.-S. holds a postdoctoral fellowship from Asociación Española Contra el Cáncer.
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