Wnt signalling and EphB-ephrin interactions in intestinal stem cells and CRC progression

114 Eph receptors in intestinal cell positioning 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: typeA ephrins (ephrinA1-ephrinA6), which are attached to the cell surface through a glycosylphosphatidylinositol (GPI) anchor, and type-B ephrins (ephrinB1ephrinB3), which contain transmembrane and intracellular domains (Figure 1). Depending on their sequence similarity and on their affinity for ephrins, Eph receptors are also classified into 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. 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). Eph–ephrin signalling regulates a number of cellular events during embryonic development such as cell migration, repulsion vs adhesion, and cell-to-cell communication. Most of these responses are achieved through the capacity of Eph–ephrin signalling to regulate actin cytoskeleton dynamics (reviewed in Pasquale, 2005).