Eph-dependent cell-cell adhesion and segregation in development and cancer

Abstract

Numerous studies attest to essential roles for Eph receptors and their ephrin ligands in controlling cell positioning and tissue patterning during normal and oncogenic development. These studies suggest multiple, sometimes contradictory, functions of Eph-ephrin signalling, which under different conditions can promote either spreading and cell-cell adhesion or cytoskeletal collapse, cell rounding, de-adhesion and cell-cell segregation. A principle determinant of the balance between these two opposing responses is the degree of receptor/ligand clustering and activation. This equilibrium is likely altered in cancers and modulated by somatic mutations of key Eph family members that have emerged as candidate cancer markers in recent profiling studies. In addition, cross-talk amongst Ephs and with other signalling pathways significantly modulates cell-cell adhesion, both between and within Eph- and ephrin-expressing cell populations. This review summarises our current understanding of how Eph receptors control cell adhesion and morphology, and presents examples demonstrating the importance of these events in normal development and cancer.

Fig. 1

Models of the structure and activation of Eph receptors. a Eph receptors contain an extracellular region with a globular ligand-binding domain, followed by cysteine-rich and fibronectin type III domains. Ligand binding promotes clustering and phosphorylation of the tyrosine kinase-containing intracellular region, at conserved sites within the juxtamembrane and kinase domains. b Inactive Ephs display an auto-inhibited conformation (left), in which the kinase domain interacts with the juxtamembrane domain, which is released upon activation to enable robust phosphorylation and phosphorylation-dependent signalling (right). Receptor-receptor interactions in the ECD further promote clustering [22], including co-clustering of EphA and EphB receptors [57]. The transmembrane ephrin-Bs also become phosphorylated on tyrosine residues by Src family kinases, which likely also promote signalling by the GPI-linked ephrin-As via clustering of lipid raft microdomains and associated signalling molecules

Fig. 2

Disruption of Eph/ephrin cell-cell interactions during cell-cell segregation. Engagement of Ephs and ephrins results in large, high affinity complexes that require disruption to allow cell-cell detachment. For ephrin-As this occurs through ephrin cleavage by the ADAM10 metalloprotease, which recognises the Eph/ephrin complex to release ephrin from the adjacent cell. ADAM10 association with EphAs is promoted by clustering and conformational change of the Eph receptor, to stimulate ephrin shedding. Metalloprotease (MP) cleavage of ephrin-Bs has also been described, as has γ-secretase-mediated release of the intracellular domain of both ephrin-Bs and Ephs. Alternatively, transendocytosis of the entire EphB/ephrin-B complex has also been described [248, 249]

Fig. 3

Eph-mediated cell-cell adhesion versus repulsion. Cell-cell adhesion occurs under conditions of low Eph kinase activity, such as at low Eph and/or ephrin density, high protein tyrosine phosphatase (PTP) activity or inactivating Eph mutations (X). Under such conditions kinase-independent Eph signalling promotes actin-cytoskeleton-mediated cell spreading and attachment, facilitated by focal adhesions and co-operation with other adhesive molecules including cadherins. In contrast robust Eph activation at high Eph/ephrin densities promotes disruption of Eph/ephrin complexes, cell detachment, and Rho-GTPase-mediated actin-cytoskeleton collapse and cell rounding. (↑activation, ↑↓ transient activation, ↓ inactivation). In epithelial cells, ADAM10-mediated cleavage of E-cadherin also contributes to ephrin-B/EphB-mediated cell segregation [254]