Eph/ephrin signaling: networks

Abstract

Bidirectional signaling has emerged as an important signature by which Ephs and ephrins control biological functions. Eph/ephrin signaling participates in a wide spectrum of developmental processes, and cross-regulation with other communication pathways lies at the heart of the complexity underlying their function in vivo. Here, we review in vitro and in vivo data describing molecular, functional, and genetic interactions between Eph/ephrin and other cell surface signaling pathways. The complexity of Eph/ephrin function is discussed in terms of the pathways that regulate Eph/ephrin signaling and also the pathways that are regulated by Eph/ephrin signaling.

Figure 1.

Main features of Eph/ephrin signaling. (A) Both classes of Eph receptors and ephrins activate bidirectional signaling. Interaction between Eph receptors and ephrins leads to activation of forward and reverse signaling in neighboring cells. (B) Eph receptors and ephrins expressed in opposing cells interact in trans and activate bidirectional signaling. Eph receptors and ephrins coexpressed in the same cell interact in cis. Cis interaction has been shown to inhibit trans interaction and/or signaling.

Figure 2.

Interactions with cell surface receptors. (A) Eph receptors interact with FGFR, Ryk, and chemokine receptors. Direct interactions are indicated by dashed green lines. Arrows represent agonistic interaction, while blunted lines indicate antagonistic regulation of downstream effectors or biological processes. Tyrosine phosphorylation events are shown in red. (B) Ephrins interact with FGFR and chemokine receptors.

Figure 3.

Regulation of adhesion proteins. Eph/ephrin signaling regulates cell–cell adhesion and cell–matrix adhesion by impinging on formation/stability of tight, adherens, and gap junctions, as well as on integrin function. In Eph-expressing cells (blue), activation of forward signaling induces the redistribution of E-cadherin to the cell surface while destabilizing claudins. In ephrin-expressing cells (orange), activation of reverse signaling leads to inhibition of GJC, while interaction with claudins destabilizes tight junctions. Both forward and reverse signaling act on integrin-mediated adhesion. Together, these cascades participate in Eph/ephrin-induced cell sorting.

Figure 4.

Interactions with synaptic proteins. (A) The figure shows a holistic view of Eph/ephrin interactions at sites of synapse formation/regulation. Eph-A4-induced forward signaling inhibits β1-integrin, which induces spine remodeling. Eph-B receptors and ephrins-B interact with NMDAR and potentiates its activity. Recruitment of Tiam1 to the Eph-B/NMDAR complex and activation of small GTPases facilitates spine formation. Activation of NMDAR induces processing of Eph receptors by MMPs and PS. (B) Interaction between Eph/VAB-1 and NMDAR participates in oocyte maturation, which also involves down-regulation of GJC.

Figure 5.

Interactions at growth cones. Binding of WRK-1 and Eph/VAB-1 in trans prevents midline crossing. VAB-1 also interacts with SAX-3 in cis. Growth cone retraction requires termination of contact between Eph- and ephrin-expressing cells. This is achieved by cleavage of ephrin ectodomain by ADAM10 in trans and/or endocytosis of Eph/ephrin complexes, followed by processing of the ectodomain in the endosomal/lyzosomal pathway. Subsequent to ectodomain shedding, processed ephrins are targets for PS cleavage that releases the ICD in the cytosol.