Concepts and consequences of Eph receptor clustering

► We describe the general concepts of Eph-facilitated cell positioning. ► We discuss molecular mechanisms of Eph cluster assembly. ► We detail concepts of homotypic and heterotypic Eph–Eph interactions. ► We describe tyrosine kinase/phosphatase control of Eph signalling clusters. ► We discuss the implications of Eph clusters during cancer progression. Polymeric receptor–ligand complexes between interacting Eph and ephrin-expressing cells are regarded as dynamic intercellular signalling scaffolds that control cell-to-cell contact: the resulting Eph–ephrin signalling clusters function as positional cues that facilitate cell navigation and tissue patterning during normal and oncogenic development. The considerable complexity of this task, coordinating a multitude of cell movements and cellular interactions, is achieved by accurate translation of spatial information from Eph and ephrin expression gradients into fine-tuned changes in cell–cell adhesion and position. Here we review emerging evidence suggesting that the required combinatorial diversity is not only achieved by the large number of possible Eph–ephrin interactions and selective use of Eph forward and ephrin reverse signals, but in particular through the composition and signal capacity of Eph–ephrin clusters, which is adjusted dynamically to reflect overall Eph and ephrin surface densities on interacting cells. Fine-tuning is provided through multi-layered cluster assembly, where homo- and heterotypic Eph and ephrin interactions define the composition – whilst intracellular signalling feedbacks determine the size and lifetime – of signalling clusters.