Upon contact with ephrin-expressing cells, Eph receptors elicit cellular signaling and biological outcomes by assembly of oligomeric signaling clusters; compelling experimental evidence over the past decade attests that it is the sum of Ephs on a given cell competing for available
ephrins on interacting cells, which determines the cellular response (Brown et al., 2000; Reber et al., 2004), typically adhesion or segregation between the interacting cells (Davy and Soriano, 2005; Pasquale, 2005; Egea and Klein, 2007). In recognition of the two Eph/ephrin specificity subclasses (Gale et al., 1996; Pasquale, 2004), it has been generally assumed that individual signaling clusters comprise Eph receptors, which are competent to interact with the corresponding
ephrins. Indeed, ephrin-Fc or ephrin-alkaline phosphatase fusion proteins have been used to define the Eph/ephrin specificity subclasses (Gale et al., 1996; Pasquale, 2004) through interaction with relevant Eph family members (Cheng et al., 1995; ...