Figure 3. Signaling pathways downstream of Eph/ephrin binding and termination of cell-cell contact.

A) Ephrin binding to Eph receptors initiates intracellular signaling events in both directions, termed “forward” in the Eph containing cells and “reverse” in the ephrin-bearing cells. Binding to EphA receptors (blue) results in activation of the RhoA GTPase via ephexin, a guanine nucleotide exchange factor (GEF), ultimately resulting in growth cone collapse. In addition, regulation of Tsc2, a GEF, and its downstream target, Rheb, results in decreased translation, contributing to growth cone collapse. Reverse signaling through the GPI-linked ephrin-As (red) is mediated by co-receptors, TrkB and p75^NTR, which results in axonal branching and axon repulsion, respectively. Forward signaling through EphB receptors (cyan) results in growth cone attraction or repulsion, depending on cellular context. Reverse signaling through ephrin-Bs (orange) is important for synapse maturation in the SC/OT. B & C) Ephrin signaling and cell-cell contact is terminated in two possible ways. Endocytosis of EphA receptors occurs in a Vav/Rac dependent manner (B). Termination of EphB/ephrin-B receptors can occur in either cell, each dependent on Rac signaling (B). Cleavage of ephrin-As by ADAM10 protease also results in signal termination and EphA receptor endocytosis (C). ADAM10 can associate with either ephrin-As or EphAs.