The Eph family forms the largest group of RTKs comprising 14 members in mammals. They play critical roles in diverse biological processes during development as well as in the mature animal. Eph receptors are activated by membrane-bound ligands called Ephrins, which are classified into two subclasses based on their mode of membrane anchorage. Ephrin-A ligands (A1-A6) are GPI-linked and preferentially bind EphA receptors. Ephrin-B ligands (B1-B3) possess a transmembrane moiety and a short cytoplasmic domain and bind to EphB receptors (EphB1-B6). A special feature of Eph receptors and ephrin ligands is that they are capable of bidirectional signaling. Signaling pathways directly associated with Eph receptor activation are termed 'forward' signaling and those associated with ephrin activation constitute 'reverse' signaling.
Following ligand binding, Eph (forward) signaling is initiated through autophosphorylation followed by the activation of downstream target proteins. The Rho family of proteins is one such target. RhoA, Rac and Cdc42 are all activated downstream of EphB. RhoA is activated downstream of FAK, while Cdc42 and Rac are activated downstream of Intersectin and Kalirin, respectively. These interactions regulate the EphB receptor-mediated morphogenesis and maturation of dendritic spines in cultured hippocampal and cortical neurons.
EphrinB ligands initiate reverse signaling through the recruitment of Grb4, an SH2/SH3 domain containing, scaffolding protein. Grb4 binds to the cytoplasmic domain of EphrinB ligands in a phosphotyrosine-dependent manner. The SH3 domain of Grb4 binds a unique set of proteins, including Axin, Abi1, CAP and Cbl that are implicated in cytoskeletal regulation. PDZ-RGS3, a GTPase-activating, PDZ domain protein is involved in linking reverse signaling to cellular guidance. Eph receptors and their ligands have been implicated in developmental patterning events, including assembly of vasculature, retinotectal axonal targeting, and developmental segmentation of embryonic tissues. Interactions between Eph receptors and Ephrin ligands are implicated in repulsive axon guidance, cell migration, topographic mapping, and angiogenesis.