Ephrin A Signaling

Neuronal growth cones in the developing nervous system are guided to their targets by attractive and repulsive guidance molecules which include members of the netrin, semaphorin, ephrin, and slit protein families. The Eph family forms the largest group of RTKs comprising 14 members in mammals, and they play a critical role in diverse biological processes during development as well as in the mature animal. They are activated by membrane bound ligands called Ephrins, which are classified into two subclasses based on their modes of membrane anchorage. The EphrinA ligands (A1-A6) are tethered to the plasma membrane by a GPI anchor and preferentially bind EphA (1-10) receptors. The EphrinB ligands (B1-B3), which possess a transmembrane moiety and a short cytoplasmic domain, bind to EphB receptors (EphB1-B6). Interactions between EphR and Ephrins are implicated in repulsive axon guidance, cell migration, topographic mapping and angiogenesis.Upon ligand engagement, autophosphorylation of juxtamembrane tyrosine residues is required for full activation of the protein tyrosine kinase domain of the receptor. Once the receptor is activated, SHP2, FAK and the p110γ isoform of PI3K associate with it to transmit downstream signals. The exchange factor Ephexin is one such protein that goes on to activate RhoA. The RhoA/ROCK/LIMK pathway results in the modulation of actin dynamics via phosphorylation of cofilin. In contrast, other GTPases such as Rac1 and Cdc42 are most often negatively regulated by EphA.EphrinA ligands can also convey reverse signals that modify cell behavior. EphrinA molecules, like many GPI-anchored proteins, are targeted to lipid rafts where they presumably assemble into protein complexes that transduce intracellular signals. Upon binding to its receptor, EphrinA and p75(NTR) colocalize within caveolae along retinal axons and form a complex that is required for Fyn phosphorylation, activating a signaling pathway leading to cytoskeletal changes. EphrinA reverse signal is also modulated by cell surface shedding of the ligand through its association with the metalloprotease ADAM10. Upon binding of EphA receptors, ADAM10 cleaves EphrinA2 from the cell surface. This serves a dual function. EphrinA cleavage from the cell surface allows EphR bearing structures such as growth cones to change their response to ligand molecules from adhesion to repulsion. In addition, the cleaved ligand is no longer able to transmit signals or activate EphA receptors, and hence both reverse and forward signaling is terminated. EphA receptor tyrosine kinases play a central role in the establishment of topographic maps in the vertebrate visual system. They are expressed in a graded fashion, with high levels in retinal ganglion cell axons in the temporal retina and low levels on axons from the nasal retina.