The Eph family of Receptor tyrosine kinases and their Ephrin ligands are important for cell positioning and morphogenesis during development. Eph receptors are classified into 10 EphA and 6 EphB receptors, which preferentially bind to the type A and type B ephrins, respectively. The EphA4 receptor can inhibit axon outgrowth and has roles in regulating axon projections during neural development. EphA4 signaling pathways require its kinase activity and involve binding and activation of Rho-GTPase guanine nucleotide-exchange factors (GEFs). EphA4 activation leads autophosphorylation of Tyr-596 and Tyr-602, and the conserved sites in EphA2 are required for binding to the GEFs, Vav2 and Vav3, and ephrin-induced cell migration. The Tyr-779 site in the kinase domain is also phosphorylated in vivo and may regulate kinase activity. Activated EphA4 leads to Src kinase phosphorylation of the GEF, ephexin-1, and this activates RhoA. Thus, EphA4 signaling involves complex tyrosine phosphorylation in its cytoplasmic region along with interaction with several GEFs.
