Nogo-A-Delta 20/Epha4 Interaction Antagonizes Apoptosis Of Neural Stem Cells By Integrating P38 And Jnk Mapk Signaling

Nogo-A protein consists of two main extracellular domains: Nogo-66 (rat amino acid [aa] 1019-1083) and Nogo-A-Delta 20 (extracellular, active 180 amino acid Nogo-A region), which serve as strong inhibitors of axon regeneration in the adult CNS (Central Nervous System). Although receptors S1PR2 and HSPGs have been identified as Nogo-A-Delta 20 binding proteins, it remains at present elusive whether other receptors directly interacting with Nogo-A-Delta 20 exist, and decrease cell death. On the other hand, the key roles of EphA4 in the regulation of glioblastoma, axon regeneration and NSCs (Neural Stem Cells) proliferation or differentiation are well understood, but little is known the relationship between EphA4 and Nogo-A-Delta 20 in NSCs apoptosis. Thus, we aim to determine whether Nogo-A-Delta 20 can bind to EphA4 and affect survival of NSCs. Here, we discover that EphA4, belonging to a member of erythropoietin-producing hepatocellular (Eph) receptors family, could be acting as a high affinity ligand for Nogo-A-Delta 20. Trans-membrane protein of EphA4 is needed for Nogo-A-Delta 20-triggered inhibition of NSCs apoptosis, which are mediated by balancing p38 inactivation and JNK MAPK pathway activation. Finally, we predict at the atomic level that essential residues Lys-205, Ile-190, Pro-194 in Nogo-A-Delta 20 and EphA4 residues Gln-390, Asn-425, Pro-426 might play critical roles in Nogo-A-Delta 20/EphA4 binding via molecular docking.