Differential association of EphA2 intracellular regions in biased signaling

Biased signaling is the ability of a receptor to differentially activate certain signaling cascades in response to different ligands. Our previous work demonstrated that the monomeric ephrinA1 ligand and the widely used dimeric ephrinA1-Fc ligand induced EphA2 receptor tyrosine kinase (RTK) biased signaling. The hypothesis that RTK biased signaling is a consequence of differential interactions between receptor intracellular regions when different ligands are bound to the extracellular region has not been experimentally verified thus far, in part because of the lack of high-resolution structures of full-length RTK oligomers. Here, we compare the effects of deletion of intracellular regions in EphA2 oligomers bound to the biased ligands, monomeric ephrinA1 or ephrinA1-Fc. Our data reveal distinct differences in the intracellular organization of EphA2 oligomers bound to the two ligands, supporting the hypothesis. They also suggest that EphA2 signaling could be modulated by agents that alter interactions between oligomerized EphA2 intracellular regions by binding at sites that can be distant from the ATP-binding pocket.