The
EphA2 receptor tyrosine kinase activates signaling pathways with different, and sometimes opposite, effects in
cancer and other pathologies. Thus, highly specific and potent biased
ligands that differentially control EphA2 signaling responses could be therapeutically valuable. Here, we use EphA2-specific monomeric
peptides to engineer dimeric
ligands with three different geometric configurations to combine a potential ability to differentially modulate EphA2 signaling responses with the high potency and prolonged receptor residence time characteristic of dimeric
ligands. The different dimeric
peptides readily induce EphA2 clustering, autophosphorylation and signaling, the best with sub-nanomolar potency. Yet, there are differences in two EphA2 signaling responses induced by
peptides with different configurations, which exhibit distinct potency and efficacy. The
peptides bias signaling when compared with the ephrinA1-Fc
ligand and do so via different mechanisms. These findings provide insights into
Eph receptor signaling, and proof-of-principle that different Eph signaling responses can be distinctly modulated.