Ligands with different dimeric configurations potently activate the EphA2 receptor and reveal its potential for biased signaling
Maricel Gomez-Soler,
Marina P. Gehring,
Bernhard C. Lechtenberg,
Elmer Zapata-Mercado,
Alyssa Ruelos,
Mike W. Matsumoto,
Kalina Hristova,
Elena B. Pasquale
Affiliations
Maricel Gomez-Soler
Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Marina P. Gehring
Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Bernhard C. Lechtenberg
Ubiquitin Signalling Division, The Walter and Eliza Hall Institute of Medical Research, Parkville Victoria 3052, Australia and Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia
Elmer Zapata-Mercado
Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
Alyssa Ruelos
Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Mike W. Matsumoto
Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Kalina Hristova
Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
Elena B. Pasquale
Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Corresponding author
Summary: 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.
