Time-resolved live-cell spectroscopy reveals EphA2 multimeric assembly

• DOI: 10.1126/science.adg5314
• Publication Date: 2023-11-16T19:00:23Z
• Authors: Xiaojun Shi; Ryan Lingerak; Cameron J. Herting; Yifan Ge; Soyeon Kim; Paul Toth; Wei Wang; Benjamin P. Brown; Jens Meiler; Khalid Sossey-Alaoui; Matthias Buck; Juha Himanen; Dolores Hambardzu...; Dimitar B. Nikolov; Adam W. Smith; Bingcheng Wang
• Keywords: Ectodomain; EPH receptor A2; Ephrin; Cell Signaling; Receptor Protein-Tyrosine Kinases

Ephrin type-A receptor 2 (EphA2) is a tyrosine kinase that initiates both ligand-dependent tumor-suppressive and ligand-independent oncogenic signaling. We used time-resolved, live-cell fluorescence spectroscopy to show the ligand-free EphA2 assembles into multimers driven by two types of intermolecular interactions in ectodomain. The first type entails extended symmetric required for ligand-induced clustering signaling inhibits activity extracellular signal–regulated (ERK) protein B (AKT) kinases suppresses cell migration. second an asymmetric interaction between amino terminus membrane proximal domain neighboring receptors, which supports promotes migration vitro tumor invasiveness vivo. Our results identify molecular drive formation multimeric clusters reveal pivotal role assembly dictating its opposing functions oncogenesis.