Time-resolved live-cell spectroscopy reveals EphA2 multimeric assembly

• 成果类型: Article
• 署名作者: Shi, Xiaojun; Lingerak, Ryan; Herting, Cameron J.; Ge, Yifan; Kim, Soyeon; Toth, Paul; Wang, Wei; Brown, Benjamin P.; Meiler, Jens; Sossey-Alaoui, Khalid; Buck, Matthias; Himanen, Juha; Hambardzumyan, Dolores; Nikolov, Dimitar B.; Smith, Adam W.; Wang, Bingcheng
• 署名单位: MetroHealth System; University System of Ohio; Case Western Reserve University; University System of Ohio; Case Western Reserve University; Emory University; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; University System of Ohio; University of Akron; Vanderbilt University; University System of Ohio; Case Western Reserve University; Memorial Sloan Kettering Cancer Center; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; University System of Ohio; Case Western Reserve University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9426
• DOI: 10.1126/science.adg5314
• 发表日期: 2023-12-01
• 页码: 1042-1050
• 关键词: receptor tyrosine kinase; molecular-dynamics; crystal-structures; signaling axis; activation; ligand; egf; glioblastoma; RECOGNITION; suppresses

摘要

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