Time-resolved live-cell spectroscopy reveals EphA2 multimeric assembly

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2023-11-16 DOI:10.1126/science.adg5314

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 Hambardzumyan, Dimitar B. Nikolov, Adam W. Smith, Bingcheng Wang

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引用次数: 0

Abstract

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.

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时间分辨活细胞光谱显示EphA2多聚体组装。

Ephrin a型受体2 (EphA2)是一种酪氨酸激酶受体，可启动依赖配体的肿瘤抑制和不依赖配体的致癌信号传导。我们使用时间分辨的活细胞荧光光谱来证明，无配体的EphA2在两种类型的分子间相互作用的驱动下组装成多聚体。第一种类型涉及配体诱导的受体聚集和肿瘤抑制信号所需的扩展对称相互作用，从而抑制致癌ERK和Akt蛋白激酶的活性并抑制细胞迁移。第二种类型是N端与邻近受体的膜近端域之间的不对称相互作用，支持致癌信号传导，促进体外迁移和体内肿瘤侵袭。我们的研究结果确定了驱动EphA2多聚信号簇形成的分子相互作用，并揭示了EphA2组装在肿瘤发生中决定其相反功能的关键作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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