Endothelial discoidin domain receptor 1 senses flow to modulate YAP activation

Jiayu Liu, Chuanrong Zhao, Xue Xiao, Aohan Li, Yueqi Liu, Jianan Zhao, Linwei Fan, Zhenhui Liang, Wei Pang, Weijuan Yao, Wei Li () and Jing Zhou ()
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Jiayu Liu: Peking University
Chuanrong Zhao: Peking University
Xue Xiao: Chinese Academy of Sciences
Aohan Li: Chinese Academy of Sciences
Yueqi Liu: Peking University
Jianan Zhao: Peking University
Linwei Fan: Peking University
Zhenhui Liang: Peking University
Wei Pang: Peking University
Weijuan Yao: Peking University
Wei Li: Chinese Academy of Sciences
Jing Zhou: Peking University

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Mechanotransduction in endothelial cells is critical to maintain vascular homeostasis and can contribute to disease development, yet the molecules responsible for sensing flow remain largely unknown. Here, we demonstrate that the discoidin domain receptor 1 (DDR1) tyrosine kinase is a direct mechanosensor and is essential for connecting the force imposed by shear to the endothelial responses. We identify the flow-induced activation of endothelial DDR1 to be atherogenic. Shear force likely causes conformational changes of DDR1 ectodomain by unfolding its DS-like domain to expose the buried cysteine-287, whose exposure facilitates force-induced receptor oligomerization and phase separation. Upon shearing, DDR1 forms liquid-like biomolecular condensates and co-condenses with YWHAE, leading to nuclear translocation of YAP. Our findings establish a previously uncharacterized role of DDR1 in directly sensing flow, propose a conceptual framework for understanding upstream regulation of the YAP signaling, and offer a mechanism by which endothelial activation of DDR1 promotes atherosclerosis.

Date: 2023
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DOI: 10.1038/s41467-023-42341-z

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