泛素连接酶
Wnt信号通路
细胞生物学
类有机物
泛素
信号转导
生物
细胞生长
化学
生物化学
基因
作者
Yvonne T. Kschonsak,Xinxin Gao,S.A. Miller,Sun‐Hee Hwang,Hadir Marei,Ping Wu,Yanjie Li,Karen Ruiz,Kristel M. Dorighi,Loryn Holokai,Pirunthan Perampalam,Wen‐Ting K. Tsai,Yee-Seir Kee,Nicholas J. Agard,Seth F. Harris,Rami N. Hannoush,Felipe de Sousa e Melo
标识
DOI:10.1016/j.chembiol.2023.11.006
摘要
Selective and precise activation of signaling transduction cascades is key for cellular reprogramming and tissue regeneration. However, the development of small- or large-molecule agonists for many signaling pathways has remained elusive and is rate limiting to realize the full clinical potential of regenerative medicine. Focusing on the Wnt pathway, here we describe a series of disulfide-constrained peptides (DCPs) that promote Wnt signaling activity by modulating the cell surface levels of ZNRF3, an E3 ubiquitin ligase that controls the abundance of the Wnt receptor complex FZD/LRP at the plasma membrane. Mechanistically, monomeric DCPs induce ZNRF3 ubiquitination, leading to its cell surface clearance, ultimately resulting in FZD stabilization. Furthermore, we engineered multimeric DCPs that induce expansive growth of human intestinal organoids, revealing a dependence between valency and ZNRF3 clearance. Our work highlights a strategy for the development of potent, biologically active Wnt signaling pathway agonists via targeting of ZNRF3.
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