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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Small-molecule synergist of the Wnt/β-catenin signaling pathway
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Small-molecule synergist of the Wnt/β-catenin signaling pathway

机译：Wnt /β-catenin信号通路的小分子增效剂

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摘要

The Wnt/β-catenin signaling pathway regulates cell fate and behavior during embryogenesis, adult tissue homeostasis, and regeneration. When inappropriately activated, the pathway has been linked to colorectal cancer and melanoma, and when attenuated it may contribute to Alzheimer's disease and osteoporosis. Small molecules that modulate Wnt signaling will likely provide new insights into the regulation of this key developmental pathway and ultimately provide pharmacological agents to control Wnt signaling in vivo. To this end, we screened a library of 100,000 small molecules for activity in a cell-based assay of Wnt/β-catenin signaling and discovered a purine derivative, QS11, that synergizes with Wnt-3a ligand in the activation of Wnt/β-catenin signal transduction. Through affinity chromatography and subsequent functional assays, we showed that QS11 binds and inhibits the GTPase activating protein of ADP-ribosylation factor 1 (ARFGAP1), suggesting that QS11 modulates Wnt/β-catenin signaling through an effect on protein trafficking. Consistent with its function as an ARFGAP inhibitor, QS11 inhibits migration of ARFGAP overexpress-ing breast cancer cells.
机译：Wnt /β-catenin信号通路在胚胎发生，成年组织稳态和再生过程中调节细胞命运和行为。如果激活途径不当，则该途径与大肠癌和黑色素瘤有关；如果减弱，则可能导致阿尔茨海默氏病和骨质疏松。调节Wnt信号传导的小分子可能会为这一关键发育途径的调控提供新见解，并最终提供药理剂来控制体内Wnt信号传导。为此，我们在基于细胞的Wnt /β-catenin信号传导检测中筛选了100,000个小分子的文库，并发现了嘌呤衍生物QS11，该衍生物与Wnt-3a配体协同激活Wnt /β-连环蛋白信号转导。通过亲和色谱和后续功能分析，我们发现QS11结合并抑制ADP-核糖基化因子1（ARFGAP1）的GTPase活化蛋白，表明QS11通过对蛋白质运输的影响来调节Wnt /β-catenin信号传导。与它作为ARFGAP抑制剂的功能一致，QS11抑制ARFGAP过表达的乳腺癌细胞的迁移。

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