Small-molecule synergist of the Wnt/β-catenin signaling pathway
Small-molecule synergist of the Wnt/β-catenin signaling pathway
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DOI：
10.1073/pnas.0702136104
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发表时间：
2007-05-01
影响因子：
11.1
通讯作者：
Ding, Sheng
中科院分区：
文献类型：
--
作者：
Zhang, Qisheng;Major, Michael B.;Ding, Sheng
Wnt/β-连环蛋白信号通路调节胚胎发生、成体组织稳态和再生过程中的细胞命运和行为。当不适当地激活时，该途径与结直肠癌和黑色素瘤有关，当减弱时，它可能导致阿尔茨海默病和骨质疏松症。调节Writ信号传导的小分子可能会为调节这一关键发育途径提供新的见解，并最终提供控制体内Writ信号传导的药理学试剂。为此，我们在Wnt/β-连环蛋白信号传导的基于细胞的测定中筛选了100，000个小分子的文库的活性，并发现了嘌呤衍生物QS 11，其在Wnt/β-连环蛋白信号转导的活化中与Wnt-3a配体协同作用。通过亲和层析和随后的功能测定，我们发现QS 11结合并抑制ADP-核糖基化因子1（ARFGAP 1）的GT3活化蛋白，表明QS 11通过对蛋白质运输的影响调节Wnt/β-连环蛋白信号传导。与其作为ARFGAP抑制剂的功能一致，QS 11抑制ARFGAP过表达乳腺癌细胞的迁移。
The Wnt/beta-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 Writ signaling will likely provide new insights into the regulation of this key developmental pathway and ultimately provide pharmacological agents to control Writ signaling in vivo. To this end, we screened a library of 100,000 small molecules for activity in a cell-based assay of Wnt/beta-catemn signaling and discovered a purine derivative, QS11, that synergizes with Wnt-3a ligand in the activation of Wnt/beta-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/beta-catenin signaling through an effect on protein trafficking. Consistent with its function as an ARFGAP inhibitor, QS11 inhibits migration of ARFGAP overexpressing breast cancer cells.