文章基本信息

标题：Ivermectin represses Wnt/β-catenin signaling by binding to TELO2, a regulator of phosphatidylinositol 3-kinase-related kinases
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作者：Honami Yonezawa ; Akari Ikeda ; Ryo Takahashi 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：3
页码：1-28
DOI：10.1016/j.isci.2022.103912
语种：English
出版社：Elsevier
摘要：SummaryIvermectin (IVM), an avermectin-derivative anthelmintic, specifically binds to glutamate-gated chloride ion channels (GluCls), causing paralysis in invertebrates. IVM also exhibits other biological activities such as Wnt/β-catenin pathway inhibition in vertebrates that do not possess GluCls. This study showed that affinity purification using immobilized IVM B1a isolated TELO2, a cofactor of phosphatidylinositol 3-kinase-related kinases (PIKKs), as a specific IVM B1a-binding protein.TELO2knockdown reduced cytoplasmic β-catenin and the transcriptional activation of β-catenin/TCF. IVM B1a bound to TELO2 through the C-terminal α-helix, in which mutations conferred IVM resistance. IVM reduced the TELO2 and PIKK protein levels and the AKT and S6 kinase phosphorylation levels. The inhibition of mTOR kinase reduced the cytoplasmic β-catenin level. Therefore, IVM binds to TELO2, inhibiting PIKKs and reducing the cytoplasmic β-catenin level. In conclusion, our data indicate TELO2 as a druggable target for human diseases involving abnormalities of the Wnt/β-catenin pathway and PIKKs, including mTOR.Graphical abstractDisplay OmittedHighlights•Ivermectin is a chemical suppressor of the eyeless phenotype in zebrafish embryos•Ivermectin physically interacts with TELO2•TELO2 mediates Wnt/β-catenin signaling inhibition by ivermectin•Ivermectin reduces the PIKK protein levels and downstream signalingBiochemistry; Small molecule; Molecular biology