biostudies-literatureUnknown25(3)Yonezawa HIvermectin (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. <i>TELO2</i> knockdown 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 inhibiiScience103912https://www.ebi.ac.uk/biostudies/studies/S-EPMC9072907biostudies-literatureIvermectin represses Wnt/β-catenin signaling by binding to TELO2, a regulator of phosphatidylinositol 3-kinase-related kinases.PMC9072907Nakamura KSugawara YEndo HGoto MIwatsuki MUehara YYonezawa HTakahashi RUjiie HNishiya NHirose TIkeda AOgawa SSunazuka TKanno MfalseIvermectin represses Wnt/β-catenin signaling by binding to TELO2, a regulator of phosphatidylinositol 3-kinase-related kinases.Ivermectin (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. <i>TELO2</i> knockdown 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 inhibi2022-01-01T00:00:00Z2022 Mar2025-04-04T09:10:03.156Z2025-04-04T09:10:03.156ZS-EPMC90729073553025610.1016/j.isci.2022.103912