RRC ID 70574
Author Yonezawa H, Ikeda A, Takahashi R, Endo H, Sugawara Y, Goto M, Kanno M, Ogawa S, Nakamura K, Ujiie H, Iwatsuki M, Hirose T, Sunazuka T, Uehara Y, Nishiya N.
Title Ivermectin represses Wnt/β-catenin signaling by binding to TELO2, a regulator of phosphatidylinositol 3-kinase-related kinases.
Journal iScience
Abstract 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. TELO2 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 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.
Volume 25(3)
Pages 103912
Published 2022-3-18
DOI 10.1016/j.isci.2022.103912
PII S2589-0042(22)00182-1
PMID 35530256
PMC PMC9072907
IF 4.447
Zebrafish RIKEN WT
Human and Animal Cells 293(RCB1637)