Ivermectin Represses Wnt/β-catenin Signaling by Binding to TELO2, a Regulator of Phosphatidylinositol 3-kinase-related Kinases

Overview

Journal iScience

Publisher Cell Press

Date 2022 May 9

PMID 35530256

Authors

Honami Yonezawa

Akari Ikeda

Ryo Takahashi

Haruka Endo

Yasuyo Sugawara

Mikako Goto

Mirute Kanno

Sosuke Ogawa

Karin Nakamura

Haruki Ujiie

Masato Iwatsuki

Tomoyasu Hirose

Toshiaki Sunazuka

Yoshimasa Uehara

Naoyuki Nishiya

Affiliations

Soon will be listed here.

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. 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.

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