| RRC ID |
70574
|
| 著者 |
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.
|
| タイトル |
Ivermectin represses Wnt/β-catenin signaling by binding to TELO2, a regulator of phosphatidylinositol 3-kinase-related kinases.
|
| ジャーナル |
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.
|
| 巻・号 |
25(3)
|
| ページ |
103912
|
| 公開日 |
2022-3-18
|
| DOI |
10.1016/j.isci.2022.103912
|
| PII |
S2589-0042(22)00182-1
|
| PMID |
35530256
|
| PMC |
PMC9072907
|
| IF |
4.447
|
| リソース情報 |
| ゼブラフィッシュ |
RIKEN WT |
| ヒト・動物細胞 |
293(RCB1637) |
