AI Article Synopsis
- * The study identified TELO2, a protein related to certain kinases (PIKKs), as a specific binding target for IVM, demonstrating that IVM can influence cellular signaling by reducing the levels of key proteins and their phosphorylation.
- * The findings suggest that targeting TELO2 with IVM could be a potential strategy for treating human diseases linked to Wnt/β-catenin pathway dysregulation and PIKK-related conditions, including mTOR-related issues.
Article 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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|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9072907 | PMC |
| http://dx.doi.org/10.1016/j.isci.2022.103912 | DOI Listing |
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