@article {Fant441, author = {Xavier Fant and Emilie Durieu and Ga{\"e}tan Chicanne and Bernard Payrastre and Diego Sbrissa and Assia Shisheva and Emmanuelle Limanton and Fran{\c c}ois Carreaux and Jean-Pierre Bazureau and Laurent Meijer}, title = {cdc-Like/Dual-Specificity Tyrosine Phosphorylation{\textendash}Regulated Kinases Inhibitor Leucettine L41 Induces mTOR-Dependent Autophagy: Implication for Alzheimer{\textquoteright}s Disease}, volume = {85}, number = {3}, pages = {441--450}, year = {2014}, doi = {10.1124/mol.113.090837}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Leucettines, a family of pharmacological inhibitors of dual-specificity tyrosine phosphorylation regulated kinases and cdc-like kinases (CLKs), are currently under investigation for their potential therapeutic application to Down syndrome and Alzheimer{\textquoteright}s disease. We here report that leucettine L41 triggers bona fide autophagy in osteosarcoma U-2 OS cells and immortalized mouse hippocampal HT22 cells, characterized by microtubule-associated protein light chain 3 membrane translocation and foci formation. Leucettine L41{\textendash}triggered autophagy requires the Unc-51{\textendash}like kinase and is sensitive to the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and 3-methyladenine, suggesting that it acts through the mammalian target of rapamycin (mTOR)/PI3K-dependent pathway. Leucettine L41 does not act by modifying the autophagic flux of vesicles. Leucettine L41{\textendash}induced autophagy correlates best with inhibition of CLKs. Leucettine L41 modestly inhibited phosphatidylinositol-3-phosphate 5-kinase, FYVE domain{\textendash}containing activity as tested both in vitro and in vivo, which may also contribute to autophagy induction. Altogether these results demonstrate that leucettines can activate the autophagic mTOR/PI3K pathway, a characteristic that may turn advantageous in the context of Alzheimer{\textquoteright}s disease treatment.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/85/3/441}, eprint = {https://molpharm.aspetjournals.org/content/85/3/441.full.pdf}, journal = {Molecular Pharmacology} }