cdc-like/dual-specificity tyrosine phosphorylation-regulated kinases inhibitor leucettine L41 induces mTOR-dependent autophagy: implication for Alzheimer's disease.

Xavier Fant 1, * Emilie Durieu 1 Gaëtan Chicanne 2 Bernard Payrastre 2 Diego Sbrissa 3 Assia Shisheva 3 Emmanuelle Limanton 4 François Carreaux 4 Jean-Pierre Bazureau 4 Laurent Meijer 5
* Auteur correspondant
1 P3H - Phophorylation de protéines et Pathologies Humaines
2 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
3 Department of Physiology
4 ISCR - Institut des Sciences Chimiques de Rennes
5 ManRos 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'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-triggered autophagy requires the Unc-51-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-induced autophagy correlates best with inhibition of CLKs. Leucettine L41 modestly inhibited phosphatidylinositol-3-phosphate 5-kinase, FYVE domain-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's disease treatment.
Type de document :
Article dans une revue
Molecular Pharmacology, American Society for Pharmacology and Experimental Therapeutics, 2014, 85 (3), pp.441-50. 〈10.1124/mol.113.090837〉
Domaine :
Liste complète des métadonnées
http://www.hal.inserm.fr/inserm-01012086
Contributeur : Marie Francoise Simon <>
Soumis le : mercredi 25 juin 2014 - 14:15:34
Dernière modification le : jeudi 13 septembre 2018 - 10:50:02

Lien texte intégral

openaccess

Identifiants

Collections

P3H | UPMC | ISCR | UNIV-TLSE3 | INC-CNRS | UR1-UFR-SPM | ISCR-CORINT | UNIV-RENNES | SCR-MI-INSA

Citation

Xavier Fant, Emilie Durieu, Gaëtan Chicanne, Bernard Payrastre, Diego Sbrissa, et al.. cdc-like/dual-specificity tyrosine phosphorylation-regulated kinases inhibitor leucettine L41 induces mTOR-dependent autophagy: implication for Alzheimer's disease.. Molecular Pharmacology, American Society for Pharmacology and Experimental Therapeutics, 2014, 85 (3), pp.441-50. 〈10.1124/mol.113.090837〉. 〈inserm-01012086〉

Exporter

BibTeX TEI DC DCterms EndNote

Partager

Métriques

Consultations de la notice

285

Contact

support.ccsd.cnrs.fr
hal.support@ccsd.cnrs.fr
Logo CCSD