title: Caspase-mediated cleavage of raptor participates in the inactivation of mTORC1 during cell death.
abstract: The mammalian target of rapamycin complex 1 (mTORC1) is a highly conserved protein complex regulating key pathways in cell growth. Hyperactivation of mTORC1 is implicated in numerous cancers, thus making it a potential broad-spectrum chemotherapeutic target. Here, we characterized how mTORC1 responds to cell death induced by various anticancer drugs such rapamycin, etoposide, cisplatin, curcumin, staurosporine and Fas ligand. All treatments induced cleavage in the mTORC1 component, raptor, resulting in decreased raptor-mTOR interaction and subsequent inhibition of the mTORC1-mediated phosphorylation of downstream substrates (S6K and 4E-BP1). The cleavage was primarily mediated by caspase-6 and occurred at two sites. Mutagenesis at one of these sites, conferred resistance to cell death, indicating that raptor cleavage is important in chemotherapeutic apoptosis.
authors.affiliation: Department of Biochemistry, University of Lausanne , Vaud, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Martin
authors.affiliation: Department of Biochemistry, University of Lausanne , Vaud, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Desponds
authors.affiliation: Department of Biochemistry, University of Lausanne , Vaud, Switzerland.
authors.forename: R O
authors.initials: RO
authors.lastname: Eren
authors.affiliation: Department of Biochemistry, University of Lausanne, Vaud, Switzerland; Protein Analysis Facility (PAF), Centre Intégratif de Génomique, Quartier UNIL-Sorge, University of Lausanne, Lausanne , Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Quadroni
authors.affiliation: Department of Biochemistry, University of Lausanne , Vaud, Switzerland.
authors.forename: M
authors.identifier: 0000-0002-5656-2139
authors.initials: M
authors.lastname: Thome
authors.affiliation: Department of Biochemistry, University of Lausanne , Vaud, Switzerland.
authors.forename: N
authors.initials: N
authors.lastname: Fasel