GSK3-mediated raptor phosphorylation supports amino-acid-dependent mTORC1-directed signalling.

The mammalian or mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a ubiquitously expressed multimeric protein kinase complex that integrates nutrient and growth factor signals for the co-ordinated regulation of cellular metabolism and cell growth. Herein, we demonstrate that suppressing the cellular activity of glycogen synthase kinase-3 (GSK3), by ...
use of pharmacological inhibitors or shRNA-mediated gene silencing, results in substantial reduction in amino acid (AA)-regulated mTORC1-directed signalling, as assessed by phosphorylation of multiple downstream mTORC1 targets. We show that GSK3 regulates mTORC1 activity through its ability to phosphorylate the mTOR-associated scaffold protein raptor (regulatory-associated protein of mTOR) on Ser(859). We further demonstrate that either GSK3 inhibition or expression of a S859A mutated raptor leads to reduced interaction between mTOR and raptor and under these circumstances, irrespective of AA availability, there is a consequential loss in phosphorylation of mTOR substrates, such as p70S6K1 (ribosomal S6 kinase 1) and uncoordinated-51-like kinase (ULK1), which results in increased autophagic flux and reduced cellular proliferation.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Amino Acids, Animals, Autophagy, Cell Line, Cell Proliferation, Gene Silencing, Glycogen Synthase Kinase 3, Humans, Lysosomes, Mechanistic Target of Rapamycin Complex 1, Mice, Molecular Sequence Data, Multiprotein Complexes, Mutation, Phosphorylation, RNA, Small Interfering, Rats, Regulatory-Associated Protein of mTOR, Serine, Signal Transduction, TOR Serine-Threonine Kinases
Biochem. J.
Date: Sep. 01, 2015
Download Curated Data For This Publication
217068
Switch View:
  • Interactions 1