GSK3-mediated raptor phosphorylation supports amino acid-dependent Q2 mTORC1-directed signalling

Clare Stretton, Thorsten M. Hoffmann, Michael J. Munson, Alan Prescott, Peter M. Taylor, Ian G. Ganley, Harinder Hundal (Lead / Corresponding author)

Research output: Contribution to journalArticle

30 Citations (Scopus)
172 Downloads (Pure)

Abstract

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 Ser859. 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.
Original languageEnglish
Pages (from-to)207-221
JournalBiochemical Journal
Volume470
Issue number2
Early online date20 Aug 2015
DOIs
Publication statusPublished - 1 Sep 2015

Fingerprint Dive into the research topics of 'GSK3-mediated raptor phosphorylation supports amino acid-dependent Q2 mTORC1-directed signalling'. Together they form a unique fingerprint.

  • Profiles

    No photo of Hari Hundal

    Hundal, Hari

    Person: Academic

    Cite this