GSK3-mediated raptor phosphorylation supports amino-acid-dependent mTORC1-directed signalling
| العنوان: | GSK3-mediated raptor phosphorylation supports amino-acid-dependent mTORC1-directed signalling |
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| المؤلفون: | Alan R. Prescott, Peter M. Taylor, Clare Stretton, Harinder S. Hundal, Ian G. Ganley, Michael J. Munson, Thorsten M. Hoffmann |
| المصدر: | Biochemical Journal |
| بيانات النشر: | Portland Press Ltd., 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | mTORC1, Biochemistry, mTORC2, Glycogen Synthase Kinase 3, Mice, 0302 clinical medicine, Serine, Amino Acids, Phosphorylation, RNA, Small Interfering, Research Articles, 0303 health sciences, Kinase, TOR Serine-Threonine Kinases, Cell biology, transcription factor EB (TFEB), biological phenomena, cell phenomena, and immunity, leucine, amino acid, Signal Transduction, Research Article, autophagy, insulin, animal structures, growth, proliferation, Molecular Sequence Data, P70-S6 Kinase 1, macromolecular substances, Mechanistic Target of Rapamycin Complex 1, Biology, Cell Line, 03 medical and health sciences, sodium-coupled neutral amino acid transporter 2 (SNAT2), Animals, Humans, p70S6K1, Amino Acid Sequence, Gene Silencing, Molecular Biology, Mechanistic target of rapamycin, PI3K/AKT/mTOR pathway, Adaptor Proteins, Signal Transducing, Cell Proliferation, 030304 developmental biology, RPTOR, Regulatory-Associated Protein of mTOR, Cell Biology, Rats, uncoordinated-51-like kinase (ULK1), Multiprotein Complexes, Mutation, biology.protein, Lysosomes, 030217 neurology & neurosurgery, L-type (leucine) amino acid transporter 1 (LAT1) |
| الوصف: | Glycogen synthase kinase-3 (GSK3) mediates phosphorylation of raptor on Ser859, which crucially supports activation of mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) signalling in response to amino acid availability. GSK3 inhibition is associated with reduced mTORC1 signalling that impacts negatively on cell growth, protein synthesis and promotes cellular autophagy. 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. |
| تدمد: | 1470-8728 0264-6021 |
| DOI: | 10.1042/bj20150404 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cd73e9cd4b76754de6e27075c2de7cb4 https://doi.org/10.1042/bj20150404 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....cd73e9cd4b76754de6e27075c2de7cb4 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14708728 02646021 |
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| DOI: | 10.1042/bj20150404 |