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J Biol Chem. 2018 Sep 21;293(38):14723-14739. doi: 10.1074/jbc.RA118.002800. Epub 2018 Jul 30.

mTOR complex 1 controls the nuclear localization and function of glycogen synthase kinase 3β.

Author information

1
From the Department of Chemistry and Biology and Graduate Program in Molecular Science, Ryerson University, Toronto, Ontario M5B 2K3.
2
the Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5S 3E5.
3
the Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4.
4
the Department of Biochemistry, University of Toronto, Toronto, Ontario M5G 1X8, and.
5
the Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario M5S 3E5, Canada.
6
From the Department of Chemistry and Biology and Graduate Program in Molecular Science, Ryerson University, Toronto, Ontario M5B 2K3, cantonescu@ryerson.ca.
7
the Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario M5B 1W8.

Abstract

Glycogen synthase kinase 3β (GSK3β) phosphorylates and thereby regulates a wide range of protein substrates involved in diverse cellular functions. Some GSK3β substrates, such as c-Myc and Snail, are nuclear transcription factors, suggesting the possibility that GSK3β function is controlled through its nuclear localization. Here, using ARPE-19 and MDA-MB-231 human cell lines, we found that inhibition of mTOR complex 1 (mTORC1) leads to partial redistribution of GSK3β from the cytosol to the nucleus and to a GSK3β-dependent reduction of the levels of both c-Myc and Snail. mTORC1 is known to be controlled by metabolic cues, such as by AMP-activated protein kinase (AMPK) or amino acid abundance, and we observed here that AMPK activation or amino acid deprivation promotes GSK3β nuclear localization in an mTORC1-dependent manner. GSK3β was detected on several distinct endomembrane compartments, including lysosomes. Consistently, disruption of late endosomes/lysosomes through a perturbation of RAS oncogene family member 7 (Rab7) resulted in loss of GSK3β from lysosomes and in enhanced GSK3β nuclear localization as well as GSK3β-dependent reduction of c-Myc levels. These findings indicate that the nuclear localization and function of GSK3β is suppressed by mTORC1 and suggest a link between metabolic conditions sensed by mTORC1 and GSK3β-dependent regulation of transcriptional networks controlling cellular biomass production.

KEYWORDS:

AMPK; Akt; PI3K; Rab7; Ran; Snail; c-Myc; lysosome; mTORC1; membrane trafficking; metabolism; nuclear translocation; signaling

PMID:
30061153
PMCID:
PMC6153275
[Available on 2019-09-21]
DOI:
10.1074/jbc.RA118.002800
[Indexed for MEDLINE]

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