Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 293, Issue 38, Pages 14723-14739Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.002800
Keywords
membrane trafficking; metabolism; signaling; nuclear translocation; lysosome; Akt; AMPK; PI3K; mTORC1; c-Myc; Snail; Ran; Rab7
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Funding
- Natural Sciences and Engineering Research Council of Canada
- Ontario Ministry of Research, Innovation, and Science
- New Investigator Award from the Canadian Institutes of Health Research
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Glycogen synthase kinase 3 beta (GSK3 beta) phosphorylates and thereby regulates a wide range of protein substrates involved in diverse cellular functions. Some GSK3 beta substrates, such as c-Myc and Snail, are nuclear transcription factors, suggesting the possibility that GSK3 beta 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 GSK3 beta from the cytosol to the nucleus and to a GSK3 beta-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 GSK3 beta nuclear localization in an mTORC1-dependent manner. GSK3 beta 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 GSK3 beta from lysosomes and in enhanced GSK3 beta nuclear localization as well as GSK3 beta-dependent reduction of c-Myc levels. These findings indicate that the nuclear localization and function of GSK3 beta is suppressed by mTORC1 and suggest a link between metabolic conditions sensed by mTORC1 and GSK3 beta-dependent regulation of transcriptional networks controlling cellular biomass production.
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