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mTORC1 controls glycogen synthase kinase 3β nuclear localization and function

Stephen J. Bautista, Ivan Boras, Adriano Vissa, Noa Mecica, Christopher M. Yip, Peter K. Kim, View ORCID ProfileCostin N. Antonescu
doi: https://doi.org/10.1101/277657
Stephen J. Bautista
Department of Chemistry and Biology and Graduate Program in Molecular Science, Ryerson University, Toronto Ontario, Canada, M5B 2K3
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Ivan Boras
Department of Chemistry and Biology and Graduate Program in Molecular Science, Ryerson University, Toronto Ontario, Canada, M5B 2K3
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Adriano Vissa
Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada, M5S 3E5Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada, M5G 0A4
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Noa Mecica
Department of Chemistry and Biology and Graduate Program in Molecular Science, Ryerson University, Toronto Ontario, Canada, M5B 2K3
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Christopher M. Yip
Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada, M5S 3E5Department of Biochemistry, University of Toronto, Toronto, Canada M5G 1X8Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Canada, M5S 3E5
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Peter K. Kim
Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada, M5G 0A4Department of Biochemistry, University of Toronto, Toronto, Canada M5G 1X8
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Costin N. Antonescu
Department of Chemistry and Biology and Graduate Program in Molecular Science, Ryerson University, Toronto Ontario, Canada, M5B 2K3Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, Ontario, Canada, M5B 1W8
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  • ORCID record for Costin N. Antonescu
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Abstract

Glycogen synthase kinase 3β (GSK3β) phosphorylates and regulates a wide range of substrates involved in diverse cellular functions. Some GSK3β substrates, such as c-myc and snail, are nuclear-resident transcription factors, suggesting possible control of GSK3β function by regulation of its nuclear localization. Inhibition of mechanistic target of rapamycin (mTORC1) led to partial redistribution of GSK3β from the cytosol to the nucleus, and GSK3β-dependent reduction of the expression of c-myc and snail. mTORC1 is controlled by metabolic cues, such as by AMP-activated protein kinase (AMPK) or amino acid abundance. Indeed AMPK activation or amino acid deprivation promoted GSK3β nuclear localization in an mTORC1-dependent manner. GSK3β was detected in several distinct endomembrane compartments, including lysosomes. Consistently, disruption of late endosomes/lysosomes through perturbation of Rab7 resulted in loss of GSK3β from lysosomes, and enhanced GSK3β nuclear localization as well as GSK3β-dependent reduction of c-myc levels. This indicates that GSK3β nuclear localization and function is suppressed by mTORC1, and suggests a new link between metabolic conditions sensed by mTORC1 and GSK3β-dependent regulation of transcriptional networks controlling biomass production.

Summary statement (15-30 words) GSK3β nuclear localization and function is negatively regulated by the metabolic and mitogenic sensor mTORC1. mTORC1 control of GSK3β localization requires Rab7 and lysosomal membrane traffic.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 06, 2018.
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mTORC1 controls glycogen synthase kinase 3β nuclear localization and function
Stephen J. Bautista, Ivan Boras, Adriano Vissa, Noa Mecica, Christopher M. Yip, Peter K. Kim, Costin N. Antonescu
bioRxiv 277657; doi: https://doi.org/10.1101/277657
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mTORC1 controls glycogen synthase kinase 3β nuclear localization and function
Stephen J. Bautista, Ivan Boras, Adriano Vissa, Noa Mecica, Christopher M. Yip, Peter K. Kim, Costin N. Antonescu
bioRxiv 277657; doi: https://doi.org/10.1101/277657

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