mTORC1 controls glycogen synthase kinase 3 nuclear localization and function

Glycogen synthase kinase 3 (GSK3 ) phosphorylates and regulates a wide range of substrates involved in diverse cellular functions. Some GSK3 substrates, such as c-myc and snail, are nuclear-resident transcription factors, suggesting possible control of GSK3 function by regulation of its nuclear loca...

Full description

Saved in:
Bibliographic Details
Published inbioRxiv
Main Authors Bautista, Stephen J, Boras, Ivan, Vissa, Adriano, Mecica, Noa, Yip, Christopher M, Kim, Peter K, Antonescu, Costin N
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 06.03.2018
Subjects
Amino acids
AMP
AMP-activated protein kinase
c-Myc protein
Cytosol
Endosomes
Gene regulation
Glycogen
Glycogen synthase kinase 3
Kinases
Localization
Lysosomes
Metabolism
Myc protein
Rapamycin
Snail protein
TOR protein
Transcription factors
Online AccessGet full text

Cover

More Information
Summary:Glycogen synthase kinase 3 (GSK3 ) phosphorylates and regulates a wide range of substrates involved in diverse cellular functions. Some GSK3 substrates, such as c-myc and snail, are nuclear-resident transcription factors, suggesting possible control of GSK3 function by regulation of its nuclear localization. Inhibition of mechanistic target of rapamycin (mTORC1) led to partial redistribution of GSK3 from the cytosol to the nucleus, and GSK3 -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 GSK3 nuclear localization in an mTORC1-dependent manner. GSK3 was detected on several distinct endomembrane compartments, including lysosomes. Consistently, disruption of late endosomes/lysosomes through perturbation of Rab7 resulted in loss of GSK3 from lysosomes, and enhanced GSK3 nuclear localization as well as GSK3 -dependent reduction of c-myc levels. This indicates that GSK3 nuclear localization and function is suppressed by mTORC1, and suggests a new link between metabolic conditions sensed by mTORC1 and GSK3 -dependent regulation of transcriptional networks controlling biomass production.
DOI:10.1101/277657