MTOR complex 1 controls the nuclear localization and function of glycogen synthase kinase 3?.

ABSTRACT: Glycogen synthase kinase 3? (GSK3?) phosphorylates and thereby regulates a wide range of protein substrates involved in diverse cellular functions. Some GSK3? substrates, such as c-Myc and Snail, are nuclear transcription factors, suggesting the possibility that GSK3? 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? from the cytosol to the nucleus and to a GSK3?-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? nuclear localization in an mTORC1-dependent manner. GSK3? 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? from lysosomes and in enhanced GSK3? nuclear localization as well as GSK3?-dependent reduction of c-Myc levels. These findings indicate that the nuclear localization and function of GSK3? is suppressed by mTORC1 and suggest a link between metabolic conditions sensed by mTORC1 and GSK3?-dependent regulation of transcriptional networks controlling cellular biomass production.

SUBMITTER: Bautista SJ 

PROVIDER: S-EPMC6153275 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature