mTORC1 controls GSK3β nuclear localization
Bibliographic record
Abstract
Glycogen synthase kinase 3β (GSK3β) is a serine/threonine kinase that regulates numerous cellular processes such as apoptosis, self‐renewal, growth, and metabolism. GSK3β phosphorylates over 100 substrates ranging from cytosolic to nuclear substrate targets, including c‐myc, a key ongogenic transcription factor, leading to control of c‐myc stability. GSK3β is itself regulated by phosphorylation on S9 by signals such as Akt (activated within the phosphatidylinositol‐3kinase, PI3K, signaling pathway), resulting in reduced GSK3β kinase activity. Given the wide range of substrates and the incomplete regulation of GSK3β by S9 phosphorylation, it is likely that other mechanisms gate GSK3β function. GSK3β may be localized within different cellular compartments such early endosomes, the nucleus, and in multivesicular bodies. However, how GSK3β localization is regulated, and how this may control GSK3β function is poorly understood, which we have examined here. Specifically, we examined how mTORC1, a key cellular sensor of mitogenic and metabolic signals, controls GSK3β localization and function. Using pharmacological inhibitors of mTORC1 and GSK3β, as well as siRNA gene silencing approaches, we uncovered that GSK3β‐mediated c‐myc degradation is negatively regulated by mTORC1. Using fluorescence microscopy approaches, we find that inhibition of PI3K‐Akt‐mTOR signaling axis, and metabolic insufficiency (e.g. amino acid deficiency), elicit GSK3β nuclear translocation from the cytosol, suggesting that mTORC1 mediates GSK3β nucleocytoplasmic shuttling. Consistent with regulation of GSK3β by mTORC1, we also uncovered that GSK3β localizes to LAMP1 positive late endosome/lysosomes, and perturbations of late endosome/lysosome membrane traffic impacted nuclear localization of GSK3β. This suggests that late endosomes/lysosomal compartments serve as organizing platforms, integrating mitogenic and metabolic signals via mTORC1 to elicit GSK3β cytosolic retention, thus impacting access of GSK3β to nuclear targets and controlling c‐myc degradation. Understanding how mTORC1 dependent signals regulate GSK3b subcellular localization to control GSK3β function may give useful insight to the development of drugs and therapies targeting GSK3β for the treatment of cancer cell growth and survival. Support or Funding Information This work is supported by a Discovery Grant from the Natural Science and Engineering Research Council (of Canada), an Early Researcher Award from the Ontario Ministry of Research, Innovation and Science, and a New Investigator Award from the Canadian Institutes of Health Research to C.N.A. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".