Mitogenic and Metabolic signals regulate mTOR complex 1 function to control GSK3β nuclear program
Bibliographic record
Abstract
Mitogenic and metabolic signalling are two cell pathways that control different aspects of cellular physiology including, growth, proliferation, metabolism, and transcription. Mitogenic signalling involves mitogens and growth factors to stimulate various receptor signalling pathways such as epidermal growth factor receptor (EGFR), while metabolic signalling involves proteins that sense changes in abundance of specific nutrients or metabolites such as amino acids and ATP. Here, I have uncovered that EGFR signalling is controlled by clathrin nanodomains at the plasma membrane, yet this requirement for clathrin does not reflect a role for receptor internalization in EGFR signalling. Specifically, I found that clathrin is required for activation of the key signaling intermediate Akt by EGFR upon EGF stimulation. Furthermore, I have also resolved a series of signals including Phospholipase C γ1 (PLCγ1) that may control EGF stimulated Akt activation by modulating the assembly of clathrin into plasma membrane nanodomains. These findings suggest that clathrin nanodomains at the plasma membrane are important for controlling EGFR signalling, thus impacting mitogenic signaling. A downstream signalling pathway controlled by Akt is the Glycogen synthase kinase 3 (GSK3) pathway. 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 regulation of its nuclear localization. I found that perturbations in 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. In addition to conditional nuclear localization, GSK3 was also detected on several distinct endomembrane compartments, including lysosomes. Consistently, disruption of various aspects of the function and regulation late endosomes/lysosomes resulted in perturbation of GSK3 nucleocytoplasmic shuttling and activity. Furthermore, I found that DEPDC5, a subunit of the lysosomal amino-acid sensing GATOR1 complex, controls amino acid sensing mechanisms to regulate GSK3 nucleocytoplasmic shuttling. These findings uncover a new signalling axis that is controlled by specific aspects of both mitogenic and metabolic signalling, which may interface with the nucleus to reprogram transcriptional cellular networks for growth and proliferation. Understanding how mTORC1- GSK3 signalling impacts transcriptional networks may be an important target for different therapies and treatments against diverse forms of cancer.
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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".