PLoS computational biology, 2021-09, Vol.17 (9), p.e1008513
2021
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Dynamic modelling of the PI3K/MTOR signalling network uncovers biphasic dependence of mTORC1 activity on the mTORC2 subunit SIN1
- Ist Teil von
- PLoS computational biology, 2021-09, Vol.17 (9), p.e1008513
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2021
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- The PI3K/MTOR signalling network regulates a broad array of critical cellular processes, including cell growth, metabolism and autophagy. The mechanistic target of rapamycin (MTOR) kinase functions as a core catalytic subunit in two physically and functionally distinct complexes mTORC1 and mTORC2, which also share other common components including MLST8 (also known as GβL) and DEPTOR. Despite intensive research, how mTORC1 and 2 assembly and activity are coordinated, and how they are functionally linked remain to be fully characterized. This is due in part to the complex network wiring, featuring multiple feedback loops and intricate post-translational modifications. Here, we integrate predictive network modelling, in vitro experiments and -omics data analysis to elucidate the emergent dynamic behaviour of the PI3K/MTOR network. We construct new mechanistic models that encapsulate critical mechanistic details, including mTORC1/2 coordination by MLST8 (de)ubiquitination and the Akt-to-mTORC2 positive feedback loop. Model simulations validated by experimental studies revealed a previously unknown biphasic, threshold-gated dependence of mTORC1 activity on the key mTORC2 subunit SIN1, which is robust against cell-to-cell variation in protein expression. In addition, our integrative analysis demonstrates that ubiquitination of MLST8, which is reversed by OTUD7B, is regulated by IRS1/2. Our results further support the essential role of MLST8 in enabling both mTORC1 and 2's activity and suggest MLST8 as a viable therapeutic target in breast cancer. Overall, our study reports a new mechanistic model of PI3K/MTOR signalling incorporating MLST8-mediated mTORC1/2 formation and unveils a novel regulatory linkage between mTORC1 and mTORC2.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1553-7358, 1553-734XeISSN: 1553-7358DOI: 10.1371/journal.pcbi.1008513Titel-ID: cdi_plos_journals_2582586289
- Format
- –
- Schlagworte
- 1-Phosphatidylinositol 3-kinase, AKT protein, Amino acids, Animals, Autophagy, Binding sites, Biological control systems, Biology and Life Sciences, Breast cancer, Calibration, Cancer, Cell Line, Cellular signal transduction, Computer and Information Sciences, Data analysis, Dynamic models, Feedback, Feedback loops, Health aspects, Insulin resistance, Integrated approach, Intracellular Signaling Peptides and Proteins, Kinases, Mathematical models, Mechanistic Target of Rapamycin Complex 1 - metabolism, Mechanistic Target of Rapamycin Complex 2 - chemistry, Mechanistic Target of Rapamycin Complex 2 - metabolism, Medical research, Medicine and Health Sciences, Medicine, Experimental, Metabolism, Modelling, Molecules, mTOR Associated Protein, LST8 Homolog - metabolism, Ordinary differential equations, Phagocytosis, Phosphatidylinositol 3-Kinases - metabolism, Physiological aspects, Positive feedback, Post-translation, Prostate cancer, Protein kinases, Protein-protein interactions, Proteins, Rapamycin, Regulation, Reproducibility of Results, Research and Analysis Methods, Signal Transduction, Signaling, Simulation, Therapeutic targets, TOR protein, TOR Serine-Threonine Kinases - metabolism, Ubiquitination, Wiring