PMID- 29330362 OWN - NLM STAT- MEDLINE DCOM- 20181217 LR - 20181217 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 8 IP - 1 DP - 2018 Jan 12 TI - Dynamic modelling of the mTOR signalling network reveals complex emergent behaviours conferred by DEPTOR. PG - 643 LID - 10.1038/s41598-017-18400-z [doi] LID - 643 AB - The mechanistic Target of Rapamycin (mTOR) signalling network is an evolutionarily conserved network that controls key cellular processes, including cell growth and metabolism. Consisting of the major kinase complexes mTOR Complex 1 and 2 (mTORC1/2), the mTOR network harbours complex interactions and feedback loops. The DEP domain-containing mTOR-interacting protein (DEPTOR) was recently identified as an endogenous inhibitor of both mTORC1 and 2 through direct interactions, and is in turn degraded by mTORC1/2, adding an extra layer of complexity to the mTOR network. Yet, the dynamic properties of the DEPTOR-mTOR network and the roles of DEPTOR in coordinating mTORC1/2 activation dynamics have not been characterised. Using computational modelling, systems analysis and dynamic simulations we show that DEPTOR confers remarkably rich and complex dynamic behaviours to mTOR signalling, including abrupt, bistable switches, oscillations and co-existing bistable/oscillatory responses. Transitions between these distinct modes of behaviour are enabled by modulating DEPTOR expression alone. We characterise the governing conditions for the observed dynamics by elucidating the network in its vast multi-dimensional parameter space, and develop strategies to identify core network design motifs underlying these dynamics. Our findings provide new systems-level insights into the complexity of mTOR signalling contributed by DEPTOR. FAU - Varusai, Thawfeek M AU - Varusai TM AD - European Bioinformatics Institute, EMBL-EBI, Wellcome Genome Campus, Hinxton, Cambridgeshire, CB10 1SD, UK. AD - Systems Biology Ireland, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland. FAU - Nguyen, Lan K AU - Nguyen LK AD - Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, 3800, Australia. lan.k.nguyen@monash.edu. AD - Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, 3800, Australia. lan.k.nguyen@monash.edu. AD - Systems Biology Ireland, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland. lan.k.nguyen@monash.edu. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180112 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Intracellular Signaling Peptides and Proteins) RN - EC 2.7.1.1 (DEPTOR protein, human) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) SB - IM MH - Computer Simulation MH - Humans MH - Intracellular Signaling Peptides and Proteins/*chemistry/*metabolism MH - Mechanistic Target of Rapamycin Complex 1/*metabolism MH - Mechanistic Target of Rapamycin Complex 2/*metabolism MH - Molecular Dynamics Simulation MH - Proteolysis MH - Signal Transduction MH - Systems Analysis PMC - PMC5766521 COIS- The authors declare that they have no competing interests. EDAT- 2018/01/14 06:00 MHDA- 2018/12/18 06:00 PMCR- 2018/01/12 CRDT- 2018/01/14 06:00 PHST- 2017/08/24 00:00 [received] PHST- 2017/12/01 00:00 [accepted] PHST- 2018/01/14 06:00 [entrez] PHST- 2018/01/14 06:00 [pubmed] PHST- 2018/12/18 06:00 [medline] PHST- 2018/01/12 00:00 [pmc-release] AID - 10.1038/s41598-017-18400-z [pii] AID - 18400 [pii] AID - 10.1038/s41598-017-18400-z [doi] PST - epublish SO - Sci Rep. 2018 Jan 12;8(1):643. doi: 10.1038/s41598-017-18400-z.