Varusai2018 - Dynamic modelling of the mTOR signalling network reveals complex emergent behaviours conferred by DEPTOR
Model Identifier
BIOMD0000000823
Short description
This is a mathematical describing the effect that DEP domain-containing mTOR-interacting protein (DEPTOR) has on the mammalian target of rapamycin (mTOR) signalling network.
Format
SBML
(L2V4)
Related Publication
-
Dynamic modelling of the mTOR signalling network reveals complex emergent behaviours conferred by DEPTOR.
- Varusai TM, Nguyen LK
- Scientific reports , 1/ 2018 , Volume 8 , Issue 1 , pages: 643 , PubMed ID: 29330362
- European Bioinformatics Institute, EMBL-EBI, Wellcome Genome Campus, Hinxton, Cambridgeshire, CB10 1SD, UK.
- 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.
Contributors
Submitter of the first revision: Johannes Meyer
Submitter of this revision: Johannes Meyer
Modellers: Johannes Meyer
Submitter of this revision: Johannes Meyer
Modellers: Johannes Meyer
Metadata information
is (2 statements)
isDescribedBy (1 statement)
hasTaxon (1 statement)
hasProperty (3 statements)
isDescribedBy (1 statement)
hasTaxon (1 statement)
hasProperty (3 statements)
Mathematical Modelling Ontology
Ordinary differential equation model
Pathway Ontology mTOR signaling pathway
NCIt DEP Domain-Containing mTOR-Interacting Protein
Pathway Ontology mTOR signaling pathway
NCIt DEP Domain-Containing mTOR-Interacting Protein
Curation status
Curated
Modelling approach(es)
Tags
Connected external resources
SBGN view in Newt Editor
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
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| Varusai2018.xml | SBML L2V4 Representation of Varusai2018 - Dynamic modelling of the mTOR signalling network reveals complex emergent behaviours conferred by DEPTOR | 79.42 KB | Preview | Download |
Additional files |
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| Varusai2018.cps | COPASI file of Varusai2018 - Dynamic modelling of the mTOR signalling network reveals complex emergent behaviours conferred by DEPTOR | 135.02 KB | Preview | Download |
| Varusai2018.sedml | SED-ML file of Varusai2018 - Dynamic modelling of the mTOR signalling network reveals complex emergent behaviours conferred by DEPTOR | 1.74 KB | Preview | Download |
- Model originally submitted by : Johannes Meyer
- Submitted: Sep 25, 2019 3:40:53 PM
- Last Modified: Sep 25, 2019 3:40:53 PM
Revisions
-
Version: 2
- Submitted on: Sep 25, 2019 3:40:53 PM
- Submitted by: Johannes Meyer
- With comment: Automatically added model identifier BIOMD0000000823
Legends
: Variable used inside SBML models
: Variable used inside SBML models
Species
| Species | Initial Concentration/Amount |
|---|---|
| IRS Insulin Receptor Substrate 1 |
100.0 mmol |
| DEPTOR DEP Domain-Containing mTOR-Interacting Protein |
350.0 mmol |
| pIRS Insulin Receptor Substrate 1 |
0.0 mmol |
| Akt AKT kinase |
100.0 mmol |
| mTORC1 mTORC1 |
250.0 mmol |
| mTORC2 mTORC2 |
200.0 mmol |
| pmTORC2 mTORC2 |
0.0 mmol |
| pIR insulin receptor |
0.0 mmol |
Reactions
| Reactions | Rate | Parameters |
|---|---|---|
| IRS => pIRS; pIR | compartment*k3c*IRS*pIR/(Km3+IRS) | Km3 = 50.0; k3c = 0.1 |
| mTORC1 + DEPTOR => mTORC1_DEPTOR | compartment*(k13f*mTORC1*DEPTOR-k13r*mTORC1_DEPTOR) | k13r = 0.006; k13f = 0.001 |
| pDEPTOR => DEPTOR | compartment*V12*pDEPTOR/(Km12+pDEPTOR) | Km12 = 7.0; V12 = 4.0 |
| pIRS => IRS | compartment*V4*pIRS/(Km4+pIRS) | V4 = 1.0; Km4 = 50.0 |
| pAkt => Akt | compartment*V6*pAkt/(Km6+pAkt) | Km6 = 34.0; V6 = 2.0 |
| mTORC1 => pmTORC1; pAkt | compartment*k7c*mTORC1*pAkt/(Km7+mTORC1) | k7c = 0.1; Km7 = 2.0 |
| pmTORC1 => mTORC1 | compartment*V8*pmTORC1/(Km8+pmTORC1) | Km8 = 1.0; V8 = 6.0 |
| mTORC2 + DEPTOR => mTORC2_DEPTOR | compartment*(k14f*mTORC2*DEPTOR-k14r*mTORC2_DEPTOR) | k14f = 0.007; k14r = 0.006 |
| pmTORC2 => mTORC2 | compartment*V10*pmTORC2/(Km10+pmTORC2) | V10 = 3.0; Km10 = 7.0 |
| IR => pIR | compartment*V1*IR/(Km1+IR) | V1 = 1.0; Km1 = 95.0 |
Curator's comment:
(added: 25 Sep 2019, 15:40:26, updated: 25 Sep 2019, 15:40:26)
(added: 25 Sep 2019, 15:40:26, updated: 25 Sep 2019, 15:40:26)
Reproduced plot of Figure 1 C in the original publication.
Model simulated and plot produced using COPASI 4.24 (Build 197).