Dataset Information

Wegner2012_TGFbetaSignalling_FeedbackLoops

ABSTRACT: This model is from the article: Dynamics and feedback loops in the transforming growth factor β signaling pathway. Wegner K, Bachmann A, Schad JU, Lucarelli P, Sahle S, Nickel P, Meyer C, Klingmüller U, Dooley S, Kummer U. Biophys Chem. 2012 Jan 5. 22284904 , Abstract: Transforming growth factor β (TGF-β) ligands activate a signaling cascade with multiple cell context dependent outcomes. Disruption or disturbance leads to variant clinical disorders. To develop strategies for disease intervention, delineation of the pathway in further detail is required. Current theoretical models of this pathway describe production and degradation of signal mediating proteins and signal transduction from the cell surface into the nucleus, whereas feedback loops have not exhaustively been included. In this study we present a mathematical model to determine the relevance of feedback regulators (Arkadia, Smad7, Smurf1, Smurf2, SnoN and Ski) on TGF-β target gene expression and the potential to initiate stable oscillations within a realistic parameter space. We employed massive sampling of the parameters space to pinpoint crucial players for potential oscillations as well as transcriptional product levels. We identified Smad7 and Smurf2 with the highest impact on the dynamics. Based on these findings, we conducted preliminary time course experiments. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2012 The BioModels.net Team. For more information see the terms of use . To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

SUBMITTER: Katja Wengler (neé Wegner)

PROVIDER: BIOMD0000000410 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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	BIOMD0000000410?filename=BIOMD0000000410-biopax2.owl	Owl
	BIOMD0000000410?filename=BIOMD0000000410-biopax3.owl	Owl
	BIOMD0000000410?filename=BIOMD0000000410.m	Other
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Dynamics and feedback loops in the transforming growth factor β signaling pathway.

Wegner Katja K Bachmann Anastasia A Schad Jan-Ulrich JU Lucarelli Philippe P Sahle Sven S Nickel Peter P Meyer Christoph C Klingmüller Ursula U Dooley Steven S Kummer Ursula U

Biophysical chemistry 20120105

Transforming growth factor β (TGF-β) ligands activate a signaling cascade with multiple cell context dependent outcomes. Disruption or disturbance leads to variant clinical disorders. To develop strategies for disease intervention, delineation of the pathway in further detail is required. Current theoretical models of this pathway describe production and degradation of signal mediating proteins and signal transduction from the cell surface into the nucleus, whereas feedback loops have not exhaus ...[more]

PMID: 22284904

Similar Datasets

Project description:Cellière2011 - Plasticity of TGF-β Signalling Transforming growth factor beta (TGF-β) signalling has been implicated as an important regulator of almost all major cell behaviours, including proliferation, differentiation, cell death, and motility. It remains unclear that how the TGF-β signalling pathway accomplishes the flexibility in its responses. What and how many parameters have to be altered for cells to respond differently to perform complex tasks? This canonical response has been explored in this model, by considering the core signalling architecture of TGF-β pathway. This model is described in the article: Plasticity of TGF-β signaling Cellière G, Fengos G, Hervé M, Iber D. BMC Syst Biol. 2011 Nov 3;5:184. Abstract: The family of TGF-β ligands is large and its members are involved in many different signaling processes. These signaling processes strongly differ in type with TGF-β ligands eliciting both sustained or transient responses. Members of the TGF-β family can also act as morphogen and cellular responses would then be expected to provide a direct read-out of the extracellular ligand concentration. A number of different models have been proposed to reconcile these different behaviours. We were interested to define the set of minimal modifications that are required to change the type of signal processing in the TGF-β signaling network. RESULTS: To define the key aspects for signaling plasticity we focused on the core of the TGF-β signaling network. With the help of a parameter screen we identified ranges of kinetic parameters and protein concentrations that give rise to transient, sustained, or oscillatory responses to constant stimuli, as well as those parameter ranges that enable a proportional response to time-varying ligand concentrations (as expected in the read-out of morphogens). A combination of a strong negative feedback and fast shuttling to the nucleus biases signaling to a transient rather than a sustained response, while oscillations were obtained if ligand binding to the receptor is weak and the turn-over of the I-Smad is fast. A proportional read-out required inefficient receptor activation in addition to a low affinity of receptor-ligand binding. We find that targeted modification of single parameters suffices to alter the response type. The intensity of a constant signal (i.e. the ligand concentration), on the other hand, affected only the strength but not the type of the response. CONCLUSIONS: The architecture of the TGF-β pathway enables the observed signaling plasticity. The observed range of signaling outputs to TGF-β ligand in different cell types and under different conditions can be explained with differences in cellular protein concentrations and with changes in effective rate constants due to cross-talk with other signaling pathways. It will be interesting to uncover the exact cellular differences as well as the details of the cross-talks in future work. This model is hosted on BioModels Database and identified by: MODEL1208280000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. PMID: 20587024 . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to [CC0 Public Domain Dedication>http://creativecommons.org/publicdomain/zero/1.0/] for more information.

Project description:This model is from the article: Quantitative analysis of transient and sustained transforming growth factor-β signaling dynamics. Zhike Zi, Zipei Feng, Douglas A Chapnick, Markus Dahl, Difan Deng, Edda Klipp, Aristidis Moustakas & Xuedong Liu Molecular Systems Biology 2011 May 24;7:492. 21613981 , Abstract: Mammalian cells can decode the concentration of extracellular transforming growth factor-β (TGF-β) and transduce this cue into appropriate cell fate decisions. How variable TGF-β ligand doses quantitatively control intracellular signaling dynamics and how continuous ligand doses are translated into discontinuous cellular fate decisions remain poorly understood. Using a combined experimental and mathematical modeling approach, we discovered that cells respond differently to continuous and pulsating TGF-β stimulation. The TGF-β pathway elicits a transient signaling response to a single pulse of TGF-β stimulation, whereas it is capable of integrating repeated pulses of ligand stimulation at short time interval, resulting in sustained phospho-Smad2 and transcriptional responses. Additionally, the TGF-β pathway displays different sensitivities to ligand doses at different time scales. While ligand-induced short-term Smad2 phosphorylation is graded, long-term Smad2 phosphorylation is switch-like to a small change in TGF-β levels. Correspondingly, the short-term Smad7 gene expression is graded, while long-term PAI-1 gene expression is switch-like, as is the long-term growth inhibitory response. Our results suggest that long-term switch-like signaling responses in the TGF-β pathway might be critical for cell fate determination. Note: Developer of the model: Zhike Zi Reference: Zi Z. et al., Quantitative Analysis of Transient and Sustained Transforming Growth Factor-beta Signaling Dynamics, Molecular Systems Biology, 2011 1. The global parameter that set the type of stimulation (a) for sustained TGF-beta stimulation: set stimulation_type = 1. (b) for single pulse of TGF-beta stimulation: set stimulation_type = 2. parameter "single_pulse_duration" is for the duration of stimulation, for example, single_pulse_duration = 0.5, for 0.5 min (30 seconds) of TGF-beta stimulation. *Note: make sure that the time course cover the time point when the event is triggered. (c) for single pulse of TGF-beta stimulation in COPASI change the trigger of event "single_pulse_TGF_beta_washout" from "and(eq(stimulation_type, 2), eq(time, single_pulse_duration))" (for SBML-SAT) to "and(eq(stimulation_type, 2), gt(time, single_pulse_duration))" (for COPASI) 2. Notes for TGF-beta dose in terms of molecules per cell (a) The following equation applies for conversion of TGF-beta dose in molecules per cell TGF_beta_dose_mol_per_cell = initial TGF_beta_ex*1e-9*Vmed*6e23 (b) for standard experimental setup 1e6 cells in 2 mL medium 0.001 nM initial TGF_beta_ex is approximately equal to the dose of 1200 TGF-beta molecules/cell 0.050 nM initial TGF_beta_ex is approximately equal to the dose of 60000 TGF-beta molecules/cell (c) For 1e6 cells in 10 mL medium, please change the initial compartment size of Vmed and the corresponding assignment rule for Vmed. initial Vmed = 1e-8 (1e6 cells in 10 mL medium) Vmed = 0.010/(1e6*exp(log(1.45)*time/1440)) (1e6 cells in 10 mL medium) 3. Please note that this model contains events and the medium compartment size is varied. 4. For the model simulation in SBML-SAT, please remove initialAssignments and save it as SBML Level 2 Verion 1 file.