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Venkatraman2012 - Interplay between PLS and TSP1 in TGF-β1 activation

ABSTRACT: Venkatraman2012 - Interplay between PLS and TSP1 in TGF-β1 activation The interplay between PLS (Plasmin) and TSP1 (Thrombospondin-1) in TGF-β1 (Transforming growth factor-β1)is shown using mathematical modelling and in vitro experimentents. This model is described in the article: Plasmin triggers a switch-like decrease in thrombospondin-dependent activation of TGF-β1. Venkatraman L, Chia SM, Narmada BC, White JK, Bhowmick SS, Forbes Dewey C Jr, So PT, Tucker-Kellogg L, Yu H. Biophys J. 2012 Sep 5;103(5):1060-8. Abstract: Transforming growth factor-β1 (TGF-β1) is a potent regulator of extracellular matrix production, wound healing, differentiation, and immune response, and is implicated in the progression of fibrotic diseases and cancer. Extracellular activation of TGF-β1 from its latent form provides spatiotemporal control over TGF-β1 signaling, but the current understanding of TGF-β1 activation does not emphasize cross talk between activators. Plasmin (PLS) and thrombospondin-1 (TSP1) have been studied individually as activators of TGF-β1, and in this work we used a systems-level approach with mathematical modeling and in vitro experiments to study the interplay between PLS and TSP1 in TGF-β1 activation. Simulations and steady-state analysis predicted a switch-like bistable transition between two levels of active TGF-β1, with an inverse correlation between PLS and TSP1. In particular, the model predicted that increasing PLS breaks a TSP1-TGF-β1 positive feedback loop and causes an unexpected net decrease in TGF-β1 activation. To test these predictions in vitro, we treated rat hepatocytes and hepatic stellate cells with PLS, which caused proteolytic cleavage of TSP1 and decreased activation of TGF-β1. The TGF-β1 activation levels showed a cooperative dose response, and a test of hysteresis in the cocultured cells validated that TGF-β1 activation is bistable. We conclude that switch-like behavior arises from natural competition between two distinct modes of TGF-β1 activation: a TSP1-mediated mode of high activation and a PLS-mediated mode of low activation. This switch suggests an explanation for the unexpected effects of the plasminogen activation system on TGF-β1 in fibrotic diseases in vivo, as well as novel prognostic and therapeutic approaches for diseases with TGF-β dysregulation. This model is hosted on BioModels Database and identified by: MODEL1303130000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . 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 for more information.

SUBMITTER: Huipeng Li

PROVIDER: BIOMD0000000447 | BioModels | 2013-03-26

REPOSITORIES: BioModels

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Plasmin triggers a switch-like decrease in thrombospondin-dependent activation of TGF-β1.

Venkatraman Lakshmi L Chia Ser-Mien SM Narmada Balakrishnan Chakrapani BC White Jacob K JK Bhowmick Sourav S SS Forbes Dewey C C So Peter T PT Tucker-Kellogg Lisa L Yu Hanry H

Biophysical journal 20120901 5

Transforming growth factor-β1 (TGF-β1) is a potent regulator of extracellular matrix production, wound healing, differentiation, and immune response, and is implicated in the progression of fibrotic diseases and cancer. Extracellular activation of TGF-β1 from its latent form provides spatiotemporal control over TGF-β1 signaling, but the current understanding of TGF-β1 activation does not emphasize cross talk between activators. Plasmin (PLS) and thrombospondin-1 (TSP1) have been studied individu ...[more]

PMID: 23009856

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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.

Dataset Information

Venkatraman2012 - Interplay between PLS and TSP1 in TGF-β1 activation

Publications

Plasmin triggers a switch-like decrease in thrombospondin-dependent activation of TGF-β1.

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