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BIOMD0000000447 - Venkatraman2012 - Interplay between PLS and TSP1 in TGF-β1 activation

 

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Reference Publication
Publication ID: 23009856
Venkatraman L, Chia SM, Narmada BC, White JK, Bhowmick SS, Forbes Dewey C Jr, So PT, Tucker-Kellogg L, Yu H.
Plasmin triggers a switch-like decrease in thrombospondin-dependent activation of TGF-β1.
Biophys. J. 2012 Sep; 103(5): 1060-1068
Singapore-MIT Alliance, Computational Systems Biology Programme, Singapore.  [more]
Model
Original Model: BIOMD0000000447.origin
Submitter: Huipeng Li
Submission ID: MODEL1303130000
Submission Date: 13 Mar 2013 06:54:49 UTC
Last Modification Date: 07 Apr 2014 02:42:37 UTC
Creation Date: 26 Mar 2013 13:34:09 UTC
Encoders:  Vijayalakshmi Chelliah
   Huipeng Li
set #1
bqbiol:isVersionOf Gene Ontology thrombospondin receptor activity
Gene Ontology transforming growth factor beta activation
set #2
bqbiol:hasProperty Mathematical Modelling Ontology MAMO_0000046
set #3
bqmodel:isDerivedFrom BioModels Database MODEL1303130001
set #4
bqbiol:hasTaxon Taxonomy Rattus rattus
Notes
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:

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.

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.

Model
Publication ID: 23009856 Submission Date: 13 Mar 2013 06:54:49 UTC Last Modification Date: 07 Apr 2014 02:42:37 UTC Creation Date: 26 Mar 2013 13:34:09 UTC
Mathematical expressions
Reactions
reaction_1 reaction_2 reaction_3 reaction_4
reaction_5 reaction_6 reaction_7 reaction_8
reaction_9 reaction_10 reaction_11 reaction_12
reaction_13 reaction_14 reaction_15 reaction_16
reaction_17 reaction_18 reaction_19 reaction_20
reaction_21 reaction_22 reaction_23 reaction_24
reaction_25 reaction_26 reaction_28 reaction_29
reaction_30 reaction_27 reaction_31 reaction_32
Physical entities
Compartments Species
compartment PLG PLS scUPA
tcUPA LTGFb1 TGFb1
TSP1 PAI1 TSP1:PLS
A2M A2M:PLS PAI1:tcUPA
PAI1:scUPA    
Global parameters
keff1 keff2 keff3 k1
k2 kothers kp1 kp2
k3 k_3 k4 k5
k_5 k6 k_6 k7
k_7 k8 k9 u_edeg
u_pdeg alpha1 alpha2  
Reactions (32)
 
 reaction_1 [scUPA] + [PLG] → [PLS] + [scUPA];   {scUPA} , {PLG}
 
 reaction_2 [PLS] + [scUPA] → [tcUPA] + [PLS];   {PLS} , {scUPA}
 
 reaction_3 [tcUPA] + [PLG] → [PLS] + [tcUPA];   {tcUPA} , {PLG}
 
 reaction_4 [PLS] + [LTGFb1] → [TGFb1] + [PLS];   {PLS} , {LTGFb1}
 
 reaction_5 [TSP1] + [LTGFb1] → [TGFb1];   {TSP1} , {LTGFb1}
 
 reaction_6 [LTGFb1] → [TGFb1];   {LTGFb1}
 
 reaction_7 [TGFb1] → [TGFb1] + [TSP1];   {TGFb1}
 
 reaction_8 [TGFb1] → [TGFb1] + [PAI1];   {TGFb1}
 
 reaction_9 [TSP1] + [PLS] ↔ [TSP1:PLS];   {TSP1} , {PLS} , {TSP1:PLS}
 
 reaction_10 [TSP1:PLS] → [PLS];   {TSP1:PLS}
 
 reaction_11 [A2M] + [PLS] ↔ [A2M:PLS];   {A2M} , {PLS} , {A2M:PLS}
 
 reaction_12 [PAI1] + [tcUPA] ↔ [PAI1:tcUPA];   {PAI1} , {tcUPA} , {PAI1:tcUPA}
 
 reaction_13 [PAI1] + [scUPA] ↔ [PAI1:scUPA];   {PAI1} , {scUPA} , {PAI1:scUPA}
 
 reaction_14  → [scUPA];  
 
 reaction_15  → [LTGFb1];  
 
 reaction_16  → [A2M];  
 
 reaction_17  → [PLG];  
 
 reaction_18 [scUPA] → ;   {scUPA}
 
 reaction_19 [tcUPA] → ;   {tcUPA}
 
 reaction_20 [PLS] → ;   {PLS}
 
 reaction_21 [TSP1] → ;   {TSP1}
 
 reaction_22 [PAI1] → ;   {PAI1}
 
 reaction_23 [LTGFb1] → ;   {LTGFb1}
 
 reaction_24 [TGFb1] → ;   {TGFb1}
 
 reaction_25 [PLG] → ;   {PLG}
 
 reaction_26 [A2M] → ;   {A2M}
 
 reaction_28 [A2M:PLS] → ;   {A2M:PLS}
 
 reaction_29 [PAI1:tcUPA] → ;   {PAI1:tcUPA}
 
 reaction_30 [PAI1:scUPA] → ;   {PAI1:scUPA}
 
 reaction_27 [TSP1:PLS] → ;   {TSP1:PLS}
 
 reaction_31 [TSP1:PLS] → ;   {TSP1:PLS}
 
 reaction_32 [TGFb1] → ;   {TGFb1}
 
Functions (1)
 
 Constant flux (irreversible) lambda(v, v)
 
 compartment Spatial dimensions: 3.0  Compartment size: 1.0
 
 PLG
Compartment: compartment
Initial concentration: 0.003
 
 PLS
Compartment: compartment
Initial concentration: 0.0
 
 scUPA
Compartment: compartment
Initial concentration: 0.001
 
 tcUPA
Compartment: compartment
Initial concentration: 0.0
 
 LTGFb1
Compartment: compartment
Initial concentration: 0.001
 
 TGFb1
Compartment: compartment
Initial concentration: 0.0
 
 TSP1
Compartment: compartment
Initial concentration: 0.0
 
 PAI1
Compartment: compartment
Initial concentration: 0.0
 
 TSP1:PLS
Compartment: compartment
Initial concentration: 0.0
 
 A2M
Compartment: compartment
Initial concentration: 0.005
 
 A2M:PLS
Compartment: compartment
Initial concentration: 0.0
 
 PAI1:tcUPA
Compartment: compartment
Initial concentration: 0.0
 
 PAI1:scUPA
Compartment: compartment
Initial concentration: 0.0
 
Global Parameters (23)
 
   keff1
Value: 0.035
Constant
 
   keff2
Value: 0.35
Constant
 
   keff3
Value: 1.4
Constant
 
   k1
Value: 0.035
Constant
 
   k2
Value: 24.5
Constant
 
   kothers
Value: 0.005
Constant
 
   kp1
Value: 0.35
Constant
 
   kp2
Value: 1.05
Constant
 
 k3
Value: 17.5
Constant
 
   k_3
Value: 0.0245
Constant
 
   k4
Value: 0.35
Constant
 
   k5
Value: 24.5
Constant
 
   k_5
Value: 0.0105
Constant
 
   k6
Value: 0.035
Constant
 
   k_6
Value: 0.0035
Constant
 
   k7
Value: 0.07
Constant
 
   k_7
Value: 0.0035
Constant
 
   k8
Value: 24.5
Constant
 
 k9
Value: 0.21
Constant
 
   u_edeg
Value: 0.0525
Constant
 
   u_pdeg
Value: 0.0175
Constant
 
   alpha1
Value: 0.0035
Constant
 
   alpha2
Value: 0.035
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000447

Curator's comment: (updated: 26 Mar 2013 11:10:29 GMT)

Figure 2b and 2c of the reference publication is reproduced here. The simulation was done using Copasi v4.8 (Build 35) and plots were generated using Gnuplot.

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