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BIOMD0000000600 - Cellière2011 - Plasticity of TGF-β Signalling

 

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Reference Publication
Publication ID: 22051045
Cellière G, Fengos G, Hervé M, Iber D.
Plasticity of TGF-β signaling.
BMC Syst Biol 2011; 5: 184
Department of Biosystems Science and Engineering (D-BSSE), Eidgenöossische Technische Hochschule Zurich (ETHZ), Mattenstrasse 26, 4058 Basel, Switzerland.  [more]
Model
Original Model: BIOMD0000000600.origin
Submitter: Georgios Fengos
Submission ID: MODEL1208280000
Submission Date: 28 Aug 2012 16:56:01 UTC
Last Modification Date: 18 Apr 2016 14:56:39 UTC
Creation Date: 18 Apr 2016 12:54:50 UTC
Encoders:  Nick Juty
   Vijayalakshmi Chelliah
   Georgios Fengos
   Ryan Gutenkunst
   Rachel Wellington
   Benjamin Zaepfel
   Dinah Davison
   Travis Struck
set #1
bqbiol:isDescribedBy PubMed 22051045
set #2
bqbiol:isVersionOf Gene Ontology transforming growth factor beta receptor signaling pathway
Notes
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:

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.

Model
Publication ID: 22051045 Submission Date: 28 Aug 2012 16:56:01 UTC Last Modification Date: 18 Apr 2016 14:56:39 UTC Creation Date: 18 Apr 2016 12:54:50 UTC
Mathematical expressions
Reactions
r1 r2 r3 r4
r5 r6 r7 r8
r9 r10 r11 r12
r13 r14 r15 r16
r17 r18 r19 r20
r21 r22 r23 r24
r25 r26 r27 r28
r29      
Physical entities
Compartments Species
cytoplasm TGFbR TGFb_TGFbR TGFb_TGFbR_P
I_Smad_TGFb_TGFbR_P Smad Smad_P
CoSmad Smad_P_Smad_P Smad_P_CoSmad
I_Smad_mRNA2 I_Smad  
nucleus Smad_N Smad_P_Smad_P_N Smad_P_N
Smad_P_CoSmad_N CoSmad_N I_Smad_mRNA1
     
extracellular TGFb    
Global parameters
h k1 k2 k3
k4 k7 k8 k9
k10 k11 k12 k13
k5 k6 k14 k15
k16 k17 k18 k19
Reactions (29)
 
 r1 [TGFb_TGFbR] → [TGFbR];  
 
 r2 [TGFbR] + [TGFb] → [TGFb_TGFbR];  
 
 r3 [TGFb_TGFbR] → [TGFb_TGFbR_P];  
 
 r4 [TGFb_TGFbR_P] → [TGFb_TGFbR];  
 
 r5 [TGFb_TGFbR_P] + [I_Smad] → [I_Smad_TGFb_TGFbR_P];  
 
 r6 [I_Smad_TGFb_TGFbR_P] → [TGFb_TGFbR] + [I_Smad];  
 
 r7 [Smad] → [Smad_P];   {TGFb_TGFbR_P} , {Smad}
 
 r8 [Smad] → [Smad_N];  
 
 r9 [Smad_N] → [Smad];  
 
 r10 2.0 × [Smad_P] → [Smad_P_Smad_P];  
 
 r11 [Smad_P_Smad_P] → 2.0 × [Smad_P];  
 
 r12 [Smad_P] + [CoSmad] → [Smad_P_CoSmad];  
 
 r13 [Smad_P_CoSmad] → [Smad_P] + [CoSmad];  
 
 r14 [CoSmad] → [CoSmad_N];  
 
 r15 [CoSmad_N] → [CoSmad];  
 
 r16 [Smad_P_Smad_P] → [Smad_P_Smad_P_N];  
 
 r17 [Smad_P] → [Smad_P_N];  
 
 r18 [Smad_P_N] → [Smad_P];  
 
 r19 [Smad_P_CoSmad] → [Smad_P_CoSmad_N];  
 
 r20 [Smad_P_N] → [Smad_N];  
 
 r21 2.0 × [Smad_P_N] → [Smad_P_Smad_P_N];  
 
 r22 [Smad_P_Smad_P_N] → 2.0 × [Smad_P_N];  
 
 r23 [Smad_P_N] + [CoSmad_N] → [Smad_P_CoSmad_N];  
 
 r24 [Smad_P_CoSmad_N] → [Smad_P_N] + [CoSmad_N];  
 
 r25  → [I_Smad_mRNA1];   {Smad_P_CoSmad_N}
 
 r26 [I_Smad_mRNA1] → [I_Smad_mRNA2];  
 
 r27 [I_Smad_mRNA2] → ;  
 
 r28  → [I_Smad];   {I_Smad_mRNA2}
 
 r29 [I_Smad] → ;  
 
Functions (4)
 
 Function for r25 [1] lambda(Smad_P_CoSmad_N, h, k14, k15, k14*Smad_P_CoSmad_N^h/(Smad_P_CoSmad_N^h+k15^h))
 
 Function for r16 [1] lambda(Smad_P_Smad_P, k12, k8, k12*k8*Smad_P_Smad_P)
 
 Function for r28 [1] lambda(I_Smad_mRNA2, k18, k18*I_Smad_mRNA2)
 
 Function for r7 [1] lambda(k7, Smad, TGFb_TGFbR_P, k7*Smad*TGFb_TGFbR_P)
 
 cytoplasm Spatial dimensions: 3.0  Compartment size: 2.3
 
 TGFbR
Compartment: cytoplasm
Initial concentration: 1010.0
 
 TGFb_TGFbR
Compartment: cytoplasm
Initial concentration: 0.0
 
 TGFb_TGFbR_P
Compartment: cytoplasm
Initial concentration: 0.0
 
 I_Smad_TGFb_TGFbR_P
Compartment: cytoplasm
Initial concentration: 0.0
 
 Smad
Compartment: cytoplasm
Initial concentration: 7000.0
 
 Smad_P
Compartment: cytoplasm
Initial concentration: 0.0
 
 CoSmad
Compartment: cytoplasm
Initial concentration: 12000.0
 
 Smad_P_Smad_P
Compartment: cytoplasm
Initial concentration: 0.0
 
 Smad_P_CoSmad
Compartment: cytoplasm
Initial concentration: 0.0
 
 I_Smad_mRNA2
Compartment: cytoplasm
Initial concentration: 0.0
 
 I_Smad
Compartment: cytoplasm
Initial concentration: 0.0
 
 nucleus Spatial dimensions: 3.0  Compartment size: 1.0
 
 Smad_N
Compartment: nucleus
Initial concentration: 82000.0
 
 Smad_P_Smad_P_N
Compartment: nucleus
Initial concentration: 0.0
 
 Smad_P_N
Compartment: nucleus
Initial concentration: 0.0
 
 Smad_P_CoSmad_N
Compartment: nucleus
Initial concentration: 0.0
 
 CoSmad_N
Compartment: nucleus
Initial concentration: 135000.0
 
 I_Smad_mRNA1
Compartment: nucleus
Initial concentration: 0.0
 
 extracellular Spatial dimensions: 3.0  Compartment size: 1.0
 
 TGFb
Compartment: extracellular
Initial concentration: 460.0
Constant
 
Global Parameters (20)
 
 h
Value: 2.06
Constant
 
 k1
Value: 0.00446
Constant
 
 k2
Value: 4.39E-6
Constant
 
 k3
Value: 0.324
Constant
 
 k4
Value: 0.00192
Constant
 
 k7
Value: 9.35E-6
Constant
 
 k8
Value: 0.0104
Constant
 
 k9
Value: 7.5E-4
Constant
 
 k10
Value: 5.12E-8
Constant
 
 k11
Value: 0.00923
Constant
 
 k12
Value: 0.0513
Constant
 
 k13
Value: 0.00164
Constant
 
 k5
Value: 5.49E-4
Constant
 
 k6
Value: 1.29E-5
Constant
 
 k14
Value: 0.038
Constant
 
 k15
Value: 28.52
Constant
 
 k16
Value: 0.0214
Constant
 
 k17
Value: 8.05E-5
Constant
 
 k18
Value: 0.0434
Constant
 
 k19
Value: 4.12E-4
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000600

Curator's comment: (updated: 18 Apr 2016 14:42:22 BST)

Figure S1 and S2 have from the reference publication have been reproduced in Copasi and Matlab SimBiology. (The "transcription factor" line corresponds to the species Smad_P_CoSmad_N.) The curation plot shown reproduces Figure S2 and was produced using Copasi for simulation and matplotlib for plotting. Python script added as additional file.

Additional file(s)
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