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BIOMD0000000173 - Schmierer_2008_Smad_Tgfb

 

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Reference Publication
Publication ID: 18443295
Schmierer B, Tournier AL, Bates PA, Hill CS.
Mathematical modeling identifies Smad nucleocytoplasmic shuttling as a dynamic signal-interpreting system.
Proc. Natl. Acad. Sci. U.S.A. 2008 May; 105(18): 6608-6613
Developmental Signalling Laboratory and Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.  [more]
Model
Original Model: BIOMD0000000173.origin
Submitter: Bernhard Schmierer
Submission ID: MODEL0451870146
Submission Date: 04 Jun 2008 08:40:17 UTC
Last Modification Date: 16 May 2012 10:03:54 UTC
Creation Date: 30 Jul 2008 10:47:57 UTC
Encoders:  Lukas Endler
   Bernhard Schmierer
set #1
bqbiol:occursIn Taxonomy Homo sapiens
bqbiol:isVersionOf KEGG Pathway TGF-beta signaling pathway - Homo sapiens (human)
Gene Ontology transforming growth factor beta receptor signaling pathway
Notes

This sbml file describes the RECI model from:
"Mathematical modeling identifies Smad nucleocytoplasmic shuttling as a dynamic signal-interpreting system" by Bernhard Schmierer, Alexander L. Tournier, Paul A. Bates and Caroline S. Hill, Proc Natl Acad Sci U S A. 2008 May 6;105(18):6608-13.
All parameter and species names are as in Figure S3 of the original publication. The original model was done in copasi.
SB-431542 addition to a concentration of 10000 nM is set at 2700 sec. The initial concentration of SB, the time point of addition and the final concentration can be set by altering the parameters SB_0 , t_SB and SB_end .
This model file has been used to reproduce Figures 2D and 5A from the research paper using SBMLodesolver. To get the results for the figures, sum the corresponding concentrations:
fig 2D: nuclear EGFP-Smad2 = G_n + pG_n + G2_n + G4_n + 2* GG_n
fig 5A (either n or c for nucleus or cytosol):
monomeric Smad2 = S2_n/c + G_n/c
monomeric P-Smad2 = pS2_n/c + pG_n/c
Smad2/Smad4 complexes = S24_n/c + G4_n/c
Smad2/Smad2 complexes = S22_n/c + G2_n/c + GG_n/c

This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2009 The BioModels Team.
For more information see the terms of use .
To cite BioModels Database, please use Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691.

Model
Publication ID: 18443295 Submission Date: 04 Jun 2008 08:40:17 UTC Last Modification Date: 16 May 2012 10:03:54 UTC Creation Date: 30 Jul 2008 10:47:57 UTC
Mathematical expressions
Reactions
Reaction 7 Shuttling S4 Reaction 5A Shuttling S2 Reaction 6A Shuttling pS2 Reaction 2A Phosphorylation S2
Reaction 3A Formation S24_C Reaction 3B Formation S24_N Reaction 8A Import S24 Reaction 9A Import S22
Reaction 4A Formation S22_C Reaction 4B Formation S22_N Reaction 10A Dephos pS2 Nuc Reaction 1 TGFb Binding
Reaction 11 Receptor Inhibition Reaction 2B Phosphorylation GS2 Reaction 10B Dephos pG Nuc Reaction 5B Shuttling G
Reaction 6B Shuttling pG Reaction 4E Formation GG_C Reaction 4F Formation GG_N Reaction 4C Formation G2_C
Reaction 4D Formation G2_N Reaction 3C Formation G4_C Reaction 3D Formation G4_N Reaction 9C Import GG
Reaction 9B Import G2 Reaction 8B Import G4    
Rules
Assignment Rule (variable: CIF (complex import factor)) Assignment Rule (variable: Kdiss (dissociation constant of Smad complexes)) Assignment Rule (variable: Kdiss SB (dissociation constant of the SB/receptor interaction)) Assignment Rule (variable: SB-431542)
Physical entities
Compartments Species
Nuc PPase Smad2_n pSmad2_n
GFP-Smad2_n pGFP-Smad2_n pSmad2/pSmad2_n
pSmad2/Smad4_n Smad4_n pGFP-Smad2/pSmad2_n
pGFP-Smad2/Smad4_n pGFP-Smad2/pGFP_Smad2_n  
Cyt pSmad2/pSmad2_c pSmad2/Smad4_c Smad4_c
Smad2_c pSmad2_c GFP-Smad2_c
pGFP-Smad2_c pGFP-Smad2/pSmad2_c pGFP-Smad2/Smad4_c
pGFP-Smad2/pGFP-Smad2_c TGFb_c R_act
R R_inact SB-431542
Global parameters
kin (import rate for monomeric Smads) kex (export rate for monomeric Smads) kphos (phosphorylation rate) kdephos (dephosphorylation rate)
kin*CIF (Complex import rate) kon (Smad complex on-rate) koff (Smad complex off-rate) CIF (complex import factor)
Kdiss (dissociation constant of Smad complexes) kon_SB (on-rate of the SB/receptor interaction) koff_SB (off-rate of the SB/receptor interaction) k_TGFb (rate of TGFb binding to receptors)
Kdiss SB (dissociation constant of the SB/receptor interaction) quantity to number factor SB conc at start SB conc after addition
time of SB addition      
Reactions (26)
 
 Reaction 7 Shuttling S4 [Smad4_c] ↔ [Smad4_n];  
 
 Reaction 5A Shuttling S2 [Smad2_c] ↔ [Smad2_n];  
 
 Reaction 6A Shuttling pS2 [pSmad2_c] ↔ [pSmad2_n];  
 
 Reaction 2A Phosphorylation S2 [R_act] + [Smad2_c] → [R_act] + [pSmad2_c];  
 
 Reaction 3A Formation S24_C [pSmad2_c] + [Smad4_c] ↔ [pSmad2/Smad4_c];  
 
 Reaction 3B Formation S24_N [pSmad2_n] + [Smad4_n] ↔ [pSmad2/Smad4_n];  
 
 Reaction 8A Import S24 [pSmad2/Smad4_c] → [pSmad2/Smad4_n];  
 
 Reaction 9A Import S22 [pSmad2/pSmad2_c] → [pSmad2/pSmad2_n];  
 
 Reaction 4A Formation S22_C 2.0 × [pSmad2_c] ↔ [pSmad2/pSmad2_c];  
 
 Reaction 4B Formation S22_N 2.0 × [pSmad2_n] ↔ [pSmad2/pSmad2_n];  
 
 Reaction 10A Dephos pS2 Nuc [pSmad2_n] + [PPase] → [Smad2_n] + [PPase];  
 
 Reaction 1 TGFb Binding [R] + [TGFb_c] → [R_act];  
 
 Reaction 11 Receptor Inhibition [R_act] + [SB-431542] ↔ [R_inact];  
 
 Reaction 2B Phosphorylation GS2 [GFP-Smad2_c] + [R_act] → [pGFP-Smad2_c] + [R_act];  
 
 Reaction 10B Dephos pG Nuc [pGFP-Smad2_n] + [PPase] → [GFP-Smad2_n] + [PPase];  
 
 Reaction 5B Shuttling G [GFP-Smad2_c] ↔ [GFP-Smad2_n];  
 
 Reaction 6B Shuttling pG [pGFP-Smad2_c] ↔ [pGFP-Smad2_n];  
 
 Reaction 4E Formation GG_C 2.0 × [pGFP-Smad2_c] ↔ [pGFP-Smad2/pGFP-Smad2_c];  
 
 Reaction 4F Formation GG_N 2.0 × [pGFP-Smad2_n] ↔ [pGFP-Smad2/pGFP_Smad2_n];  
 
 Reaction 4C Formation G2_C [pSmad2_c] + [pGFP-Smad2_c] ↔ [pGFP-Smad2/pSmad2_c];  
 
 Reaction 4D Formation G2_N [pSmad2_n] + [pGFP-Smad2_n] ↔ [pGFP-Smad2/pSmad2_n];  
 
 Reaction 3C Formation G4_C [pGFP-Smad2_c] + [Smad4_c] ↔ [pGFP-Smad2/Smad4_c];  
 
 Reaction 3D Formation G4_N [pGFP-Smad2_n] + [Smad4_n] ↔ [pGFP-Smad2/Smad4_n];  
 
 Reaction 9C Import GG [pGFP-Smad2/pGFP-Smad2_c] → [pGFP-Smad2/pGFP_Smad2_n];  
 
 Reaction 9B Import G2 [pGFP-Smad2/pSmad2_c] → [pGFP-Smad2/pSmad2_n];  
 
 Reaction 8B Import G4 [pGFP-Smad2/Smad4_c] → [pGFP-Smad2/Smad4_n];  
 
Rules (4)
 
 Assignment Rule (name: CIF) CIF (complex import factor) = kin_CIF/kin
 
 Assignment Rule (name: K_diss) Kdiss (dissociation constant of Smad complexes) = koff/kon
 
 Assignment Rule (name: K_dissSB) Kdiss SB (dissociation constant of the SB/receptor interaction) = koff_SB/kon_SB
 
 Assignment Rule (name: SB) SB-431542 = piecewise(SB_add, time > t_SB, SB_0)
 
 Nuc Spatial dimensions: 3.0  Compartment size: 1.0E-12
 
 PPase
Compartment: Nuc
Initial concentration: 1.0
Constant
 
 Smad2_n
Compartment: Nuc
Initial concentration: 28.514773357617
 
 pSmad2_n
Compartment: Nuc
Initial concentration: 0.0
 
 GFP-Smad2_n
Compartment: Nuc
Initial concentration: 28.514773357617
 
 pGFP-Smad2_n
Compartment: Nuc
Initial concentration: 0.0
 
 pSmad2/pSmad2_n
Compartment: Nuc
Initial concentration: 0.0
 
 pSmad2/Smad4_n
Compartment: Nuc
Initial concentration: 0.0
 
 Smad4_n
Compartment: Nuc
Initial concentration: 50.78093897
 
 pGFP-Smad2/pSmad2_n
Compartment: Nuc
Initial concentration: 0.0
 
 pGFP-Smad2/Smad4_n
Compartment: Nuc
Initial concentration: 0.0
 
 pGFP-Smad2/pGFP_Smad2_n
Compartment: Nuc
Initial concentration: 0.0
 
 Cyt Spatial dimensions: 3.0  Compartment size: 2.27E-12
 
 pSmad2/pSmad2_c
Compartment: Cyt
Initial concentration: 0.0
 
 pSmad2/Smad4_c
Compartment: Cyt
Initial concentration: 0.0
 
 Smad4_c
Compartment: Cyt
Initial concentration: 50.78103407
 
 Smad2_c
Compartment: Cyt
Initial concentration: 60.5899176013587
 
 pSmad2_c
Compartment: Cyt
Initial concentration: 0.0
 
 GFP-Smad2_c
Compartment: Cyt
Initial concentration: 60.5899176013587
 
 pGFP-Smad2_c
Compartment: Cyt
Initial concentration: 0.0
 
 pGFP-Smad2/pSmad2_c
Compartment: Cyt
Initial concentration: 0.0
 
 pGFP-Smad2/Smad4_c
Compartment: Cyt
Initial concentration: 0.0
 
 pGFP-Smad2/pGFP-Smad2_c
Compartment: Cyt
Initial concentration: 0.0
 
 TGFb_c
Compartment: Cyt
Initial concentration: 0.0659999824780232
Constant
 
 R_act
Compartment: Cyt
Initial concentration: 0.0
 
 R
Compartment: Cyt
Initial concentration: 1.0
 
 R_inact
Compartment: Cyt
Initial concentration: 0.0
 
  SB-431542
Compartment: Cyt
Initial concentration: 0.0
 
Global Parameters (17)
 
   kin (import rate for monomeric Smads)
Value: 5.93E-15   (Units: litrepersecond)
Constant
 
   kex (export rate for monomeric Smads)
Value: 1.26E-14   (Units: litrepersecond)
Constant
 
   kphos (phosphorylation rate)
Value: 4.037081673984E-4   (Units: pernMpersecond)
Constant
 
   kdephos (dephosphorylation rate)
Value: 0.00656639   (Units: pernMpersecond)
Constant
 
   kin*CIF (Complex import rate)
Value: 3.36347821E-14   (Units: litrepersecond)
Constant
 
   kon (Smad complex on-rate)
Value: 0.00183925592901392   (Units: pernMpersecond)
Constant
 
   koff (Smad complex off-rate)
Value: 0.016   (Units: persecond)
Constant
 
   CIF (complex import factor)
Value: 5.67197   (Units: dimensionless)
 
   Kdiss (dissociation constant of Smad complexes)
Value: 8.69917   (Units: nM)
 
   kon_SB (on-rate of the SB/receptor interaction)
Value: 0.146422317103884   (Units: pernMpersecond)
Constant
 
   koff_SB (off-rate of the SB/receptor interaction)
Value: 100.0   (Units: persecond)
Constant
 
   k_TGFb (rate of TGFb binding to receptors)
Value: 0.07423555020288   (Units: pernMpersecond)
Constant
 
   Kdiss SB (dissociation constant of the SB/receptor interaction)
Value: 682.956   (Units: nM)
 
   quantity to number factor
Value: 6.0221415E14   (Units: dimensionless)
Constant
 
   SB conc at start
Constant
 
   SB conc after addition
Value: 10000.0   (Units: nM)
Constant
 
   time of SB addition
Value: 2700.0   (Units: Predefined unit time)
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000173

Curator's comment: (updated: 21 May 2008 15:47:00 BST)

reproduction of fig 5 A in the paper
the time was rescaled to minutes and some concentrations needed to be summed up, as indicated in the model notes
the integraton was done using SBMlodeSolver-20080507

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