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BIOMD0000000270 - Schilling2009 - ERK distributive

 

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Reference Publication
Publication ID: 20029368
Schilling M, Maiwald T, Hengl S, Winter D, Kreutz C, Kolch W, Lehmann WD, Timmer J, Klingmüller U.
Theoretical and experimental analysis links isoform-specific ERK signalling to cell fate decisions.
Mol. Syst. Biol. 2009; 5: 334
Division Systems Biology of Signal Transduction, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.  [more]
Model
Original Model: BIOMD0000000270.origin
Submitter: Marcel Schilling
Submission ID: MODEL1001120000
Submission Date: 12 Jan 2010 10:09:07 UTC
Last Modification Date: 23 Apr 2015 17:04:31 UTC
Creation Date: 27 Oct 2010 16:50:24 UTC
Encoders:  Lukas Endler
   Marcel Schilling
set #1
bqbiol:occursIn Brenda Tissue Ontology erythroblast
bqbiol:hasTaxon Taxonomy Mus musculus
bqbiol:hasVersion Gene Ontology MAPK cascade
Gene Ontology erythropoietin receptor activity
Gene Ontology cytokine-mediated signaling pathway
set #2
bqbiol:hasVersion KEGG Pathway MAPK signaling pathway - Mus musculus (mouse)
KEGG Pathway Jak-STAT signaling pathway - Mus musculus (mouse)
Notes
Schilling2009 - ERK distributive

This model has been exported from PottersWheel on 2009-04-20 18:57:44.  The PottersWheel Model Definition file can be obtained from the curation tab.

This model is described in the article:

Schilling M, Maiwald T, Hengl S, Winter D, Kreutz C, Kolch W, Lehmann WD, Timmer J, Klingmüller U.
Mol. Syst. Biol. 2009; 5: 334

Abstract:

Cell fate decisions are regulated by the coordinated activation of signalling pathways such as the extracellular signal-regulated kinase (ERK) cascade, but contributions of individual kinase isoforms are mostly unknown. By combining quantitative data from erythropoietin-induced pathway activation in primary erythroid progenitor (colony-forming unit erythroid stage, CFU-E) cells with mathematical modelling, we predicted and experimentally confirmed a distributive ERK phosphorylation mechanism in CFU-E cells. Model analysis showed bow-tie-shaped signal processing and inherently transient signalling for cytokine-induced ERK signalling. Sensitivity analysis predicted that, through a feedback-mediated process, increasing one ERK isoform reduces activation of the other isoform, which was verified by protein over-expression. We calculated ERK activation for biochemically not addressable but physiologically relevant ligand concentrations showing that double-phosphorylated ERK1 attenuates proliferation beyond a certain activation level, whereas activated ERK2 enhances proliferation with saturation kinetics. Thus, we provide a quantitative link between earlier unobservable signalling dynamics and cell fate decisions.

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: 20029368 Submission Date: 12 Jan 2010 10:09:07 UTC Last Modification Date: 23 Apr 2015 17:04:31 UTC Creation Date: 27 Oct 2010 16:50:24 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_27 reaction_28
reaction_29 reaction_30 reaction_31 reaction_32
reaction_33 reaction_34 reaction_35 reaction_36
reaction_37 reaction_38 reaction_39 reaction_40
reaction_41 reaction_42    
Rules
Assignment Rule (variable: rescaled_pEpoR) Assignment Rule (variable: rescaled_pJAK2) Assignment Rule (variable: rescaled_ppERK1) Assignment Rule (variable: rescaled_ppERK2)
Assignment Rule (variable: rescaled_ppMEK1) Assignment Rule (variable: rescaled_ppMEK2) Assignment Rule (variable: rescaled_pSOS) Assignment Rule (variable: rescaled_SOS)
Assignment Rule (variable: rescaled_mSOS)      
Physical entities
Compartments Species
cell JAK2 EpoR SHP1
SOS Raf MEK2
MEK1 ERK1 ERK2
pJAK2 pEpoR mSHP1
actSHP1 mSOS pRaf
ppMEK2 ppMEK1 ppERK1
ppERK2 pSOS pMEK2
pMEK1 pERK1 pERK2
Delay01_mSHP1 Delay02_mSHP1 Delay03_mSHP1
Delay04_mSHP1 Delay05_mSHP1 Delay06_mSHP1
Delay07_mSHP1 Delay08_mSHP1 Epo
Global parameters
JAK2_phosphorylation_by_Epo EpoR_phosphorylation_by_pJAK2 SHP1_activation_by_pEpoR SHP1_delay
actSHP1_deactivation pEpoR_dephosphorylation_by_actSHP1 pJAK2_dephosphorylation_by_actSHP1 SOS_recruitment_by_pEpoR
mSOS_release_from_membrane mSOS_induced_Raf_phosphorylation pRaf_dephosphorylation First_MEK2_phosphorylation_by_pRaf
Second_MEK2_phosphorylation_by_pRaf First_MEK1_phosphorylation_by_pRaf Second_MEK1_phosphorylation_by_pRaf First_MEK_dephosphorylation
Second_MEK_dephosphorylation First_ERK1_phosphorylation_by_ppMEK Second_ERK1_phosphorylation_by_ppMEK First_ERK2_phosphorylation_by_ppMEK
Second_ERK2_phosphorylation_by_ppMEK First_ERK_dephosphorylation Second_ERK_dephosphorylation ppERK_neg_feedback_on_mSOS
pSOS_dephosphorylation scale_pEpoR scale_pJAK2 scale_ppERK
scale_SOS scale_ppMEK rescaled_pEpoR rescaled_ppMEK1
rescaled_ppMEK2 rescaled_ppERK1 rescaled_ppERK2 rescaled_pJAK2
rescaled_pSOS rescaled_SOS rescaled_mSOS  
Reactions (42)
 
 reaction_1 [JAK2] → [pJAK2];   {Epo}
 
 reaction_2 [EpoR] → [pEpoR];   {pJAK2}
 
 reaction_3 [SHP1] → [mSHP1];   {pEpoR}
 
 reaction_4 [mSHP1] → [Delay01_mSHP1];  
 
 reaction_5 [Delay01_mSHP1] → [Delay02_mSHP1];  
 
 reaction_6 [Delay02_mSHP1] → [Delay03_mSHP1];  
 
 reaction_7 [Delay03_mSHP1] → [Delay04_mSHP1];  
 
 reaction_8 [Delay04_mSHP1] → [Delay05_mSHP1];  
 
 reaction_9 [Delay05_mSHP1] → [Delay06_mSHP1];  
 
 reaction_10 [Delay06_mSHP1] → [Delay07_mSHP1];  
 
 reaction_11 [Delay07_mSHP1] → [Delay08_mSHP1];  
 
 reaction_12 [Delay08_mSHP1] → [actSHP1];  
 
 reaction_13 [actSHP1] → [SHP1];  
 
 reaction_14 [pEpoR] → [EpoR];   {actSHP1}
 
 reaction_15 [pJAK2] → [JAK2];   {actSHP1}
 
 reaction_16 [SOS] → [mSOS];   {pEpoR}
 
 reaction_17 [mSOS] → [SOS];  
 
 reaction_18 [Raf] → [pRaf];   {mSOS}
 
 reaction_19 [pRaf] → [Raf];  
 
 reaction_20 [MEK2] → [pMEK2];   {pRaf}
 
 reaction_21 [MEK1] → [pMEK1];   {pRaf}
 
 reaction_22 [pMEK2] → [ppMEK2];   {pRaf}
 
 reaction_23 [pMEK1] → [ppMEK1];   {pRaf}
 
 reaction_24 [ppMEK2] → [pMEK2];  
 
 reaction_25 [ppMEK1] → [pMEK1];  
 
 reaction_26 [pMEK2] → [MEK2];  
 
 reaction_27 [pMEK1] → [MEK1];  
 
 reaction_28 [ERK1] → [pERK1];   {ppMEK2}
 
 reaction_29 [ERK2] → [pERK2];   {ppMEK2}
 
 reaction_30 [ERK1] → [pERK1];   {ppMEK1}
 
 reaction_31 [ERK2] → [pERK2];   {ppMEK1}
 
 reaction_32 [pERK1] → [ppERK1];   {ppMEK2}
 
 reaction_33 [pERK2] → [ppERK2];   {ppMEK2}
 
 reaction_34 [pERK1] → [ppERK1];   {ppMEK1}
 
 reaction_35 [pERK2] → [ppERK2];   {ppMEK1}
 
 reaction_36 [ppERK1] → [pERK1];  
 
 reaction_37 [ppERK2] → [pERK2];  
 
 reaction_38 [pERK1] → [ERK1];  
 
 reaction_39 [pERK2] → [ERK2];  
 
 reaction_40 [mSOS] → [pSOS];   {ppERK1}
 
 reaction_41 [mSOS] → [pSOS];   {ppERK2}
 
 reaction_42 [pSOS] → [SOS];  
 
Rules (9)
 
 Assignment Rule (name: rescaled_pEpoR) rescaled_pEpoR = scale_pEpoR*pEpoR
 
 Assignment Rule (name: rescaled_pJAK2) rescaled_pJAK2 = scale_pJAK2*pJAK2
 
 Assignment Rule (name: rescaled_ppERK1) rescaled_ppERK1 = scale_ppERK*ppERK1
 
 Assignment Rule (name: rescaled_ppERK2) rescaled_ppERK2 = scale_ppERK*ppERK2
 
 Assignment Rule (name: rescaled_ppMEK1) rescaled_ppMEK1 = scale_ppMEK*ppMEK1
 
 Assignment Rule (name: rescaled_ppMEK2) rescaled_ppMEK2 = scale_ppMEK*ppMEK2
 
 Assignment Rule (name: rescaled_pSOS) rescaled_pSOS = scale_SOS*pSOS
 
 Assignment Rule (name: rescaled_SOS) rescaled_SOS = scale_SOS*SOS
 
 Assignment Rule (name: rescaled_mSOS) rescaled_mSOS = scale_SOS*mSOS
 
 cell Spatial dimensions: 3.0  Compartment size: 1.0
 
 JAK2
Compartment: cell
Initial concentration: 2.0
 
 EpoR
Compartment: cell
Initial concentration: 1.0
 
 SHP1
Compartment: cell
Initial concentration: 10.7991
 
 SOS
Compartment: cell
Initial concentration: 2.5101
 
 Raf
Compartment: cell
Initial concentration: 3.7719
 
 MEK2
Compartment: cell
Initial concentration: 11.0
 
 MEK1
Compartment: cell
Initial concentration: 24.0
 
 ERK1
Compartment: cell
Initial concentration: 7.0
 
 ERK2
Compartment: cell
Initial concentration: 21.0
 
 pJAK2
Compartment: cell
Initial concentration: 0.0
 
 pEpoR
Compartment: cell
Initial concentration: 0.0
 
 mSHP1
Compartment: cell
Initial concentration: 0.0
 
 actSHP1
Compartment: cell
Initial concentration: 0.0
 
 mSOS
Compartment: cell
Initial concentration: 0.0
 
 pRaf
Compartment: cell
Initial concentration: 0.0
 
 ppMEK2
Compartment: cell
Initial concentration: 0.0
 
 ppMEK1
Compartment: cell
Initial concentration: 0.0
 
 ppERK1
Compartment: cell
Initial concentration: 0.0
 
 ppERK2
Compartment: cell
Initial concentration: 0.0
 
 pSOS
Compartment: cell
Initial concentration: 0.0
 
 pMEK2
Compartment: cell
Initial concentration: 0.0
 
 pMEK1
Compartment: cell
Initial concentration: 0.0
 
 pERK1
Compartment: cell
Initial concentration: 0.0
 
 pERK2
Compartment: cell
Initial concentration: 0.0
 
 Delay01_mSHP1
Compartment: cell
Initial concentration: 0.0
 
 Delay02_mSHP1
Compartment: cell
Initial concentration: 0.0
 
 Delay03_mSHP1
Compartment: cell
Initial concentration: 0.0
 
 Delay04_mSHP1
Compartment: cell
Initial concentration: 0.0
 
 Delay05_mSHP1
Compartment: cell
Initial concentration: 0.0
 
 Delay06_mSHP1
Compartment: cell
Initial concentration: 0.0
 
 Delay07_mSHP1
Compartment: cell
Initial concentration: 0.0
 
 Delay08_mSHP1
Compartment: cell
Initial concentration: 0.0
 
 Epo
Compartment: cell
Initial concentration: 50.0  (Units: U)
 
Global Parameters (39)
 
 JAK2_phosphorylation_by_Epo
Value: 0.0122149   (Units: per min per (Uml))
Constant
 
 EpoR_phosphorylation_by_pJAK2
Value: 3.15714   (Units: second order rate constant)
Constant
 
 SHP1_activation_by_pEpoR
Value: 0.408408   (Units: second order rate constant)
Constant
 
 SHP1_delay
Value: 0.408408   (Units: per minute)
Constant
 
 actSHP1_deactivation
Value: 0.0248773   (Units: per minute)
Constant
 
 pEpoR_dephosphorylation_by_actSHP1
Value: 1.19995   (Units: second order rate constant)
Constant
 
 pJAK2_dephosphorylation_by_actSHP1
Value: 0.368384   (Units: second order rate constant)
Constant
 
 SOS_recruitment_by_pEpoR
Value: 0.10271   (Units: second order rate constant)
Constant
 
 mSOS_release_from_membrane
Value: 15.5956   (Units: per minute)
Constant
 
 mSOS_induced_Raf_phosphorylation
Value: 0.144515   (Units: second order rate constant)
Constant
 
 pRaf_dephosphorylation
Value: 0.374228   (Units: per minute)
Constant
 
 First_MEK2_phosphorylation_by_pRaf
Value: 3.11919   (Units: second order rate constant)
Constant
 
 Second_MEK2_phosphorylation_by_pRaf
Value: 215.158   (Units: second order rate constant)
Constant
 
 First_MEK1_phosphorylation_by_pRaf
Value: 0.687193   (Units: second order rate constant)
Constant
 
 Second_MEK1_phosphorylation_by_pRaf
Value: 667.957   (Units: second order rate constant)
Constant
 
 First_MEK_dephosphorylation
Value: 0.130937   (Units: per minute)
Constant
 
 Second_MEK_dephosphorylation
Value: 0.0732724   (Units: per minute)
Constant
 
 First_ERK1_phosphorylation_by_ppMEK
Value: 2.4927   (Units: second order rate constant)
Constant
 
 Second_ERK1_phosphorylation_by_ppMEK
Value: 59.5251   (Units: second order rate constant)
Constant
 
 First_ERK2_phosphorylation_by_ppMEK
Value: 2.44361   (Units: second order rate constant)
Constant
 
 Second_ERK2_phosphorylation_by_ppMEK
Value: 53.0816   (Units: second order rate constant)
Constant
 
 First_ERK_dephosphorylation
Value: 39.0886   (Units: per minute)
Constant
 
 Second_ERK_dephosphorylation
Value: 3.00453   (Units: per minute)
Constant
 
 ppERK_neg_feedback_on_mSOS
Value: 5122.68   (Units: second order rate constant)
Constant
 
 pSOS_dephosphorylation
Value: 0.124944   (Units: per minute)
Constant
 
 scale_pEpoR
Value: 0.493312   (Units: arb. unit. per 10000 molecules)
Constant
 
 scale_pJAK2
Value: 0.21008   (Units: arb. unit. per 10000 molecules)
Constant
 
 scale_ppERK
Value: 13.5981   (Units: arb. unit. per 10000 molecules)
Constant
 
 scale_SOS
Value: 1.10228   (Units: arb. unit. per 10000 molecules)
Constant
 
 scale_ppMEK
Value: 40.5364   (Units: arb. unit. per 10000 molecules)
Constant
 
  rescaled_pEpoR
Value: NaN   (Units: arb. units)
 
  rescaled_ppMEK1
Value: NaN   (Units: arb. units)
 
  rescaled_ppMEK2
Value: NaN   (Units: arb. units)
 
  rescaled_ppERK1
Value: NaN   (Units: arb. units)
 
  rescaled_ppERK2
Value: NaN   (Units: arb. units)
 
  rescaled_pJAK2
Value: NaN   (Units: arb. units)
 
  rescaled_pSOS
Value: NaN   (Units: arb. units)
 
  rescaled_SOS
Value: NaN   (Units: arb. units)
 
  rescaled_mSOS
Value: NaN   (Units: arb. units)
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000270

Curator's comment: (updated: 20 Oct 2010 17:57:56 BST)

Reproduction of figure 1 B of the original publication using Copasi 4.6.
In the time-courses the rescaled concentrations in arbitrary units are shown. These values are calculated by multiplying the concentrations with the scaling factors for each protein given in supplementary figure 10 of the publication.

Additional file(s)
  • PottersWheel File:
    The original model had the PottersWheel model definition file in model notes. We have extracted and provided it here as an addition file.
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