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BIOMD0000000149 - Kim2007 - Crosstalk between Wnt and ERK pathways

 

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Reference Publication
Publication ID: 17237813
Kim D, Rath O, Kolch W, Cho KH.
A hidden oncogenic positive feedback loop caused by crosstalk between Wnt and ERK pathways.
Oncogene 2007 Jul; 26(31): 4571-4579
College of Medicine, Seoul National University, Jongno-gu, Seoul, Korea.  [more]
Model
Original Model: BIOMD0000000149.origin
Submitter: Harish Dharuri
Submission ID: MODEL4159212701
Submission Date: 07 Sep 2007 07:16:04 UTC
Last Modification Date: 22 Oct 2014 12:15:45 UTC
Creation Date: 10 Jul 2007 13:55:45 UTC
Encoders:  Harish Dharuri
   Vijayalakshmi Chelliah
set #1
bqmodel:isDerivedFrom PubMed 14551908
DOI 10.1007/3-540-36481-1_11
set #2
bqbiol:hasPart Gene Ontology canonical Wnt signaling pathway
Gene Ontology MAPK cascade
set #3
bqbiol:hasVersion Human Disease Ontology colorectal cancer
set #4
bqbiol:hasTaxon Taxonomy Homo sapiens
bqbiol:hasPart KEGG Pathway MAPK signaling pathway - Homo sapiens (human)
KEGG Pathway Wnt signaling pathway - Homo sapiens (human)
set #5
bqbiol:occursIn Brenda Tissue Ontology HEK-293 cell
Notes
Kim2007 - Crosstalk between Wnt and ERK pathways

Experimental studies have shown that both Wnt and the MAPK pathways are involved in the pathogenesis of various kinds of cancers (eg. colorectal cancer). The crosstalk between the two pathways have also been identified. Here, Kim et al., (2007) have integrated the experimental evidences on crosstalk mechanisms between the two pathways into a pathway model, and have identified the existence of a hidden positive feedback loop and suggest that this positive feedback loop might participate in the pathogenesis of colorectal cancer.

This model is described in the article:

Kim D, Rath O, Kolch W, Cho KH.
Oncogene 2007 Jul; 26(31): 4571-4579

Abstract:

The Wnt and the extracellular signal regulated-kinase (ERK) pathways are both involved in the pathogenesis of various kinds of cancers. Recently, the existence of crosstalk between Wnt and ERK pathways was reported. Gathering all reported results, we have discovered a positive feedback loop embedded in the crosstalk between the Wnt and ERK pathways. We have developed a plausible model that represents the role of this hidden positive feedback loop in the Wnt/ERK pathway crosstalk based on the integration of experimental reports and employing established basic mathematical models of each pathway. Our analysis shows that the positive feedback loop can generate bistability in both the Wnt and ERK signaling pathways, and this prediction was further validated by experiments. In particular, using the commonly accepted assumption that mutations in signaling proteins contribute to cancerogenesis, we have found two conditions through which mutations could evoke an irreversible response leading to a sustained activation of both pathways. One condition is enhanced production of beta-catenin, the other is a reduction of the velocity of MAP kinase phosphatase(s). This enables that high activities of Wnt and ERK pathways are maintained even without a persistent extracellular signal. Thus, our study adds a novel aspect to the molecular mechanisms of carcinogenesis by showing that mutational changes in individual proteins can cause fundamental functional changes well beyond the pathway they function in by a positive feedback loop embedded in crosstalk. Thus, crosstalk between signaling pathways provides a vehicle through which mutations of individual components can affect properties of the system at a larger scale.

Figure 6 of the reference publication has been reproduced. The model as such reproduces the plots corresponding to the normal conditions. To obtain simulations under 1) beta-cataenin mutation; set V12=0.846 (two-fold of the beta-catenin synthetic rate than the normal system. i.e. 2*0.426), 2) PP2A mutation; set Vmax4=Vmax5=33.75 (three-fourths of the PP2A activity that the normal system. i.e. (3/4)*45). The simulation was performed using Copasi 4.10 (Build 55).

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: 17237813 Submission Date: 07 Sep 2007 07:16:04 UTC Last Modification Date: 22 Oct 2014 12:15:45 UTC Creation Date: 10 Jul 2007 13:55:45 UTC
Mathematical expressions
Reactions
Dishevelled activation Dishevelled inactivation Dishevelled mediated GSK/Axin/APC complex disassembly Activation of GSK/Axin/APC complex
Inactivation of GSK/Axin/APC complex GSK/Axin/APC complex reassembly Axin/APC complex formation bCatenin binding to GSK/Axin/APC complex
bCatenin phosphorylation GSK.Axin/APC/bCatenin complex disassembly Phosphorylated bCatenin degradation bCatenin synthesis
Unphosphorylated bCatenin degradation Axin synthesis Axin degradation bCatenin/TCF complex formation
APC/bCatenin complex formation Ras activation Ras inactivation Raf activation
Raf inactivation MEK activation MEK inactivation ERK activation
ERK inactivation Raf/RKIP complex disassembly Raf-RKIP complex formation RKIP dephosphorylation
Unknown factor-X formation Factor-X degradation Factor-X mediated Raf activation ERK mediated GSK3beta phosphorylation
GSK3beta dephosphorylation      
Rules
Assignment Rule (variable: X13X14)      
Events
event_0000001 event_0000002    
Physical entities
Compartments Species
cytoplasm Dshi Dsha APC_ast/Axin_ast/GSK3beta
APC/Axin/GSK3beta GSK3beta APC/Axin
APC bCatenin/APC_Ast/Axin_ast/GSK3beta bCatenin_ast/APC_ast/Axin_ast/GSK3beta
bCatenin_ast Axin bCatenin/APC
Rasi Rasa Raf-1
Raf-1_ast MEK MEK_ast
ERK ERK_ast Raf1/RKIP
RKIP RKIP_ast unknown molecule X
GSK3beta    
nucleus bCatenin TCF bCatenin/TCF
     
Global parameters
k1 W k2 k3
k4 k5 k_plus6 k_minus6
k_plus7 k_minus7 k_plus8 k_minus8
k9 k10 k11 V12
k13 k14 k21 k15
k_plus16 k_minus16 k_plus17 k_minus17
Vmax1 Km1 Ki Vmax2
Km2 kcat1 Km3 Vmax3
Km4 kcat2 Km5 Vmax4
Km6 kcat3 Km7 Vmax5
Km8 kcat4 Km9 k18
k19 Vmax6 Km10 kcat5
n1 Km11 k20 kcat6
Km12 kcat7 Km13 Vmax7
Km14 flag_for_wnt_signal X13X14  
Reactions (33)
 
 Dishevelled activation [Dshi] → [Dsha];  
 
 Dishevelled inactivation [Dsha] → [Dshi];  
 
 Dishevelled mediated GSK/Axin/APC complex disassembly [APC/Axin/GSK3beta] → [APC/Axin] + [GSK3beta];   {Dsha}
 
 Activation of GSK/Axin/APC complex [APC/Axin/GSK3beta] → [APC_ast/Axin_ast/GSK3beta];  
 
 Inactivation of GSK/Axin/APC complex [APC_ast/Axin_ast/GSK3beta] → [APC/Axin/GSK3beta];  
 
 GSK/Axin/APC complex reassembly [APC/Axin] + [GSK3beta] ↔ [APC/Axin/GSK3beta];  
 
 Axin/APC complex formation [Axin] + [APC] ↔ [APC/Axin];  
 
 bCatenin binding to GSK/Axin/APC complex [bCatenin] + [APC_ast/Axin_ast/GSK3beta] ↔ [bCatenin/APC_Ast/Axin_ast/GSK3beta];  
 
 bCatenin phosphorylation [bCatenin/APC_Ast/Axin_ast/GSK3beta] → [bCatenin_ast/APC_ast/Axin_ast/GSK3beta];  
 
 GSK.Axin/APC/bCatenin complex disassembly [bCatenin_ast/APC_ast/Axin_ast/GSK3beta] → [APC_ast/Axin_ast/GSK3beta] + [bCatenin_ast];  
 
 Phosphorylated bCatenin degradation [bCatenin_ast] → ;  
 
 bCatenin synthesis  → [bCatenin];  
 
 Unphosphorylated bCatenin degradation [bCatenin] → ;  
 
 Axin synthesis  → [Axin];   {bCatenin} , {bCatenin/TCF}
 
 Axin degradation [Axin] → ;  
 
 bCatenin/TCF complex formation [TCF] + [bCatenin] ↔ [bCatenin/TCF];  
 
 APC/bCatenin complex formation [bCatenin] + [APC] ↔ [bCatenin/APC];  
 
 Ras activation [Rasi] → [Rasa];   {ERK_ast}
 
 Ras inactivation [Rasa] → [Rasi];  
 
 Raf activation [Raf-1] → [Raf-1_ast];   {Rasa}
 
 Raf inactivation [Raf-1_ast] → [Raf-1];  
 
 MEK activation [MEK] → [MEK_ast];   {Raf-1_ast}
 
 MEK inactivation [MEK_ast] → [MEK];  
 
 ERK activation [ERK] → [ERK_ast];   {MEK_ast}
 
 ERK inactivation [ERK_ast] → [ERK];  
 
 Raf/RKIP complex disassembly [Raf1/RKIP] → [Raf-1] + [RKIP_ast];   {ERK_ast}
 
 Raf-RKIP complex formation [Raf-1] + [RKIP] ↔ [Raf1/RKIP];  
 
 RKIP dephosphorylation [RKIP_ast] → [RKIP];  
 
 Unknown factor-X formation  → [unknown molecule X];   {bCatenin/TCF}
 
 Factor-X degradation [unknown molecule X] → ;  
 
 Factor-X mediated Raf activation [Raf-1] → [Raf-1_ast];   {unknown molecule X}
 
 ERK mediated GSK3beta phosphorylation [GSK3beta] → [GSK3beta];   {ERK_ast}
 
 GSK3beta dephosphorylation [GSK3beta] → [GSK3beta];  
 
Rules (1)
 
 Assignment Rule (name: X13X14) X13X14 = X13+X14
 
Events (2)
 
 event_0000001
W = 1
 
 event_0000002
W = 0
 
 cytoplasm Spatial dimensions: 3.0  Compartment size: 1.0
 
 Dshi
Compartment: cytoplasm
Initial concentration: 100.0
 
 Dsha
Compartment: cytoplasm
Initial concentration: 0.0
 
 APC_ast/Axin_ast/GSK3beta
Compartment: cytoplasm
Initial concentration: 0.0153
 
 APC/Axin/GSK3beta
Compartment: cytoplasm
Initial concentration: 0.0076
 
 GSK3beta
Compartment: cytoplasm
Initial concentration: 49.1372
 
 APC/Axin
Compartment: cytoplasm
Initial concentration: 0.0015
 
 APC
Compartment: cytoplasm
Initial concentration: 96.6019
 
 bCatenin/APC_Ast/Axin_ast/GSK3beta
Compartment: cytoplasm
Initial concentration: 0.0020
 
 bCatenin_ast/APC_ast/Axin_ast/GSK3beta
Compartment: cytoplasm
Initial concentration: 0.0020
 
 bCatenin_ast
Compartment: cytoplasm
Initial concentration: 0.9881
 
 Axin
Compartment: cytoplasm
Initial concentration: 8.0E-4
 
 bCatenin/APC
Compartment: cytoplasm
Initial concentration: 3.4392
 
 Rasi
Compartment: cytoplasm
Initial concentration: 200.0
 
 Rasa
Compartment: cytoplasm
Initial concentration: 0.0
 
 Raf-1
Compartment: cytoplasm
Initial concentration: 112.5585
 
 Raf-1_ast
Compartment: cytoplasm
Initial concentration: 6.486
 
 MEK
Compartment: cytoplasm
Initial concentration: 296.1137
 
 MEK_ast
Compartment: cytoplasm
Initial concentration: 3.8863
 
 ERK
Compartment: cytoplasm
Initial concentration: 297.8897
 
 ERK_ast
Compartment: cytoplasm
Initial concentration: 2.1103
 
 Raf1/RKIP
Compartment: cytoplasm
Initial concentration: 180.9595
 
 RKIP
Compartment: cytoplasm
Initial concentration: 418.1788
 
 RKIP_ast
Compartment: cytoplasm
Initial concentration: 0.8619
 
   unknown molecule X
Compartment: cytoplasm
Initial concentration: 10.263
 
 GSK3beta
Compartment: cytoplasm
Initial concentration: 0.85544
 
 nucleus Spatial dimensions: 3.0  Compartment size: 1.0
 
 bCatenin
Compartment: nucleus
Initial concentration: 42.7224
 
 TCF
Compartment: nucleus
Initial concentration: 6.1879
 
 bCatenin/TCF
Compartment: nucleus
Initial concentration: 8.8121
 
Global Parameters (59)
 
   k1
Value: 0.182
Constant
 
   W  
 
   k2
Value: 0.0182
Constant
 
   k3
Value: 0.05
Constant
 
   k4
Value: 0.267
Constant
 
   k5
Value: 0.133
Constant
 
   k_plus6
Value: 0.0909
Constant
 
   k_minus6
Value: 0.909
Constant
 
   k_plus7
Value: 1.0
Constant
 
   k_minus7
Value: 50.0
Constant
 
   k_plus8
Value: 1.0
Constant
 
   k_minus8
Value: 120.0
Constant
 
   k9
Value: 206.0
Constant
 
   k10
Value: 206.0
Constant
 
   k11
Value: 0.417
Constant
 
   V12
Value: 0.423
Constant
 
   k13
Value: 2.57E-4
Constant
 
   k14
Value: 8.22E-5
Constant
 
   k21
Value: 1.0E-6
Constant
 
   k15
Value: 0.167
Constant
 
   k_plus16
Value: 1.0
Constant
 
   k_minus16
Value: 30.0
Constant
 
   k_plus17
Value: 1.0
Constant
 
   k_minus17
Value: 1200.0
Constant
 
   Vmax1
Value: 150.0
Constant
 
   Km1
Value: 10.0
Constant
 
   Ki
Value: 9.0
Constant
 
   Vmax2
Value: 15.0
Constant
 
   Km2
Value: 8.0
Constant
 
   kcat1
Value: 1.5
Constant
 
   Km3
Value: 15.0
Constant
 
   Vmax3
Value: 45.0
Constant
 
   Km4
Value: 15.0
Constant
 
   kcat2
Value: 1.5
Constant
 
   Km5
Value: 15.0
Constant
 
   Vmax4
Value: 45.0
Constant
 
   Km6
Value: 15.0
Constant
 
   kcat3
Value: 1.5
Constant
 
   Km7
Value: 15.0
Constant
 
   Vmax5
Value: 45.0
Constant
 
   Km8
Value: 15.0
Constant
 
   kcat4
Value: 1.5
Constant
 
   Km9
Value: 9.0
Constant
 
   k18
Value: 0.15
Constant
 
   k19
Value: 39.0
Constant
 
   Vmax6
Value: 45.0
Constant
 
   Km10
Value: 12.0
Constant
 
   kcat5
Value: 0.6
Constant
 
   n1
Value: 2.0
Constant
 
   Km11
Value: 15.0
Constant
 
   k20
Value: 0.015
Constant
 
   kcat6
Value: 1.5
Constant
 
   Km12
Value: 15.0
Constant
 
   kcat7
Value: 1.5
Constant
 
   Km13
Value: 15.0
Constant
 
   Vmax7
Value: 45.0
Constant
 
   Km14
Value: 15.0
Constant
 
   flag_for_wnt_signal  
 
   X13X14  
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000149

Curator's comment: (updated: 31 Jul 2013 14:01:12 BST)

Figure 6 of the reference publication has been reproduced. The model as such reproduces the plots corresponding to the normal conditions. To obtain simulations under 1) beta-cataenin mutation; set V12=0.846 (two-fold of the beta-catenin synthetic rate than the normal system. i.e. 2*0.423), 2) PP2A mutation; set Vmax4=Vmax5=33.75 (three-fourths of the PP2A activity that the normal system. i.e. (3/4)*45). The simulations were performed using Copasi 4.10 (Build 55) and the plots were obtained using Gnuplot.

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