Kim2007 - Crosstalk between Wnt and ERK pathways

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Short description
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).

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Format
SBML (L2V4)
Related Publication
  • A hidden oncogenic positive feedback loop caused by crosstalk between Wnt and ERK pathways.
  • Kim D, Rath O, Kolch W, Cho KH
  • Oncogene , 7/ 2007 , Volume 26 , pages: 4571-4579
  • College of Medicine, Seoul National University, Jongno-gu, Seoul, Korea.
  • 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.
Contributors
Harish Dharuri

Metadata information

is
BioModels Database MODEL4159212701
BioModels Database BIOMD0000000149
isDescribedBy
PubMed 17237813
hasTaxon
Taxonomy Homo sapiens
isDerivedFrom
hasVersion
Human Disease Ontology colorectal cancer
occursIn
Brenda Tissue Ontology HEK-293 cell
Curation status
Curated
  • Model originally submitted by : Harish Dharuri
  • Submitted: Sep 7, 2007 8:16:04 AM
  • Last Modified: Oct 22, 2014 1:15:45 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Oct 22, 2014 1:15:45 PM
    • Submitted by: Harish Dharuri
    • With comment: Current version of Kim2007 - Crosstalk between Wnt and ERK pathways
  • Version: 1 public model Download this version
    • Submitted on: Sep 7, 2007 8:16:04 AM
    • Submitted by: Harish Dharuri
    • With comment: Original import of Kim2007_Wnt_ERK_Crosstalk
Curator's comment:
(added: 31 Jul 2013, 14:01:12, updated: 31 Jul 2013, 14:01:12)
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.