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  • Original Article
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A hidden oncogenic positive feedback loop caused by crosstalk between Wnt and ERK Pathways

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 β-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.

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Abbreviations

APC:

adenomatous polyposis coli

Dsh:

dishevelled

EGFR:

epidermal growth factor receptor

ERK:

extracellular signal related-kinase

GSK-3β:

glycogen synthase kinase 3β

MKP:

MAP kinase phosphatase

PP1:

protein phosphatase 1

PP2A:

protein phosphatase 2A

RKIP:

Raf-1 kinase inhibitor protein

TCF:

T-cell factor

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Acknowledgements

This work was supported by a Grant 2005-B0000002 from the Korea Bio-Hub Program of Korea Ministry of Commerce, Industry & Energy, by a grant from the Korea Ministry of Science and Technology (Korean Systems Biology Research Grant, M10503010001-05N030100111), by the 21C Frontier Microbial Genomics and Application Center Program, Ministry of Science & Technology (Grant MG05-0204-3-0), Republic of Korea, and by the European Union FP6 project ‘Computational Systems Biology of Cell Signalling’ (LSHG-CT-2004-512060) and Cancer Research UK. D Kim and K-H Cho were supported by the second stage Brain Korea 21 Project in 2006.

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Correspondence to W Kolch or K-H Cho.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Kim, D., Rath, O., Kolch, W. et al. A hidden oncogenic positive feedback loop caused by crosstalk between Wnt and ERK Pathways. Oncogene 26, 4571–4579 (2007). https://doi.org/10.1038/sj.onc.1210230

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