Original Article

Oncogene (2007) 26, 4571–4579; doi:10.1038/sj.onc.1210230; published online 22 January 2007

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

D Kim1,5, O Rath2,5, W Kolch2,3 and K-H Cho1,4

  1. 1College of Medicine, Seoul National University, Jongno-gu, Seoul, Korea
  2. 2Beatson Institute for Cancer Research, Glasgow, UK
  3. 3Institute of Biomedical and Life Science, University of Glasgow, Glasgow, UK
  4. 4Bio-MAX Institute, Seoul National University, Gwanak-gu, Seoul, Korea

Correspondence: Professor K-H Cho, Bio-MAX Institute, Seoul National University, 3rd Floor, IVI, San 4-8, Bongcheon 7-dong, Gwanak-gu, Seoul, 151-818, Republic of Korea. E-mail: ckh-sb@snu.ac.kr; Web address: http://systemsbiology.snu.ac.kr; W Kolch, The Beatson Institute for Cancer Research, Switchback Road, Garscube Estate, Glasgow G61 1BD, UK. E-mail: w.kolch@beatson.gla.ac.uk

5These authors contributed equally to this study.

Received 3 March 2006; Revised 1 November 2006; Accepted 22 November 2006; Published online 22 January 2007.

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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.

Keywords:

signaling pathways, crosstalk, positive feedback loop, Wnt pathway, ERK pathway, colorectal cancer

Abbreviations:

APC, adenomatous polyposis coli; Dsh, dishevelled; EGFR, epidermal growth factor receptor; ERK, extracellular signal related-kinase; GSK-3beta, glycogen synthase kinase 3beta; 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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