Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

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

Oncogene volume 26, pages 4571–4579 (2007)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

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

References

  • Aberle H, Bauer A, Stappert J, Kispert A, Kemler R . (1997). beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J 16: 3797–3804.

    Article  CAS  Google Scholar 

  • Almeida M, Han L, Bellido T, Manolagas SC, Kousteni S . (2005). Wnt proteins prevent apoptosis of both uncommitted osteoblast progenitors and differentiated osteoblasts by beta-catenin-dependent and -independent signaling cascades involving Src/ERK and phosphatidylinositol 3-kinase/AKT. J Biol Chem 280: 41342–41351.

    Article  CAS  Google Scholar 

  • Amaral MC, Casillas AM, Nel AE . (1993). Contrasting effects of two tumour promoters, phorbol myristate acetate and okadaic acid, on T-cell responses and activation of p42 MAP-kinase/ERK-2. Immunology 79: 24–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Aust DE, Haase M, Dobryden L, Markwarth A, Lohrs U, Wittekind C et al. (2005). Mutations of the BRAF gene in ulcerative colitis-related colorectal carcinoma. Int J Cancer 115: 673–677.

    Article  CAS  Google Scholar 

  • Behrens J . (2005). The role of the Wnt signalling pathway in colorectal tumorigenesis. Biochem Soc Trans 33: 672–675.

    Article  CAS  Google Scholar 

  • Behrens J, Lustig B . (2004). The Wnt connection to tumorigenesis. Int J Dev Biol 48: 477–487.

    Article  CAS  Google Scholar 

  • Casillas AM, Amaral K, Chegini-Farahani S, Nel AE . (1993). Okadaic acid activates p42 mitogen-activated protein kinase (MAP kinase; ERK-2) in B-lymphocytes but inhibits rather than augments cellular proliferation: contrast with phorbol 12-myristate 13-acetate. Biochem J 290 (Part 2): 545–550.

    Article  CAS  Google Scholar 

  • Cho KH, Baek S, Sung MH . (2006). Wnt pathway mutations selected by optimal beta-catenin signaling for tumorigenesis. FEBS Lett 580: 3665–3670.

    Article  CAS  Google Scholar 

  • Cho K-H, Shin S-Y, Kim H-W, Wolkenhauer O, McFerran B, Kolch W . (2003). Mathematical modeling of the influence of RKIP on the ERK pathway. Lecture Notes Comp Sci 2602: 127–141.

    Article  Google Scholar 

  • Civenni G, Holbro T, Hynes NE . (2003). Wnt1 and Wnt5a induce cyclin D1 expression through ErbB1 transactivation in HC11 mammary epithelial cells. EMBO Rep 4: 166–171.

    Article  CAS  Google Scholar 

  • Ding Q, Xia W, Liu JC, Yang JY, Lee DF, Xia J et al. (2005). Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol Cell 19: 159–170.

    Article  CAS  Google Scholar 

  • Downward J . (2003). Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3: 11–22.

    Article  CAS  Google Scholar 

  • Esufali S, Bapat B . (2004). Cross-talk between Rac1 GTPase and dysregulated Wnt signaling pathway leads to cellular redistribution of beta-catenin and TCF/LEF-mediated transcriptional activation. Oncogene 23: 8260–8271.

    Article  CAS  Google Scholar 

  • Fang JY, Richardson BC . (2005). The MAPK signalling pathways and colorectal cancer. Lancet Oncol 6: 322–327.

    Article  CAS  Google Scholar 

  • Ferrell Jr JE . (2002). Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability. Curr Opin Cell Biol 14: 140–148.

    Article  CAS  Google Scholar 

  • Harada N, Tamai Y, Ishikawa T, Sauer B, Takaku K, Oshima M et al. (1999). Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene. EMBO J 18: 5931–5942.

    Article  CAS  Google Scholar 

  • Kim CJ, Cho YG, Park YG, Nam SW, Kim SY, Lee SH et al. (2005). Pin1 overexpression in colorectal cancer and its correlation with aberrant beta-catenin expression. World J Gastroenterol 11: 5006–5009.

    Article  CAS  Google Scholar 

  • Kim K, Pang KM, Evans M, Hay ED . (2000). Overexpression of beta-catenin induces apoptosis independent of its transactivation function with LEF-1 or the involvement of major G1 cell cycle regulators. Mol Biol Cell 11: 3509–3523.

    Article  CAS  Google Scholar 

  • Kinzler KW, Vogelstein B . (1996). Lessons from hereditary colorectal cancer. Cell 87: 159–170.

    Article  CAS  Google Scholar 

  • Kolch W . (2005). Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol 6: 827–837.

    Article  CAS  Google Scholar 

  • Kolch W, Calder M, Gilbert D . (2005). When kinases meet mathematics: the systems biology of MAPK signalling. FEBS Lett 579: 1891–1895.

    Article  CAS  Google Scholar 

  • Kolch W, Kotwaliwale A, Vass K, Janosch P . (2002). The role of Raf kinases in malignant transformation. Expert Rev Mol Med 2002: 1–18.

    Article  Google Scholar 

  • Lee E, Salic A, Kruger R, Heinrich R, Kirschner MW . (2003). The roles of APC and Axin derived from experimental and theoretical analysis of the Wnt pathway. PLoS Biol 1: E10.

    Article  Google Scholar 

  • Loda M, Capodieci P, Mishra R, Yao H, Corless C, Grigioni W et al. (1996). Expression of mitogen-activated protein kinase phosphatase-1 in the early phases of human epithelial carcinogenesis. Am J Pathol 149: 1553–1564.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lustig B, Jerchow B, Sachs M, Weiler S, Pietsch T, Karsten U et al. (2002). Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol Cell Biol 22: 1184–1193.

    Article  CAS  Google Scholar 

  • Minoo P, Baker K, Goswami R, Chong G, Foulkes W, Ruszkiewicz A et al. (2006). Extensive DNA methylation in normal colorectal mucosa in hyperplastic polyposis. Gut 55: 1467–1474.

    Article  CAS  Google Scholar 

  • Mirabelli-Primdahl L, Gryfe R, Kim H, Millar A, Luceri C, Dale D et al. (1999). Beta-catenin mutations are specific for colorectal carcinomas with microsatellite instability but occur in endometrial carcinomas irrespective of mutator pathway. Cancer Res 59: 3346–3351.

    CAS  PubMed  Google Scholar 

  • Reya T, Clevers H . (2005). Wnt signalling in stem cells and cancer. Nature 434: 843–850.

    Article  CAS  Google Scholar 

  • Rottinger E, Besnardeau L, Lepage T . (2004). A Raf/MEK/ERK signaling pathway is required for development of the sea urchin embryo micromere lineage through phosphorylation of the transcription factor Ets. Development 131: 1075–1087.

    Article  Google Scholar 

  • Sancho E, Batlle E, Clevers H . (2003). Live and let die in the intestinal epithelium. Curr Opin Cell Biol 15: 763–770.

    Article  CAS  Google Scholar 

  • Sancho E, Batlle E, Clevers H . (2004). Signaling pathways in intestinal development and cancer. Annu Rev Cell Dev Biol 20: 695–723.

    Article  CAS  Google Scholar 

  • Takagi Y, Futamura M, Yamaguchi K, Aoki S, Takahashi T, Saji S . (2000). Alterations of the PPP2R1B gene located at 11q23 in human colorectal cancers. Gut 47: 268–271.

    Article  CAS  Google Scholar 

  • Wolkenhauer O, Sreenath SN, Wellstead P, Ullah M, Cho KH . (2005). A systems- and signal-oriented approach to intracellular dynamics. Biochem Soc Trans 33: 507–515.

    Article  CAS  Google Scholar 

  • Yan H, Dobbie Z, Gruber SB, Markowitz S, Romans K, Giardiello FM et al. (2002). Small changes in expression affect predisposition to tumorigenesis. Nat Genet 30: 25–26.

    Article  CAS  Google Scholar 

  • Yeung K, Seitz T, Li S, Janosch P, McFerran B, Kaiser C et al. (1999). Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP. Nature 401: 173–177.

    Article  CAS  Google Scholar 

  • Yun MS, Kim SE, Jeon SH, Lee JS, Choi KY . (2005). Both ERK and Wnt/beta-catenin pathways are involved in Wnt3a-induced proliferation. J Cell Sci 118: 313–322.

    Article  CAS  Google Scholar 

Download references

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.

Author information

Author notes

  1. D Kim and O Rath: These authors contributed equally to this study.

Authors and Affiliations

  1. College of Medicine, Seoul National University, Jongno-gu, Seoul, Korea

    D Kim & K-H Cho

  2. Beatson Institute for Cancer Research, Glasgow, UK

    O Rath & W Kolch

  3. Institute of Biomedical and Life Science, University of Glasgow, Glasgow, UK

    W Kolch

  4. Bio-MAX Institute, Seoul National University, Gwanak-gu, Seoul, Korea

    K-H Cho

Authors
  1. D Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. O Rath
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W Kolch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K-H Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to W Kolch or K-H Cho.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210230

Keywords

Search

Advanced search

Quick links