Axin inhibits extracellular signal-regulated kinase pathway by ras degradation via β-catenin

Hoo Jeon Soung, Ju Yong Yoon, Young Nyun Park, Woo Jeong Jeong, Sewoon Kim, Eek Hoon Jho, Young Joon Surh, Kang Yell Choi

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Abstract

Interactions between the Wnt/β-catenin and the extracellular signal-regulated kinase (ERK) pathways have been posited, but the molecular mechanisms and cooperative roles of such interaction in carcinogenesis are poorly understood. In the present study, the Raf-1, MEK, and ERK activities were concomitantly decreased in fibroblasts, which inhibit morphological transformation and proliferation by Axin induction. The inhibition of the components of the ERK pathway by Axin occurred in cells retaining wild-type β-catenin, including primary hepatocytes, but not in cells retaining non-degradable mutant β-catenin. Axin inhibits cellular proliferation and ERK pathway activation induced by either epidermal growth factor or Ras, indicating a role of Axin in the regulation of growth induced by ERK pathway activation. ERK pathway regulation by Axin occurs at least partly via reduction of the protein level of Ras. Both wild-type and mutant Ras proteins are subjected to regulation by Axin, which occurs in cells retaining wild-type but not mutant β-catenin gene. The role of β-catenin in the regulation of the Ras-ERK pathway was further confirmed by Ras reduction and subsequent inhibitions of the ERK pathway components by knock down of mutated form of β-catenin. The Ras regulation by Axin was blocked by treatment of leupeptin, an inhibitor of the lysosomal protein degradation machinery. Overall, Axin inhibits proliferation of cells at least partly by reduction of Ras protein level via β-catenin. This study provides evidences for the role of the Ras-ERK pathway in carcinogenesis caused by mutations of the Wnt/β-catenin pathway components.

Original languageEnglish
Pages (from-to)14482-14492
Number of pages11
JournalJournal of Biological Chemistry
Volume282
Issue number19
DOIs
Publication statusPublished - 2007 May 11

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Soung, H. J., Yoon, J. Y., Park, Y. N., Jeong, W. J., Kim, S., Jho, E. H., Surh, Y. J., & Choi, K. Y. (2007). Axin inhibits extracellular signal-regulated kinase pathway by ras degradation via β-catenin. Journal of Biological Chemistry, 282(19), 14482-14492. https://doi.org/10.1074/jbc.M611129200