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

Cited 60 time in Web of Science Cited 62 time in Scopus

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

Issue Date
American Society for Biochemistry and Molecular Biology Inc.
Journal of Biological Chemistry, Vol.282 No.19, pp.14482-14492
Interactions between the Wnt/beta-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 beta-catenin, including primary hepatocytes, but not in cells retaining non-degradable mutant beta-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 beta-catenin gene. The role of beta-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 beta-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 beta-catenin. This study provides evidences for the role of the Ras-ERK pathway in carcinogenesis caused by mutations of the Wnt/beta-catenin pathway components.
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  • College of Pharmacy
  • Department of Pharmacy
Research Area Agricultural Sciences


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