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J. Biol. Chem., Vol. 282, Issue 19, 14482-14492, May 11, 2007

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Axin Inhibits Extracellular Signal-regulated Kinase Pathway by Ras Degradation via -Catenin^*

Soung Hoo Jeon, Ju-Yong Yoon¹, Young-Nyun Park, Woo-Jeong Jeong¹, Sewoon Kim^¶, Eek-Hoon Jho^¶, Young-Joon Surh^||, and Kang-Yell Choi²

From the National Research Laboratory of Molecular Complex Control, and Department of Biotechnology, Yonsei University, Seoul 120-749, the Department of Pathology, Center for Chronic Metabolic Disease, BK21 project for Medical Science, Yonsei University College of Medicine, Seoul 120-749, the ^¶Department of Life Science, University of Seoul, Seoul 130-743, and the ^||Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-ku, Seoul 151-742, Korea

Interactions between the Wnt/-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 -catenin, including primary hepatocytes, but not in cells retaining non-degradable mutant -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 -catenin gene. The role of -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 -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 -catenin. This study provides evidences for the role of the Ras-ERK pathway in carcinogenesis caused by mutations of the Wnt/-catenin pathway components.

Received for publication, December 5, 2006 , and in revised form, March 6, 2007.

^* This work was supported in part by a National Research Laboratory Grant from the Korea Science and Engineering Foundation (KOSEF) and by the Korea government (MOST) (Grants 2005-01564, 2006-02681, and R112000078010020). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental text and Figs. S1 and S2.

¹ Supported by a BK21 studentship from the ministry of education and human resources development.

² To whom correspondence should be addressed: Tel.: 82-2-2123-2887; Fax: 82-2-362-7265; E-mail: kychoi{at}yonsei.ac.kr.

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