Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
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
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
Abstract:
Interactions between the Wnt/-catenin and the extracellularsignal-regulated kinase (ERK) pathways have been posited, butthe molecular mechanisms and cooperative roles of such interactionin carcinogenesis are poorly understood. In the present study,the Raf-1, MEK, and ERK activities were concomitantly decreasedin fibroblasts, which inhibit morphological transformation andproliferation by Axin induction. The inhibition of the componentsof the ERK pathway by Axin occurred in cells retaining wild-type-catenin, including primary hepatocytes, but not in cells retainingnon-degradable mutant -catenin. Axin inhibits cellular proliferationand ERK pathway activation induced by either epidermal growthfactor or Ras, indicating a role of Axin in the regulation ofgrowth induced by ERK pathway activation. ERK pathway regulationby Axin occurs at least partly via reduction of the proteinlevel of Ras. Both wild-type and mutant Ras proteins are subjectedto regulation by Axin, which occurs in cells retaining wild-typebut not mutant -catenin gene. The role of -catenin in the regulationof the Ras-ERK pathway was further confirmed by Ras reductionand subsequent inhibitions of the ERK pathway components byknock down of mutated form of -catenin. The Ras regulation byAxin was blocked by treatment of leupeptin, an inhibitor ofthe lysosomal protein degradation machinery. Overall, Axin inhibitsproliferation of cells at least partly by reduction of Ras proteinlevel via -catenin. This study provides evidences for the roleof the Ras-ERK pathway in carcinogenesis caused by mutationsof the Wnt/-catenin pathway components.
Received for publication December 5, 2006.
Revision received March 6, 2007.
* This work was supported in part by a National Research LaboratoryGrant 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 articlewere defrayed in part by the payment of page charges. This articlemust therefore be hereby marked "advertisement" in accordancewith 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 educationand 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.
The editors suggest the following Related Resources on Science sites:
In Science Signaling
EDITORS' CHOICE
John F. Foley (15 May 2007) Sci. STKE2007 (386), tw168.
[DOI: 10.1126/stke.3862007tw168] |Abstract »
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Ras Stabilization Through Aberrant Activation of Wnt/{beta}-Catenin Signaling Promotes Intestinal Tumorigenesis.
W.-J. Jeong, J. Yoon, J.-C. Park, S.-H. Lee, S.-H. Lee, S. Kaduwal, H. Kim, J.-B. Yoon, and K.-Y. Choi (2012)
Science Signaling
5, ra30
|Abstract »|Full Text »|PDF »
The Protein Stability of Axin, a Negative Regulator of Wnt Signaling, Is Regulated by Smad Ubiquitination Regulatory Factor 2 (Smurf2).
Functional Roles of Multiple Feedback Loops in Extracellular Signal-Regulated Kinase and Wnt Signaling Pathways That Regulate Epithelial-Mesenchymal Transition.
S.-Y. Shin, O. Rath, A. Zebisch, S.-M. Choo, W. Kolch, and K.-H. Cho (2010)
Cancer Res.
70, 6715-6724
|Abstract »|Full Text »|PDF »
De novo synthesis of {beta}-catenin via H-Ras and MEK regulates airway smooth muscle growth.
R. Gosens, H. A. Baarsma, I. H. Heijink, T. A. Oenema, A. J. Halayko, H. Meurs, and M. Schmidt (2010)
FASEB J
24, 757-768
|Abstract »|Full Text »|PDF »
A clathrin-dependent pathway leads to KRas signaling on late endosomes en route to lysosomes.
A. Lu, F. Tebar, B. Alvarez-Moya, C. Lopez-Alcala, M. Calvo, C. Enrich, N. Agell, T. Nakamura, M. Matsuda, and O. Bachs (2009)
J. Cell Biol.
184, 863-879
|Abstract »|Full Text »|PDF »
H-Ras is degraded by Wnt/{beta}-catenin signaling via {beta}-TrCP-mediated polyubiquitylation.
S.-E. Kim, J.-Y. Yoon, W.-J. Jeong, S.-H. Jeon, Y. Park, J.-B. Yoon, Y. N. Park, H. Kim, and K.-Y. Choi (2009)
J. Cell Sci.
122, 842-848
|Abstract »|Full Text »|PDF »
Mitogen-Activated Protein (MAP) Kinase/MAP Kinase Phosphatase Regulation: Roles in Cell Growth, Death, and Cancer.
-Catenin
,
Ju-Yong Yoon
,
Woo-Jeong Jeong
-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 
