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Sci. Signal., 10 April 2012
Vol. 5, Issue 219, p. ra30
[DOI: 10.1126/scisignal.2002242]

RESEARCH ARTICLES

Ras Stabilization Through Aberrant Activation of Wnt/β-Catenin Signaling Promotes Intestinal Tumorigenesis

Woo-Jeong Jeong1,2*, Juyong Yoon1,2*, Jong-Chan Park1,2, Soung-Hoon Lee1,2, Seung-Hoon Lee1,3, Saluja Kaduwal1,2, Hoguen Kim4, Jong-Bok Yoon1,3, and Kang-Yell Choi1,2{dagger}

1 Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea.
2 Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
3 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
4 Department of Pathology, Center for Chronic Metabolic Disease, College of Medicine, Yonsei University, Seoul 120-749, Korea.

* These authors contributed equally to this work.

Abstract: Although the guanosine triphosphate/guanosine diphosphate loading switch is a major regulatory mechanism that controls the activity of the guanosine triphosphatase Ras, we report a distinct mechanism for regulating Ras activity through phosphorylation-mediated degradation and describe the role of this second regulatory mechanism in the suppression of cellular transformation and tumors induced by Ras mutations. We found that negative regulators of Wnt/β-catenin signaling contributed to the polyubiquitin-dependent degradation of Ras after its phosphorylation by glycogen synthase kinase 3β (GSK3β) and the subsequent recruitment of β-TrCP–E3 ligase. We found a positive association between tumorigenesis and Ras stabilization resulting from the aberrant activation of Wnt/β-catenin signaling in adenomas from two mouse models of colon cancer, human colonic tumors from various stages, and colon polyps of patients with familial adenomatous polyposis. Our results indicated that GSK3β plays an essential role in Ras degradation and that inhibition of this degradation pathway by aberrant Wnt/β-catenin signaling may contribute to Ras-induced transformation in colorectal tumorigenesis.

{dagger} To whom correspondence should be addressed. E-mail: kychoi{at}yonsei.ac.kr

Citation: W.-J. Jeong, J. Yoon, J.-C. Park, S.-H. Lee, S.-H. Lee, S. Kaduwal, H. Kim, J.-B. Yoon, K.-Y. Choi, Ras Stabilization Through Aberrant Activation of Wnt/β-Catenin Signaling Promotes Intestinal Tumorigenesis. Sci. Signal. 5, ra30 (2012).

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