Ras stabilization through aberrant activation of Wnt/β-catenin signaling promotes intestinal tumorigenesis

Woo Jeong Jeong, Juyong Yoon, Jong Chan Park, Soung Hoon Lee, Seung Hoon Lee, Saluja Kaduwal, Hoguen Kim, Jong Bok Yoon, Kang Yell Choi

Research output: Contribution to journalArticle

96 Citations (Scopus)

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.

Original languageEnglish
Article numberra30
JournalScience Signaling
Volume5
Issue number219
DOIs
Publication statusPublished - 2012 Apr 10

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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