title: Ras stabilization through aberrant activation of Wnt/β-catenin signaling promotes intestinal tumorigenesis.
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.
authors.affiliation: Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea.
authors.forename: Woo-Jeong
authors.initials: WJ
authors.lastname: Jeong
authors.forename: Juyong
authors.initials: J
authors.lastname: Yoon
authors.forename: Jong-Chan
authors.initials: JC
authors.lastname: Park
authors.forename: Soung-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Saluja
authors.initials: S
authors.lastname: Kaduwal
authors.forename: Hoguen
authors.initials: H
authors.lastname: Kim
authors.forename: Jong-Bok
authors.initials: JB
authors.lastname: Yoon
authors.forename: Kang-Yell
authors.initials: KY
authors.lastname: Choi
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D007414:Intestinal Neoplasms / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D010766:Phosphorylation; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D051153:Wnt Proteins; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D018631:ras Proteins