title: Ras regulates SCF(β-TrCP) protein activity and specificity via its effector protein NORE1A.
abstract: Ras is the most frequently activated oncogene found in human cancer, but its mechanisms of action remain only partially understood. Ras activates multiple signaling pathways to promote transformation. However, Ras can also exhibit a potent ability to induce growth arrest and death. NORE1A (RASSF5) is a direct Ras effector that acts as a tumor suppressor by promoting apoptosis and cell cycle arrest. Expression of NORE1A is frequently lost in human tumors, and its mechanism of action remains unclear. Here we show that NORE1A forms a direct, Ras-regulated complex with β-TrCP, the substrate recognition component of the SCF(β-TrCP) ubiquitin ligase complex. This interaction allows Ras to stimulate the ubiquitin ligase activity of SCF(β-TrCP) toward its target β-catenin, resulting in degradation of β-catenin by the 26 S proteasome. However, the action of Ras/NORE1A/β-TrCP is substrate-specific because IκB, another substrate of SCF(β-TrCP), is not sensitive to NORE1A-promoted degradation. We identify a completely new signaling mechanism for Ras that allows for the specific regulation of SCF(β-TrCP) targets. We show that the NORE1A levels in a cell may dictate the effects of Ras on the Wnt/β-catenin pathway. Moreover, because NORE1A expression is frequently impaired in tumors, we provide an explanation for the observation that β-TrCP can act as a tumor suppressor or an oncogene in different cell systems.
authors.affiliation: From the Molecular Targets Group, James Graham Brown Cancer Center, Departments of Biochemistry and Molecular Biology.
authors.forename: M Lee
authors.initials: ML
authors.lastname: Schmidt
authors.affiliation: Medicine, and.
authors.forename: Howard
authors.initials: H
authors.lastname: Donninger
authors.affiliation: Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky 40202 gjclar01@louisville.edu.
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Clark
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D015398:Signal Transduction; D013379:Substrate Specificity; D051176:beta Catenin / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C495270:CTNNB1 protein, human; C454042:RASSF5 protein, human; D051176:beta Catenin; D044843:SKP Cullin F-Box Protein Ligases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D020559:Monomeric GTP-Binding Proteins; D018631:ras Proteins
keywords: E3 Ubiquitin Ligase; Oncogene; Ras Protein; Tumor Suppressor Gene; Wnt Signaling