Date on Master's Thesis/Doctoral Dissertation

8-2015

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Biochemistry and Molecular Biology

Degree Program

Biochemistry and Molecular Biology, PhD

Committee Chair

Clark, Geoffrey

Committee Co-Chair (if applicable)

Clark, Barbara

Committee Member

Clark, Barbara

Committee Member

Mitchell, Robert

Committee Member

Dholakia, Jaydev

Committee Member

Geoghegan, Thomas

Subject

Ras oncogenes; Ras proteins; Cellular signal transduction; Cancer--Research

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 in order to promote transformation, but 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 promoting senescence and apoptosis. Its expression is frequently lost in human tumors and its mechanism of action remains unclear. Here I show that NORE1A forms a direct, Ras regulated, complex with β-TrCP, the substrate recognition component of the SCF-β-TrCP ubiquitin ligase complex. NORE1A also binds GSK-3β resulting in enhanced kinase activity, which is required to phosphorylate SCF-β-TrCP substrates before their recognition by the ubiquitin ligase complex. Thus, by acting as a scaffold between β-TrCP and GSK-3β, NORE1A allows for Ras to both qualitatively and quantitatively enhance the proteosomal degradation of SCF-β-TrCP targets, such as β- catenin and TAZ. However, this control is substrate specific, as IκB, another substrate of SCF-β-TrCP, is not sensitive to NORE1A promoted degradation. Thus, I identify a completely novel signaling mechanism for Ras that allows the coordinate regulation of the Wnt/β-catenin and Hippo pathways, and potentially multiple other SCF-β-TrCP targets. The mechanism is frequently impaired in tumors by loss of NORE1A expression and provides an explanation for the observation that β-TrCP can act as a tumor suppressor or an oncogene in different cell systems.

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