Ras Regulates SCFβ-TrCP Protein Activity and Specificity via Its Effector Protein NORE1A

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 beta-TrCP, the substrate recognition component of the SCF beta-TrCP ubiquitin ligase complex. This interaction allows Ras to stimulate the ubiquitin ligase activity of SCF beta-TrCP toward its target beta-catenin, resulting in degradation of beta-catenin by the 26 S proteasome. However, the action of Ras/NORE1A/beta-TrCP is substrate-specific because I kappa B, another substrate of SCF beta-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 beta-TrCP targets. We show that the NORM levels in a cell may dictate the effects of Ras on the Wnt/beta-catenin pathway. Moreover, because NORE1A expression is frequently impaired in tumors, we provide an explanation for the observation that beta-TrCP can act as a tumor suppressor or an oncogene in different cell systems.