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.
Highlights
NORE1A is a Ras effector with a poorly defined function
Because NORE1A expression is frequently impaired in tumors, we provide an explanation for the observation that -TrCP can act as a tumor suppressor or an oncogene in different cell systems
NORE1A suppresses tumor cell growth and is frequently inactivated in human tumors, and its inactivation is implicated in a hereditary cancer syndrome [16, 21, 23]
Summary
Results: NORE1A forms a direct, Ras-regulated complex with -TrCP and activates the SCF-TrCP ubiquitin ligase complex to promote -catenin degradation. We show that the NORE1A levels in a cell may dictate the effects of Ras on the Wnt/-catenin pathway. It connects Ras to the pro-apoptotic Hippo pathway, but this does not seem to be essential for its tumor suppressor function It modulates p53 [18, 19], which may explain its ability to promote cell cycle arrest. Because SCF-TrCP modulates the Wnt/-catenin pathway by targeting -catenin for degradation by the proteasome [11], NORE1A might serve to link Ras to the control of -catenin. We sought to determine the role of NORE1A in the control of the SCF-TrCP ubiquitin ligase and Wnt/-catenin signaling. The cellular levels of NORE1A may dictate how Ras modulates -catenin and determine the substrate profile of the SCF-TrCP ubiquitin ligase. Cells were transfected for 24 h before lysing and reading using a Luminat LB 9507 from Berthold Technologies
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