One of the major challenges in colorectal cancer includes poor understanding of the factors regulating its initiation and progression. Hyperactive Wnt signaling driven by excess active beta catenin due to either loss of the APC tumor suppressor gene or mutation of beta catenin is considered as an inciting event in vast majority of colorectal cancer patients. Although many of the components of this signaling pathway are known, the mechanisms that regulate the active beta catenin remain incompletely understood. We have recently described c-Cbl, a known tumor suppressor, as a novel inhibitor of Wnt signaling and an E3 ubiquitin ligase for active nuclear beta catenin. Leveraging the findings that in colorectal cancer cells, c-Cbl can also suppresses the phospho-resistant S33A mutant beta catenin and the active beta catenin resulting from APC inactivation, the crucial triggers for adenoma formation, this grant seeks to examine the role of c-Cbl in colorectal cancer tumorigenesis. Using biochemical, genetic, cellular and molecular biology approaches, we will examine how c- Cbl regulates the fundamental colorectal cancer cell biological functions and inhibits the beta catenin-mediated transcription in nucleus. We will validate these observations and gain further mechanistic understanding in the multistep colorectal cancer pathogenesis using mouse xenograft and knock out animal models. We will further validate our findings in human colorectal cancer tissues. This series of experiments will provide a window into the unique regulatory role of c-Cbl in colorectal cancer and pave the road for further translational studies.