Background: Several E3 ligases regulate cytosolicβ-catenin during Wnt-off phase. The fate of critical form activeβ-catenin in Wnt-on phase remains poorly defined. Results: Casitas B-lineage lymphoma (c-Cbl) ubiquitinates cytosolic β-catenin and translocates to the nucleus with Wnt induction to also ubiquitinate active nuclear β-catenin. Conclusion: c-Cbl is a unique E3 ligase targeting active nuclear β-catenin. Significance: This study uncovers a novel layer of Wnt regulation.