An F‐box protein, FWD1, mediates ubiquitin‐dependent proteolysis of β‐catenin

β‐catenin plays an essential role in the Wingless/Wnt signaling cascade and is a component of the cadherin cell adhesion complex. Deregulation of β‐catenin accumulation as a result of mutations in adenomatous polyposis coli (APC) tumor suppressor protein is believed to initiate colorectal neoplasia. β‐catenin levels are regulated by the ubiquitin‐dependent proteolysis system and β‐catenin ubiquitination is preceded by phosphorylation of its N‐terminal region by the glycogen synthase kinase‐3β (GSK‐3β)/Axin kinase complex. Here we show that FWD1 (the mouse homologue of Slimb/βTrCP), an F‐box/WD40‐repeat protein, specifically formed a multi‐molecular complex with β‐catenin, Axin, GSK‐3β and APC. Mutations at the signal‐induced phosphorylation site of β‐catenin inhibited its association with FWD1. FWD1 facilitated ubiquitination and promoted degradation of β‐catenin, resulting in reduced cytoplasmic β‐catenin levels. In contrast, a dominant‐negative mutant form of FWD1 inhibited the ubiquitination process and stabilized β‐catenin. These results suggest that the Skp1/Cullin/F‐box protein FWD1 (SCFFWD1)–ubiquitin ligase complex is involved in β‐catenin ubiquitination and that FWD1 serves as an intracellular receptor for phosphorylated β‐catenin. FWD1 also links the phosphorylation machinery to the ubiquitin–proteasome pathway to ensure prompt and efficient proteolysis of β‐catenin in response to external signals. SCFFWD1 may be critical for tumor development and suppression through regulation of β‐catenin protein stability.