An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin.
beta-catenin plays an essential role in the Wingless/Wnt signaling cascade and is a component of the cadherin cell adhesion complex. Deregulation of beta-catenin accumulation as a result of mutations in adenomatous polyposis coli (APC) tumor suppressor protein is believed to initiate colorectal neoplasia. beta-catenin levels are regulated by the ubiquitin-dependent ... proteolysis system and beta-catenin ubiquitination is preceded by phosphorylation of its N-terminal region by the glycogen synthase kinase-3beta (GSK-3beta)/Axin kinase complex. Here we show that FWD1 (the mouse homologue of Slimb/betaTrCP), an F-box/WD40-repeat protein, specifically formed a multi-molecular complex with beta-catenin, Axin, GSK-3beta and APC. Mutations at the signal-induced phosphorylation site of beta-catenin inhibited its association with FWD1. FWD1 facilitated ubiquitination and promoted degradation of beta-catenin, resulting in reduced cytoplasmic beta-catenin levels. In contrast, a dominant-negative mutant form of FWD1 inhibited the ubiquitination process and stabilized beta-catenin. These results suggest that the Skp1/Cullin/F-box protein FWD1 (SCFFWD1)-ubiquitin ligase complex is involved in beta-catenin ubiquitination and that FWD1 serves as an intracellular receptor for phosphorylated beta-catenin. FWD1 also links the phosphorylation machinery to the ubiquitin-proteasome pathway to ensure prompt and efficient proteolysis of beta-catenin in response to external signals. SCFFWD1 may be critical for tumor development and suppression through regulation of beta-catenin protein stability.
Mesh Terms:
Adenomatous Polyposis Coli Protein, Animals, Carrier Proteins, Cytoskeletal Proteins, GTP-Binding Proteins, Mice, Models, Biological, Mutation, Neoplasm Proteins, Peptide Synthases, Protein Binding, Proteins, Recombinant Proteins, Repressor Proteins, SKP Cullin F-Box Protein Ligases, Trans-Activators, Ubiquitins, beta Catenin, beta-Transducin Repeat-Containing Proteins
Adenomatous Polyposis Coli Protein, Animals, Carrier Proteins, Cytoskeletal Proteins, GTP-Binding Proteins, Mice, Models, Biological, Mutation, Neoplasm Proteins, Peptide Synthases, Protein Binding, Proteins, Recombinant Proteins, Repressor Proteins, SKP Cullin F-Box Protein Ligases, Trans-Activators, Ubiquitins, beta Catenin, beta-Transducin Repeat-Containing Proteins
EMBO J.
Date: May. 04, 1999
PubMed ID: 10228155
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