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

Masatoshi Kitagawa, Shigetsugu Hatakeyama, Michiko Shirane, Masaki Matsumoto, Noriko Ishida, Kimihiko Hattori, Ikuo Nakamichi, Akira Kikuchi, Kei Ichi Nakayama, Keiko Nakayama

Research output: Contribution to journalArticlepeer-review

487 Citations (Scopus)


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 (SCF(FWD1))-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. SCF(FWD1) may be critical for tumor development and suppression through regulation of β-catenin protein stability.

Original languageEnglish
Pages (from-to)2401-2410
Number of pages10
JournalEMBO Journal
Issue number9
Publication statusPublished - 1999 May 4


  • F-box protein
  • FWD1
  • SCF complex
  • Ubiquitin ligase
  • β-catenin


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