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  • The EMBO Journal (1999) 18, 2401 - 2410
  • doi:10.1093/emboj/18.9.2401

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

Masatoshi Kitagawa1,2,5, Shigetsugu Hatakeyama1,2,5, Michiko Shirane1,2, Masaki Matsumoto1,2, Noriko Ishida1,2, Kimihiko Hattori1,2, Ikuo Nakamichi1,2, Akira Kikuchi3, Kei-ichi Nakayama1,2,4 and Keiko Nakayama2,4

  1. Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
  2. CREST, Japan Science and Technology Corporation (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
  3. First Department of Biochemistry, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-0037, Japan
  4. Laboratory of Embryonic and Genetic Engineering, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
  5. M.Kitagawa and S.Hatakeyama contributed equally to this work

Correspondence to:

Kei-ichi Nakayama, E-mail: nakayak1@bioreg.kyushu-u.ac.jp

Received 11 November 1998; Accepted 4 March 1999; Revised 4 March 1999

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.

  • Keywords:

    • beta-catenin,
    • F-box protein,
    • FWD1,
    • SCF complex,
    • ubiquitin ligase