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

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Abstract

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
Volume18
Issue number9
DOIs
Publication statusPublished - May 4 1999

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Kitagawa, M., Hatakeyama, S., Shirane, M., Matsumoto, M., Ishida, N., Hattori, K., Nakamichi, I., Kikuchi, A., Nakayama, K. I., & Nakayama, K. (1999). An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of β-catenin. EMBO Journal, 18(9), 2401-2410. https://doi.org/10.1093/emboj/18.9.2401