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

被引:461
作者
Kitagawa, M
Hatakeyama, S
Shirane, M
Matsumoto, M
Ishida, N
Hattori, K
Nakamichi, I
Kikuchi, A
Nakayama, K
Nakayama, K
机构
[1] Kyushu Univ, Med Inst Bioregulat, Dept Mol & Cellular Biol, Higashi Ku, Fukuoka 8128582, Japan
[2] Kyushu Univ, Med Inst Bioregulat, Lab Embryon & Genet Engn, Higashi Ku, Fukuoka 8128582, Japan
[3] Japan Sci & Technol Corp, CREST, Kawaguchi, Saitama 3320012, Japan
[4] Hiroshima Univ, Sch Med, Dept Biochem 1, Minami Ku, Hiroshima 7340037, Japan
关键词
beta-catenin; F-box protein; FWD1; SCF complex; ubiquitin ligase;
D O I
10.1093/emboj/18.9.2401
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-3 beta (GSK-3 beta)/Axin kinase complex. Here we show that FWD1 (the mouse homologue of Slimb/beta TrCP), an F-box/WD40-repeat protein, specifically formed a multi-molecular complex with beta-catenin, Axin, GSK-3 beta 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.
引用
收藏
页码:2401 / 2410
页数:10
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