An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of β-catenin
An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of β-catenin
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DOI：
10.1093/emboj/18.9.2401
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发表时间：
1999-05-04
期刊：
影响因子：
11.4
通讯作者：
Nakayama, K
中科院分区：
文献类型：
--
作者：
Kitagawa, M;Hatakeyama, S;Nakayama, K
β-连环蛋白在无翼/Wnt信号转导通路中发挥重要作用，是钙粘附素细胞黏附复合体的组成部分。结肠腺瘤性息肉病(APC)肿瘤抑制蛋白突变导致的β-连环蛋白积聚的解除调控被认为是引发大肠肿瘤的原因。β-连环蛋白水平受依赖于泛素的蛋白分解系统的调节，在泛素化之前，其N-末端区域被糖原合成酶-3β(GSK-3β)/Axin激酶复合体磷酸化。在这里，我们发现了F-box/WD40-重复蛋白FWD1(SLimb/beta TrCP的小鼠同源物)，它与β-连环素、Axin、GSK-3β和APC特异性地形成多分子复合体，信号诱导的β-连环素磷酸化位点突变抑制了它与FWD1的结合，FWD1促进了泛素化，促进了β-连环素的降解，导致细胞质中的β-连环素水平降低。相反，显性-负性突变形式的FWD1抑制了泛素化过程并稳定了β-连环素，这些结果表明Skp1/cullin/F-box蛋白FWD1(SCFFWD1)-泛素连接酶复合体参与了β-连环素的泛素化，FWD1是细胞内磷酸化的β-连环素的受体，FWD1还将磷酸化机制连接到泛素-蛋白酶体途径，以确保β-连环素对外界信号的快速有效的蛋白分解。SCFFWD1可能通过调节β-连环蛋白的稳定性对肿瘤的发展和抑制起关键作用。
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.