Murine Frizzled-1 behaves as an antagonist of the canonical Wnt/β-catenin signaling
Murine Frizzled-1 behaves as an antagonist of the canonical Wnt/β-catenin signaling
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DOI：
10.1074/jbc.m309233200
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发表时间：
2004-02-13
影响因子：
4.8
通讯作者：
Rawadi, G
中科院分区：
文献类型：
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作者：
Roman-Roman, S;Shi, DL;Rawadi, G
Wnt信号级联的激活在发育和疾病期间提供关键信号。Wnt信号由七跨膜Frizzleds（Fzs）和单跨膜低密度脂蛋白受体相关蛋白5或6转导。在分析间充质细胞中骨形态发生蛋白2调控的基因的过程中，我们发现了小鼠Frizzled-1（mFz 1）基因表达的显着诱导。出乎意料的过度表达mFz 1显着抑制诱导的碱性磷酸酶介导的骨形态发生蛋白2或Wnt 3a在这些细胞。此外，mFz 1过表达显着抑制β-连环蛋白易位到细胞核和T细胞因子信号传导介导的Wnt 3a。重要的是，在非洲爪蟾胚胎中显微注射mFz 1转录物抑制了Wnt 1在动物帽试验中诱导Wnt/β-连环蛋白靶基因Siamois表达的能力和整个胚胎中次级轴的形成。通过使用嵌合构建体，其中mFz 1的N-和C-末端区段被Xfz 3的相应部分取代，我们证明了拮抗活性存在于N-末端部分的富含半胱氨酸的结构域中。过表达Galpha（q）-（305-359）可阻止mFz 1的拮抗活性，Galpha（q）-（305-359）特异性解偶联G（q）偶联受体，表明Galpha（q）信号传导有助于mFz 1抑制Wnt/β-连环蛋白途径。这是首次报道卷曲受体拮抗Wnt/β-连环蛋白。
Activation of the Wnt signaling cascade provides key signals during development and in disease. Wnt signals are transduced by seven-transmembrane Frizzleds (Fzs) and the single transmembrane low density lipoprotein receptor-related proteins 5 or 6. In the course of the analysis of genes regulated by bone morphogenetic protein 2 in mesenchymal cells we found a significant induction of murine Frizzled-1 (mFz1) gene expression. Unexpectedly overexpression of mFz1 dramatically repressed the induction of alkaline phosphatase mediated by either bone morphogenetic protein 2 or Wnt3a in these cells. Moreover mFz1 overexpression significantly repressed both beta-catenin translocation into the nucleus and T cell factor signaling mediated by Wnt3a. Importantly microinjection of mFz1 transcript in Xenopus embryo inhibited the ability of Wnt1 to induce the expression of the Wnt/beta-catenin target gene Siamois in animal cap assay and secondary axis formation in whole embryo. By using chimeric constructs in which N- and C-terminal segments of mFz1 were replaced by the corresponding parts of Xfz3 we demonstrated that the antagonistic activity resides in the cysteine-rich domain of the N- terminal part. The antagonist activity of mFz1 could be prevented by overexpression of Galpha(q)-(305-359), which specifically uncouples G(q)-coupled receptors, suggesting that Galpha(q) signaling contributes to the inhibition of Wnt/beta-catenin pathway by mFz1. This is the first time that a Frizzled receptor has been reported to antagonize Wnt/beta-catenin.