Frizzled receptor dimerization is sufficient to activate the Wnt/β-catenin pathway
Frizzled receptor dimerization is sufficient to activate the Wnt/β-catenin pathway
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DOI：
10.1242/jcs.00451
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发表时间：
2003-06-15
影响因子：
4
通讯作者：
Umbhauer, M
中科院分区：
文献类型：
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作者：
Carron, C;Pascal, A;Umbhauer, M
Wnt信号传导在细胞命运决定、组织形成和肿瘤发生中具有重要作用。Wnt蛋白通过卷曲家族的七次跨膜受体发出信号，以激活靶基因的β-连环蛋白依赖性转录。使用早期非洲爪蟾胚胎，我们表明，卷曲受体可以二聚化，二聚化与Wnt/β-连环蛋白通路的激活。免疫共沉淀研究显示，受体Xfz 3在非洲爪蟾胚胎中表达时以二聚体形式存在，并且已显示其激活Wnt/β-连环蛋白途径，如靶基因siamois的表达所揭示的。Xfz 3二聚化需要分子内和/或分子间二硫键，并且受体的N-末端胞外区，包括富含半胱氨酸的结构域（CRD），足以进行二聚化。当在胚胎中过表达时，受体Xfz 7的行为与Xfz 3不同，因为Xfz 7是单体的，并且不能直接激活Wnt/β-连环蛋白途径。然而，该途径的激活可以通过人工强制Xfz 7二聚化来实现。这些结果为卷曲受体的二聚化提供了第一个直接证据，并表明二聚化有助于Wnt/β-连环蛋白信号的转导。
Wnt signaling has an important role in cell-fate determination, tissue patterning and tumorigenesis. Wnt proteins signal through seven-pass transmembrane receptors of the frizzled family to activate beta-catenin-dependent transcription of target genes. Using early Xenopus embryos, we show that frizzled receptors can dimerize and that dimerization is correlated with activation of the Wnt/beta-catenin pathway. Co-immunoprecipitation studies revealed that the receptor Xfz3 exists as a dimer when expressed in Xenopus embryos, and it has been shown to activate the Wnt/beta-catenin pathway as revealed by expression of the target gene siamois. Xfz3 dimerization requires intramolecular and/or intermolecular disulfide linkages, and the N-terminal extracellular region of the receptor, including the cysteine-rich domain (CRD), is sufficient for dimerization. The receptor Xfz7 behaves differently from Xfz3 when overexpressed in the embryo as Xfz7 is monomeric and is unable to directly activate the Wnt/beta-catenin pathway. However, activation of this pathway can be achieved by artificially forcing Xfz7 dimerization. These results provide the first direct evidence for the dimerization of frizzled receptors and suggest that dimerization contributes to transducing the Wnt/beta-catenin signal.