Carron Clémence, Pascal Aude, Djiane Alexandre, Boucaut Jean-Claude, Shi De-Li, Umbhauer Muriel
Laboratoire de Biologie du Développement, Groupe de Biologie Expérimentale, UMR CNRS 7622, Université Paris VI, 9 quai Saint-Bernard, France.
J Cell Sci. 2003 Jun 15;116(Pt 12):2541-50. doi: 10.1242/jcs.00451. Epub 2003 May 6.
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.
Wnt信号传导在细胞命运决定、组织模式形成和肿瘤发生中发挥着重要作用。Wnt蛋白通过卷曲蛋白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。利用非洲爪蟾早期胚胎，我们发现卷曲蛋白受体可以二聚化，并且二聚化与Wnt/β-连环蛋白信号通路的激活相关。免疫共沉淀研究表明，受体Xfz3在非洲爪蟾胚胎中表达时以二聚体形式存在，并且如靶基因siamois的表达所示，它已被证明能激活Wnt/β-连环蛋白信号通路。Xfz3二聚化需要分子内和/或分子间二硫键连接，并且受体的N端细胞外区域，包括富含半胱氨酸的结构域（CRD），足以实现二聚化。当在胚胎中过表达时，受体Xfz7的行为与Xfz3不同，因为Xfz7是单体，无法直接激活Wnt/β-连环蛋白信号通路。然而，通过人工促使Xfz7二聚化可以实现该信号通路的激活。这些结果为卷曲蛋白受体的二聚化提供了首个直接证据，并表明二聚化有助于转导Wnt/β-连环蛋白信号。
