Frizzled receptor dimerization is sufficient to activate the Wnt/beta-catenin pathway.
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.
Carron
Clémence
C
Laboratoire de Biologie du Développement, Groupe de Biologie Expérimentale, UMR CNRS 7622, Université Paris VI, 9 quai Saint-Bernard, France.
Pascal
Aude
A
Djiane
Alexandre
A
Boucaut
Jean-Claude
JC
Shi
De-Li
DL
Umbhauer
Muriel
M
D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D019281:Dimerization; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D005260:Female; D051157:Frizzled Receptors; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008623:Mercaptoethanol / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism*; D051153:Wnt Proteins; D029867:Xenopus Proteins; D014982:Xenopus laevis / Q000196:embryology / Q000378:metabolism; D029961:Zebrafish Proteins; D051176:beta Catenin
C495266:CTNNB1 protein, Xenopus; D003598:Cytoskeletal Proteins; C486340:FZD3 protein, Xenopus; D051157:Frizzled Receptors; C492040:Fzd7 protein, Xenopus; D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; C093133:SIA1 protein, Xenopus; D015534:Trans-Activators; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D008623:Mercaptoethanol