Murine Frizzled-1 behaves as an antagonist of the canonical Wnt/beta-catenin signaling.
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 Galphaq-(305-359), which specifically uncouples Gq-coupled receptors, suggesting that Galphaq 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.
Roman-Roman
Sergio
S
ProSkelia Pharmaceuticals, 102 route de Noisy, 93230 Romainville, France..
Shi
De-Li
DL
Stiot
Véronique
V
Haÿ
Eric
E
Vayssière
Béatrice
B
Garcia
Teresa
T
Baron
Roland
R
Rawadi
Georges
G
D021581:Active Transport, Cell Nucleus; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003553:Cystine / Q000737:chemistry; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation; D051157:Frizzled Receptors; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter / Q000378:metabolism / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D014162:Transfection; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D051155:Wnt1 Protein; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D014981:Xenopus; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; C495266:CTNNB1 protein, Xenopus; C495267:CTNNB1 protein, mouse; D017077:Culture Media, Conditioned; D003598:Cytoskeletal Proteins; C489741:FZD1 protein, Xenopus; D051157:Frizzled Receptors; C489739:Fzd1 protein, mouse; D008164:Luminescent Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; C495249:WNT1 protein, Xenopus; C555506:WNT3A protein, Xenopus; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D049452:Green Fluorescent Proteins; D003553:Cystine; D008156:Luciferases; D000469:Alkaline Phosphatase; D043802:GTP-Binding Protein alpha Subunits, Gq-G11