A frizzled homolog functions in a vertebrate Wnt signaling pathway.
BACKGROUND
Wnts are secreted proteins implicated in cell-cell interactions during embryogenesis and tumorigenesis, but receptors involved in transducing Wnt signals have not yet been definitively identified. Members of a large family of putative transmembrane receptors homologous to the frizzled protein in Drosophila have been identified recently in both vertebrates and invertebrates, raising the question of whether they are involved in transducing signals for any known signaling factors.


RESULTS
To test the potential involvement of frizzled homologs in Wnt signaling, we examined the effects of overexpressing rat frizzled-1 (Rfz-1) on the subcellular distribution of Wnts and of dishevelled, a cytoplasmic component of the Wnt signalling pathway. We demonstrate that ectopic expression of Rfz-1 recruits the dishevelled proten-as well as Xenopus Wnt-8 (Xwnt-8), but not the functionally distinct Xwnt-5A-to the plasma membrane. Moreover, Rfz-1 is sufficient to induce the expression of two Xwnt-8-responsive genes, siamois and Xnr-3, in Xenopus explants in a manner which is antagonized by glycogen synthase kinase-3, which also antagonizes Wnt signaling. When Rfz-1 and Xwnt-8 are expressed together in this assay, we observe greater induction of these genes, indicating that Rfz-1 can synergize with a Wnt.


CONCLUSIONS
The results demonstrate that a vertebrate frizzled homolog is involved in Wnt signaling in a manner which discriminates between functionally distinct Wnts, which involves translocation of the dishevelled protein to the plasma membrane, and which works in a synergistic manner with Wnts to induce gene expression. These data support the likely function of frizzled homologs as Wnt receptors, or as components of a receptor complex.
Yang-Snyder
J
J
Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle 98195, USA.
Miller
J R
JR
Brown
J D
JD
Lai
C J
CJ
Moon
R T
RT
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D004475:Ectoderm; D051157:Frizzled Receptors; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D010750:Phosphoproteins; D011506:Proteins / Q000032:analysis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D012333:RNA, Messenger; D051381:Rats; D043562:Receptors, G-Protein-Coupled; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000032:analysis; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D014981:Xenopus / Q000196:embryology; D029867:Xenopus Proteins; D029961:Zebrafish Proteins
D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D051157:Frizzled Receptors; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; C093133:SIA1 protein, Xenopus; D016212:Transforming Growth Factor beta; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; C000606588:dsh protein, Drosophila; C058784:fz protein, Drosophila; C094620:nodal3.1 protein, Xenopus; C495248:wnt8a protein, Xenopus