The human Frizzled 6 (HFz6) acts as a negative regulator of the canonical Wnt. beta-catenin signaling cascade.
Previously we have cloned the human Frizzled 1 (HFz1) and shown that it transmits the Wnt-3a-induced canonical pathway. We also cloned the human Frizzled 6 (HFz6) and show in the present study that, as opposed to HFz1, HFz6 did not activate the canonical Wnt pathway following exposure to various Wnts, whether belonging to the Wnt-1 or to the Wnt-5a group. Moreover we show that HFz6 repressed Wnt-3a-induced canonical signaling when co-expressed with HFz1. HFz6 repressed the canonical Wnt cascade activated also by various Wnt signaling intracellular mediators such as Dishevelled-1, a stabilized beta-catenin(S33Y) mutant, and LiCl-mediated repression of glycogen synthase kinase-3beta activity. Removal of HFz6 N'- or C'-terminal sequences abolished HFz6 repressive activity. As the HFz6 repressive effect was not associated with a decrease in the level of beta-catenin, it is suggested that HFz6 does not affect beta-catenin stabilization, implying that HFz6 transmits a repressive signaling that cross-talks with and inhibits the canonical Wnt pathway downstream of beta-catenin destruction complex. HFz6 did not affect the level of nuclear T-cell factor 4 (TCF4) nor did it affect beta-catenin.TCF4 complex formation. However, electrophoretic mobility shift assays indicated that HFz6 repressed the binding of TCF/lymphoid enhancer factor transcription factors to target DNA. Moreover we present data suggesting that HFz6 activates the transforming growth factor-beta-activated kinase-NEMO-like kinase pathway that blocks TCF/lymphoid enhancer factor binding to target promoters, thereby inhibiting the ability of beta-catenin to activate transcription of Wnt target genes.
Golan
Tamar
T
Department of Human Microbiology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Yaniv
Abraham
A
Bafico
Anna
A
Liu
Guizhong
G
Gazit
Arnona
A
D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites; D015152:Blotting, Northern; D002460:Cell Line; D019938:Cyclin D1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D000072261:Dishevelled Proteins; D051157:Frizzled Receptors; D017930:Genes, Reporter; D005822:Genetic Vectors; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D051153:Wnt Proteins; D051155:Wnt1 Protein; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D029961:Zebrafish Proteins; D051176:beta Catenin
D048868:Adaptor Proteins, Signal Transducing; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; C000606578:DVL1 protein, human; D000072261:Dishevelled Proteins; C484687:FZD6 protein, human; D051157:Frizzled Receptors; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; C495247:WNT1 protein, human; C555510:WNT3A protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D029961:Zebrafish Proteins; D051176:beta Catenin; D019938:Cyclin D1; D004247:DNA; D008156:Luciferases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride