Wnt/Wingless signaling through β-catenin requires the function of both LRP/Arrow and frizzled classes of receptors Journal Article
| Authors: | Schweizer, L.; Varmus, H. |
| Article Title: | Wnt/Wingless signaling through β-catenin requires the function of both LRP/Arrow and frizzled classes of receptors |
| Abstract: | Background: Wnt/Wingless (Wg) signals are transduced by seven-transmembrane Frizzleds (Fzs) and the single-transmembrane LDL-receptor-related proteins 5 or 6 (LRP5/6) or Arrow. The aminotermini of LRP and Fz were reported to associate only in the presence of Wnt, implying that Wnt ligands form a trimeric complex with two different receptors. However, it was recently reported that LRPs activate the Wnt/β-catenin pathway by binding to Axin in a Dishevelled - independent manner, while Fzs transduce Wnt signals through Dishevelled to stabilize β-catenin. Thus, it is possible that Wnt proteins form separate complexes with Fzs and LRPs, transducing Wnt signals separately, but converging downstream in the Wnt/β-catenin pathway. The question then arises whether both receptors are absolutely required to transduce Wnt signals. Results: We have established a sensitive luciferase reporter assay in Drosophila S2 cells to determine the level of Wg - stimulated signaling. We demonstrate here that Wg can synergize with DFz2 and function cooperatively with LRP to activate the β-catenin/Armadillo signaling pathway. Double-strand RNA interference that disrupts the synthesis of either receptor type dramatically impairs Wg signaling activity. Importantly, the pronounced synergistic effect of adding Wg and DFz2 is dependent on Arrow and Dishevelled. The synergy requires the cysteine-rich extracellular domain of DFz2, but not its carboxyterminus. Finally, mammalian LRP6 and its activated forms, which lack most of the extracellular domain of the protein, can activate the Wg signaling pathway and cooperate with Wg and DFz2 in S2 cells. We also show that the aminoterminus of LRP/Arr is required for the synergy between Wg and DFz2. Conclusion: Our study indicates that Wg signal transduction in S2 cells depends on the function of both LRPs and DFz2, and the results are consistent with the proposal that Wnt/Wg signals through the aminoterminal domains of its dual receptors, activating target genes through Dishevelled. © 2003 Scheweizer and Varmus; licensee BioMed Central Ltd. |
| Keywords: | signal transduction; controlled study; unclassified drug; mutation; proto-oncogene proteins; nonhuman; protein domain; sensitivity analysis; animal cell; mammalia; animals; gene targeting; complex formation; reverse transcription polymerase chain reaction; carboxy terminal sequence; protein protein interaction; cell line; luciferase; drosophila; rna interference; transfection; gene activation; amino terminal sequence; recombinant fusion proteins; reverse transcriptase polymerase chain reaction; protein synthesis; rna, messenger; trans-activators; luciferases; beta catenin; blotting, northern; transcriptional activation; drosophila proteins; receptors, g-protein-coupled; cysteine; wnt1 protein; armadillo; double stranded rna; axin; cytoskeletal proteins; frizzled protein; low density lipoprotein receptor related protein; frizzled receptors; low density lipoprotein receptor related protein 5; low density lipoprotein receptor related protein 6; low density lipoprotein receptor-related protein-1; article; receptors, neurotransmitter |
| Journal Title: | BMC Cell Biology |
| Volume: | 4 |
| ISSN: | 1471-2121 |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2003-05-02 |
| Start Page: | 4 |
| Language: | English |
| DOI: | 10.1186/1471-2121-4-4 |
| PUBMED: | 12729465 |
| PROVIDER: | scopus |
| PMCID: | PMC156895 |
| DOI/URL: | |
| Notes: | Export Date: 12 September 2014 -- Source: Scopus |
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