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Wnt/Wingless signaling through β-catenin requires the function of both LRP/Arrow and frizzled classes of receptors
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 tri...
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Formato: | Texto |
Lenguaje: | English |
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BioMed Central
2003
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC156895/ https://www.ncbi.nlm.nih.gov/pubmed/12729465 http://dx.doi.org/10.1186/1471-2121-4-4 |
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author | Schweizer, Liang Varmus, Harold |
author_facet | Schweizer, Liang Varmus, Harold |
author_sort | Schweizer, Liang |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-156895 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2003 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-1568952003-06-10 Wnt/Wingless signaling through β-catenin requires the function of both LRP/Arrow and frizzled classes of receptors Schweizer, Liang Varmus, Harold BMC Cell Biol Research Article 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. BioMed Central 2003-05-02 /pmc/articles/PMC156895/ /pubmed/12729465 http://dx.doi.org/10.1186/1471-2121-4-4 Text en Copyright © 2003 Schweizer and Varmus; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. |
spellingShingle | Research Article Schweizer, Liang Varmus, Harold Wnt/Wingless signaling through β-catenin requires the function of both LRP/Arrow and frizzled classes of receptors |
title | Wnt/Wingless signaling through β-catenin requires the function of both LRP/Arrow and frizzled classes of receptors |
title_full | Wnt/Wingless signaling through β-catenin requires the function of both LRP/Arrow and frizzled classes of receptors |
title_fullStr | Wnt/Wingless signaling through β-catenin requires the function of both LRP/Arrow and frizzled classes of receptors |
title_full_unstemmed | Wnt/Wingless signaling through β-catenin requires the function of both LRP/Arrow and frizzled classes of receptors |
title_short | Wnt/Wingless signaling through β-catenin requires the function of both LRP/Arrow and frizzled classes of receptors |
title_sort | wnt/wingless signaling through β-catenin requires the function of both lrp/arrow and frizzled classes of receptors |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC156895/ https://www.ncbi.nlm.nih.gov/pubmed/12729465 http://dx.doi.org/10.1186/1471-2121-4-4 |
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