R-Spondin potentiates Wnt/β-catenin signaling through orphan receptors LGR4 and LGR5.
The Wnt/β-catenin signaling pathbway controls many important biological processes. R-Spondin (RSPO) proteins are a family of secreted molecules that strongly potentiate Wnt/β-catenin signaling, however, the molecular mechanism of RSPO action is not yet fully understood. We performed an unbiased siRN...
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Public Library of Science (PLoS)
2012
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oai:doaj.org-article:bd2794bcdd5c40a0903a9b2a0d7c9a222021-11-18T07:12:20ZR-Spondin potentiates Wnt/β-catenin signaling through orphan receptors LGR4 and LGR5.1932-620310.1371/journal.pone.0040976https://doaj.org/article/bd2794bcdd5c40a0903a9b2a0d7c9a222012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22815884/?tool=EBIhttps://doaj.org/toc/1932-6203The Wnt/β-catenin signaling pathbway controls many important biological processes. R-Spondin (RSPO) proteins are a family of secreted molecules that strongly potentiate Wnt/β-catenin signaling, however, the molecular mechanism of RSPO action is not yet fully understood. We performed an unbiased siRNA screen to identify molecules specifically required for RSPO, but not Wnt, induced β-catenin signaling. From this screen, we identified LGR4, then an orphan G protein-coupled receptor (GPCR), as the cognate receptor of RSPO. Depletion of LGR4 completely abolished RSPO-induced β-catenin signaling. The loss of LGR4 could be compensated by overexpression of LGR5, suggesting that LGR4 and LGR5 are functional homologs. We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5, and that overexpression of LGR4 strongly sensitizes cells to RSPO-activated β-catenin signaling. Supporting the physiological significance of RSPO-LGR4 interaction, Lgr4-/- crypt cultures failed to grow in RSPO-containing intestinal crypt culture medium. No coupling between LGR4 and heterotrimeric G proteins could be detected in RSPO-treated cells, suggesting that LGR4 mediates RSPO signaling through a novel mechanism. Identification of LGR4 and its relative LGR5, an adult stem cell marker, as the receptors of RSPO will facilitate the further characterization of these receptor/ligand pairs in regenerative medicine applications.Heinz RuffnerJoëlle SprungerOlga CharlatJuliet Leighton-DaviesBianka GrosshansAdrian SalatheSvenja ZietzlingValérie BeckMaxime TherierAndrea IskenYang XieYue ZhangHuaixiang HaoXiaoying ShiDong LiuQinhui SongIeuan ClayGabriele HintzenJan TchorzLaure C BouchezGregory MichaudPeter FinanVic E MyerTewis BouwmeesterJeff PorterMarc HildFred BassilanaChristian N ParkerFeng CongPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 7, p e40976 (2012) |
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Medicine R Science Q Heinz Ruffner Joëlle Sprunger Olga Charlat Juliet Leighton-Davies Bianka Grosshans Adrian Salathe Svenja Zietzling Valérie Beck Maxime Therier Andrea Isken Yang Xie Yue Zhang Huaixiang Hao Xiaoying Shi Dong Liu Qinhui Song Ieuan Clay Gabriele Hintzen Jan Tchorz Laure C Bouchez Gregory Michaud Peter Finan Vic E Myer Tewis Bouwmeester Jeff Porter Marc Hild Fred Bassilana Christian N Parker Feng Cong R-Spondin potentiates Wnt/β-catenin signaling through orphan receptors LGR4 and LGR5. |
| description |
The Wnt/β-catenin signaling pathbway controls many important biological processes. R-Spondin (RSPO) proteins are a family of secreted molecules that strongly potentiate Wnt/β-catenin signaling, however, the molecular mechanism of RSPO action is not yet fully understood. We performed an unbiased siRNA screen to identify molecules specifically required for RSPO, but not Wnt, induced β-catenin signaling. From this screen, we identified LGR4, then an orphan G protein-coupled receptor (GPCR), as the cognate receptor of RSPO. Depletion of LGR4 completely abolished RSPO-induced β-catenin signaling. The loss of LGR4 could be compensated by overexpression of LGR5, suggesting that LGR4 and LGR5 are functional homologs. We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5, and that overexpression of LGR4 strongly sensitizes cells to RSPO-activated β-catenin signaling. Supporting the physiological significance of RSPO-LGR4 interaction, Lgr4-/- crypt cultures failed to grow in RSPO-containing intestinal crypt culture medium. No coupling between LGR4 and heterotrimeric G proteins could be detected in RSPO-treated cells, suggesting that LGR4 mediates RSPO signaling through a novel mechanism. Identification of LGR4 and its relative LGR5, an adult stem cell marker, as the receptors of RSPO will facilitate the further characterization of these receptor/ligand pairs in regenerative medicine applications. |
| format |
article |
| author |
Heinz Ruffner Joëlle Sprunger Olga Charlat Juliet Leighton-Davies Bianka Grosshans Adrian Salathe Svenja Zietzling Valérie Beck Maxime Therier Andrea Isken Yang Xie Yue Zhang Huaixiang Hao Xiaoying Shi Dong Liu Qinhui Song Ieuan Clay Gabriele Hintzen Jan Tchorz Laure C Bouchez Gregory Michaud Peter Finan Vic E Myer Tewis Bouwmeester Jeff Porter Marc Hild Fred Bassilana Christian N Parker Feng Cong |
| author_facet |
Heinz Ruffner Joëlle Sprunger Olga Charlat Juliet Leighton-Davies Bianka Grosshans Adrian Salathe Svenja Zietzling Valérie Beck Maxime Therier Andrea Isken Yang Xie Yue Zhang Huaixiang Hao Xiaoying Shi Dong Liu Qinhui Song Ieuan Clay Gabriele Hintzen Jan Tchorz Laure C Bouchez Gregory Michaud Peter Finan Vic E Myer Tewis Bouwmeester Jeff Porter Marc Hild Fred Bassilana Christian N Parker Feng Cong |
| author_sort |
Heinz Ruffner |
| title |
R-Spondin potentiates Wnt/β-catenin signaling through orphan receptors LGR4 and LGR5. |
| title_short |
R-Spondin potentiates Wnt/β-catenin signaling through orphan receptors LGR4 and LGR5. |
| title_full |
R-Spondin potentiates Wnt/β-catenin signaling through orphan receptors LGR4 and LGR5. |
| title_fullStr |
R-Spondin potentiates Wnt/β-catenin signaling through orphan receptors LGR4 and LGR5. |
| title_full_unstemmed |
R-Spondin potentiates Wnt/β-catenin signaling through orphan receptors LGR4 and LGR5. |
| title_sort |
r-spondin potentiates wnt/β-catenin signaling through orphan receptors lgr4 and lgr5. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/bd2794bcdd5c40a0903a9b2a0d7c9a22 |
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