Inhibition of Wnt signalling by Notch via two distinct mechanisms
Abstract Notch and Wnt are two essential signalling pathways that help to shape animals during development and to sustain adult tissue homeostasis. Although they are often active at the same time within a tissue, they typically have opposing effects on cell fate decisions. In fact, crosstalk between...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-88618-5 |
| _version_ | 1818430924173344768 |
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| author | Ahmet Acar Ana Hidalgo-Sastre Michael K. Leverentz Christopher G. Mills Simon Woodcock Martin Baron Giovanna M. Collu Keith Brennan |
| author_facet | Ahmet Acar Ana Hidalgo-Sastre Michael K. Leverentz Christopher G. Mills Simon Woodcock Martin Baron Giovanna M. Collu Keith Brennan |
| author_sort | Ahmet Acar |
| collection | DOAJ |
| description | Abstract Notch and Wnt are two essential signalling pathways that help to shape animals during development and to sustain adult tissue homeostasis. Although they are often active at the same time within a tissue, they typically have opposing effects on cell fate decisions. In fact, crosstalk between the two pathways is important in generating the great diversity of cell types that we find in metazoans. Several different mechanisms have been proposed that allow Notch to limit Wnt signalling, driving a Notch-ON/Wnt-OFF state. Here we explore these different mechanisms in human cells and demonstrate two distinct mechanisms by which Notch itself, can limit the transcriptional activity of β-catenin. At the membrane, independently of DSL ligands, Notch1 can antagonise β-catenin activity through an endocytic mechanism that requires its interaction with Deltex and sequesters β-catenin into the membrane fraction. Within the nucleus, the intracellular domain of Notch1 can also limit β-catenin induced transcription through the formation of a complex that requires its interaction with RBPjκ. We believe these mechanisms contribute to the robustness of cell-fate decisions by sharpening the distinction between opposing Notch/Wnt responses. |
| first_indexed | 2024-12-14T15:41:08Z |
| format | Article |
| id | doaj.art-3b960ed61ced47819d25ef2b2656f61c |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T15:41:08Z |
| publishDate | 2021-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-3b960ed61ced47819d25ef2b2656f61c2022-12-21T22:55:37ZengNature PortfolioScientific Reports2045-23222021-04-0111111210.1038/s41598-021-88618-5Inhibition of Wnt signalling by Notch via two distinct mechanismsAhmet Acar0Ana Hidalgo-Sastre1Michael K. Leverentz2Christopher G. Mills3Simon Woodcock4Martin Baron5Giovanna M. Collu6Keith Brennan7Department of Biological Sciences, Middle East Technical UniversityFaculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterFaculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterFaculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterFaculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterFaculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterDepartment of Developmental and Regenerative Biology, Icahn School of Medicine At Mount SinaiFaculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterAbstract Notch and Wnt are two essential signalling pathways that help to shape animals during development and to sustain adult tissue homeostasis. Although they are often active at the same time within a tissue, they typically have opposing effects on cell fate decisions. In fact, crosstalk between the two pathways is important in generating the great diversity of cell types that we find in metazoans. Several different mechanisms have been proposed that allow Notch to limit Wnt signalling, driving a Notch-ON/Wnt-OFF state. Here we explore these different mechanisms in human cells and demonstrate two distinct mechanisms by which Notch itself, can limit the transcriptional activity of β-catenin. At the membrane, independently of DSL ligands, Notch1 can antagonise β-catenin activity through an endocytic mechanism that requires its interaction with Deltex and sequesters β-catenin into the membrane fraction. Within the nucleus, the intracellular domain of Notch1 can also limit β-catenin induced transcription through the formation of a complex that requires its interaction with RBPjκ. We believe these mechanisms contribute to the robustness of cell-fate decisions by sharpening the distinction between opposing Notch/Wnt responses.https://doi.org/10.1038/s41598-021-88618-5 |
| spellingShingle | Ahmet Acar Ana Hidalgo-Sastre Michael K. Leverentz Christopher G. Mills Simon Woodcock Martin Baron Giovanna M. Collu Keith Brennan Inhibition of Wnt signalling by Notch via two distinct mechanisms Scientific Reports |
| title | Inhibition of Wnt signalling by Notch via two distinct mechanisms |
| title_full | Inhibition of Wnt signalling by Notch via two distinct mechanisms |
| title_fullStr | Inhibition of Wnt signalling by Notch via two distinct mechanisms |
| title_full_unstemmed | Inhibition of Wnt signalling by Notch via two distinct mechanisms |
| title_short | Inhibition of Wnt signalling by Notch via two distinct mechanisms |
| title_sort | inhibition of wnt signalling by notch via two distinct mechanisms |
| url | https://doi.org/10.1038/s41598-021-88618-5 |
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