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...

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Autores principales:	Ahmet Acar, Ana Hidalgo-Sastre, Michael K. Leverentz, Christopher G. Mills, Simon Woodcock, Martin Baron, Giovanna M. Collu, Keith Brennan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3b960ed61ced47819d25ef2b2656f61c
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spelling	oai:doaj.org-article:3b960ed61ced47819d25ef2b2656f61c2021-12-02T13:41:34ZInhibition of Wnt signalling by Notch via two distinct mechanisms10.1038/s41598-021-88618-52045-2322https://doaj.org/article/3b960ed61ced47819d25ef2b2656f61c2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88618-5https://doaj.org/toc/2045-2322Abstract 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.Ahmet AcarAna Hidalgo-SastreMichael K. LeverentzChristopher G. MillsSimon WoodcockMartin BaronGiovanna M. ColluKeith BrennanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
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
title	Inhibition of Wnt signalling by Notch via two distinct mechanisms
title_short	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_sort	inhibition of wnt signalling by notch via two distinct mechanisms
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/3b960ed61ced47819d25ef2b2656f61c
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Inhibition of Wnt signalling by Notch via two distinct mechanisms

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