RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73

Title: RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73
Authors: Papaspyropoulos, AngelosBradley, LeanneThapa, AsmitaRaso, CinziaKriegsheim, Alexander vonMatallanas, DavidO'Neill, Ericet al.
Permanent link: http://hdl.handle.net/10197/11888
Date: 30-Jan-2018
Online since: 2021-01-26T07:18:12Z
Abstract: Transition from pluripotency to differentiation is a pivotal yet poorly understood developmental step. Here, we show that the tumour suppressor RASSF1A is a key player driving the early specification of cell fate. RASSF1A acts as a natural barrier to stem cell self-renewal and iPS cell generation, by switching YAP from an integral component in the β-catenin-TCF pluripotency network to a key factor that promotes differentiation. We demonstrate that epigenetic regulation of the Rassf1A promoter maintains stemness by allowing a quaternary association of YAP-TEAD and β-catenin-TCF3 complexes on the Oct4 distal enhancer. However, during differentiation, promoter demethylation allows GATA1-mediated RASSF1A expression which prevents YAP from contributing to the TEAD/β-catenin-TCF3 complex. Simultaneously, we find that RASSF1A promotes a YAP-p73 transcriptional programme that enables differentiation. Together, our findings demonstrate that RASSF1A mediates transcription factor selection of YAP in stem cells, thereby acting as a functional "switch" between pluripotency and initiation of differentiation.
Funding Details: Science Foundation Ireland
Wellcome Trust
Funding Details: CRUK A19277
MRC
Pancreatic Cancer UK
Federal Agency for Scientific Organizations
Type of material: Journal Article
Publisher: Springer
Journal: Nature Communications
Volume: 9
Copyright (published version): 2018 the Authors
Keywords: Protein-serine-threonine kinasesAdaptor proteinsDNA-binding proteinsTumor suppressor proteinsPhosphoproteinsTranscription factorsSignal transductionCell differentiationGene expression regulationOctamer transcription factor-3Wnt proteinsBeta cateninBasic helix-loop-helix transcription factorsEmbryonic stem cellsTumor protein p73Signal transducing
DOI: 10.1038/s41467-017-02786-5
Language: en
Status of Item: Peer reviewed
ISSN: 2041-1723
This item is made available under a Creative Commons License: https://creativecommons.org/licenses/by/3.0/ie/
Appears in Collections:SBI Research Collection
Medicine Research Collection

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