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Regulation of mouse embryonic stem cell self-renewal by a Yes-YAP-TEAD2 signaling pathway downstream of LIF
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2011 (English)In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 124, no 7, 1136-1144 p.Article in journal (Refereed) Published
Abstract [en]

The cytoplasmic tyrosine kinase Yes has previously been shown to have an important role in maintaining mouse and human embryonic stem (ES) self-renewal through an unknown pathway downstream of leukemia inhibitory factor (LIF) and one or more factors in serum. Here, we show that TEAD2 and its transcriptional co-activator, the Yes-associated protein YAP, co-operate in a signaling pathway downstream of Yes. We show that YAP, TEAD2 and Yes are highly expressed in self-renewing ES cells, are activated by LIF and serum, and are downregulated when cells are induced to differentiate. We also demonstrate that kinase-active Yes binds and phosphorylates YAP, and activates YAP-TEAD2-dependent transcription. We found that TEAD2 associates directly with the Oct-3/4 promoter. Moreover, activation of the Yes pathway induced activity of the Oct-3/4 and Nanog promoters, whereas suppression of this pathway inhibited promoter activity. Nanog, in turn, suppressed TEAD2-dependent promoter activity, whereas siRNA-mediated knockdown of Nanog induced it, suggesting a negative regulatory feedback loop. Episomal supertransfection of cells with inhibitory TEAD2-EnR induced endodermal differentiation, which suggests that this pathway is necessary for ES cell maintenance.

Place, publisher, year, edition, pages
2011. Vol. 124, no 7, 1136-1144 p.
Keyword [en]
Embryonic stem cells, Leukemia inhibitory factor, Self-renewal, Src family kinases, Yes-associated protein
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-157481DOI: 10.1242/jcs.075796ISI: 000288318400016OAI: oai:DiVA.org:uu-157481DiVA: diva2:436002
Available from: 2012-02-17 Created: 2011-08-22 Last updated: 2017-12-08Bibliographically approved

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