Regulation of mouse embryonic stem cell self-renewal by a Yes-YAP-TEAD2 signaling pathway downstream of LIF
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
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.
Embryonic stem cells, Leukemia inhibitory factor, Self-renewal, Src family kinases, Yes-associated protein
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-157481DOI: 10.1242/jcs.075796ISI: 000288318400016OAI: oai:DiVA.org:uu-157481DiVA: diva2:436002