Phosphoproteomics identifies a bimodal EPHA2 receptor switch that promotes embryonic stem cell differentiation

Rosalia Fernandez-Alonso, Francisco Bustos, Manon Budzyk, Pankaj Kumar, Andreas O. Helbig, Jens Hukelmann, Angus I. Lamond, Fredrik Lanner, Houjiang Zhou, Evangelia Petsalaki and Greg M. Findlay ()
Additional contact information
Rosalia Fernandez-Alonso: University of Dundee
Francisco Bustos: University of Dundee
Manon Budzyk: University of Dundee
Pankaj Kumar: Division of Obstetrics and Gynecology, Karolinska Institutet
Andreas O. Helbig: Christian Albrechts University
Jens Hukelmann: University of Dundee
Angus I. Lamond: University of Dundee
Fredrik Lanner: Division of Obstetrics and Gynecology, Karolinska Institutet
Houjiang Zhou: University of Dundee
Evangelia Petsalaki: Wellcome Genome Campus
Greg M. Findlay: University of Dundee

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Embryonic Stem Cell (ESC) differentiation requires complex cell signalling network dynamics, although the key molecular events remain poorly understood. Here, we use phosphoproteomics to identify an FGF4-mediated phosphorylation switch centred upon the key Ephrin receptor EPHA2 in differentiating ESCs. We show that EPHA2 maintains pluripotency and restrains commitment by antagonising ERK1/2 signalling. Upon ESC differentiation, FGF4 utilises a bimodal strategy to disable EPHA2, which is accompanied by transcriptional induction of EFN ligands. Mechanistically, FGF4-ERK1/2-RSK signalling inhibits EPHA2 via Ser/Thr phosphorylation, whilst FGF4-ERK1/2 disrupts a core pluripotency transcriptional circuit required for Epha2 gene expression. This system also operates in mouse and human embryos, where EPHA receptors are enriched in pluripotent cells whilst surrounding lineage-specified trophectoderm expresses EFNA ligands. Our data provide insight into function and regulation of EPH-EFN signalling in ESCs, and suggest that segregated EPH-EFN expression coordinates cell fate with compartmentalisation during early embryonic development.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-020-15173-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15173-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-15173-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().