IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v11y2020i1d10.1038_s41467-020-15173-4.html
   My bibliography  Save this article

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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Rosalia Fernandez-Alonso & Francisco Bustos & Manon Budzyk & Pankaj Kumar & Andreas O. Helbig & Jens Hukelmann & Angus I. Lamond & Fredrik Lanner & Houjiang Zhou & Evangelia Petsalaki & Greg M. Findla, 2020. "Phosphoproteomics identifies a bimodal EPHA2 receptor switch that promotes embryonic stem cell differentiation," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15173-4
    DOI: 10.1038/s41467-020-15173-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-020-15173-4
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-020-15173-4?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Bernhard C. Lechtenberg & Marina P. Gehring & Taylor P. Light & Christopher R. Horne & Mike W. Matsumoto & Kalina Hristova & Elena B. Pasquale, 2021. "Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker," Nature Communications, Nature, vol. 12(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15173-4. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.