Phosphoproteomics identifies a bimodal EPHA2 receptor switch that promotes embryonic stem cell differentiation.
Rosalia Fernandez-AlonsoFrancisco BustosManon BudzykPankaj KumarAndreas O HelbigJens HukelmannAngus I LamondFredrik LannerHoujiang ZhouEvangelia PetsalakiGreg M FindlayPublished in: Nature communications (2020)
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.
Keyphrases
- cell fate
- gene expression
- signaling pathway
- stem cells
- cell proliferation
- pi k akt
- induced apoptosis
- single cell
- endothelial cells
- poor prognosis
- dna methylation
- transcription factor
- magnetic resonance imaging
- binding protein
- cell therapy
- magnetic resonance
- genome wide
- bone marrow
- oxidative stress
- protein kinase
- endoplasmic reticulum stress
- heat shock
- machine learning