The endothelial transcription factor ERG mediates Angiopoietin-1-dependent control of Notch signalling and vascular stability

Nat Commun. 2017 Jul 11;8:16002. doi: 10.1038/ncomms16002.

Abstract

Notch and Angiopoietin-1 (Ang1)/Tie2 pathways are crucial for vascular maturation and stability. Here we identify the transcription factor ERG as a key regulator of endothelial Notch signalling. We show that ERG controls the balance between Notch ligands by driving Delta-like ligand 4 (Dll4) while repressing Jagged1 (Jag1) expression. In vivo, this regulation occurs selectively in the maturing plexus of the mouse developing retina, where Ang1/Tie2 signalling is active. We find that ERG mediates Ang1-dependent regulation of Notch ligands and is required for the stabilizing effects of Ang1 in vivo. We show that Ang1 induces ERG phosphorylation in a phosphoinositide 3-kinase (PI3K)/Akt-dependent manner, resulting in ERG enrichment at Dll4 promoter and multiple enhancers. Finally, we demonstrate that ERG directly interacts with Notch intracellular domain (NICD) and β-catenin and is required for Ang1-dependent β-catenin recruitment at the Dll4 locus. We propose that ERG coordinates Ang1, β-catenin and Notch signalling to promote vascular stability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Angiopoietin-1 / metabolism*
  • Animals
  • Calcium-Binding Proteins
  • Female
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Jagged-1 Protein / metabolism
  • Male
  • Mice, Inbred C57BL
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Notch / metabolism*
  • Transcriptional Regulator ERG / metabolism
  • Vascular Remodeling*
  • Wnt Signaling Pathway

Substances

  • Adaptor Proteins, Signal Transducing
  • Angiopoietin-1
  • Calcium-Binding Proteins
  • DLL4 protein, human
  • ERG protein, human
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jagged-1 Protein
  • Receptors, Notch
  • Transcriptional Regulator ERG
  • Proto-Oncogene Proteins c-akt