The endothelial transcription factor ERG mediates Angiopoietin-1-dependent control of Notch signalling and vascular stability
File(s)Shah_et_al-2017-Nature_Communications.pdf (3.57 MB)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2017-07-11
Date Acceptance
2017-05-17
Citation
Nature Communications, 2017, 8, pp.1-16
ISSN
2041-1723
Publisher
Nature Publishing Group
Start Page
1
End Page
16
Journal / Book Title
Nature Communications
Volume
8
Copyright Statement
© The Author(s) 2017. Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduc tion in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directly fromthe copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Sponsor
British Heart Foundation
British Heart Foundation
British Heart Foundation
Identifier
https://www.nature.com/articles/ncomms16002
Grant Number
RG/11/17/29256
PG/10/94/28651
RG/17/4/32662
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
REGULATES ANGIOGENESIS
EMBRYONIC LETHALITY
DLL4 REGULATION
BLOOD-VESSELS
ARTERIAL
LIGAND
MICE
EXPRESSION
HOMEOSTASIS
PATHWAY
Adaptor Proteins, Signal Transducing
Angiopoietin-1
Animals
Calcium-Binding Proteins
Female
Human Umbilical Vein Endothelial Cells
Humans
Intercellular Signaling Peptides and Proteins
Jagged-1 Protein
Male
Mice, Inbred C57BL
Phosphatidylinositol 3-Kinases
Phosphorylation
Proto-Oncogene Proteins c-akt
Receptors, Notch
Transcriptional Regulator ERG
Vascular Remodeling
Wnt Signaling Pathway
Animals
Mice, Inbred C57BL
Humans
Intercellular Signaling Peptides and Proteins
Angiopoietin-1
Adaptor Proteins, Signal Transducing
Calcium-Binding Proteins
Phosphorylation
Female
Male
Proto-Oncogene Proteins c-akt
Receptors, Notch
Phosphatidylinositol 3-Kinases
Human Umbilical Vein Endothelial Cells
Wnt Signaling Pathway
Vascular Remodeling
Transcriptional Regulator ERG
Jagged-1 Protein
Publication Status
Published
Article Number
16002
Date Publish Online
2017-07-11