ERG activity is regulated by endothelial FAK coupling with TRIM25/USP9x in vascular patterning.
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Date
2022-07-01ICR Author
Author
D'Amico, G
Fernandez, I
Gómez-Escudero, J
Kim, H
Maniati, E
Azman, MS
Mardakheh, FK
Serrels, B
Serrels, A
Parsons, M
Squire, A
Birdsey, GM
Randi, AM
Bolado-Carrancio, A
Gangeswaran, R
Reynolds, LE
Bodrug, N
Wang, Y
Wang, J
Meier, P
Hodivala-Dilke, KM
Type
Journal Article
Metadata
Show full item recordAbstract
Precise vascular patterning is crucial for normal growth and development. The ERG transcription factor drives Delta-like ligand 4 (DLL4)/Notch signalling and is thought to act as a pivotal regulator of endothelial cell (EC) dynamics and developmental angiogenesis. However, molecular regulation of ERG activity remains obscure. Using a series of EC-specific focal adhesion kinase (FAK)-knockout (KO) and point-mutant FAK-knock-in mice, we show that loss of ECFAK, its kinase activity or phosphorylation at FAK-Y397, but not FAK-Y861, reduces ERG and DLL4 expression levels together with concomitant aberrations in vascular patterning. Rapid immunoprecipitation mass spectrometry of endogenous proteins identified that endothelial nuclear-FAK interacts with the deubiquitinase USP9x and the ubiquitin ligase TRIM25. Further in silico analysis confirms that ERG interacts with USP9x and TRIM25. Moreover, ERG levels are reduced in FAKKO ECs via a ubiquitin-mediated post-translational modification programme involving USP9x and TRIM25. Re-expression of ERG in vivo and in vitro rescues the aberrant vessel-sprouting defects observed in the absence of ECFAK. Our findings identify ECFAK as a regulator of retinal vascular patterning by controlling ERG protein degradation via TRIM25/USP9x.
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Subject
Endothelial cell signalling
Retinal angiogenesis
Vascular patterning regulation
Animals
Endothelial Cells
Focal Adhesion Protein-Tyrosine Kinases
Mice
Neovascularization, Physiologic
Signal Transduction
Transcription Factors
Ubiquitins
Research team
Cell Death and Immunity
Language
eng
Date accepted
2022-04-29
License start date
2022-07-01
Citation
Development (Cambridge), 2022, 149 (13), pp. dev200528 -
Publisher
COMPANY BIOLOGISTS LTD