ERG activity is regulated by endothelial FAK coupling with TRIM25/USP9x in vascular patterning
| Autor: | Gabriela D'Amico, Isabelle Fernandez, Jesús Gómez-Escudero, Hyojin Kim, Eleni Maniati, Muhammad Syahmi Azman, Faraz K. Mardakheh, Bryan Serrels, Alan Serrels, Maddy Parsons, Anthony Squire, Graeme M. Birdsey, Anna M. Randi, Alfonso Bolado-Carrancio, Rathi Gangeswaran, Louise E. Reynolds, Natalia Bodrug, Yaohe Wang, Jun Wang, Pascal Meier, Kairbaan M. Hodivala-Dilke |
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| Přispěvatelé: | British Heart Foundation |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Endothelial cell signaling
Retinal angiogenesis Vascular patterning regulation Medizin Endothelial Cells Neovascularization Physiologic 06 Biological Sciences Mice Endothelial cell signalling Focal Adhesion Protein-Tyrosine Kinases Animals Ubiquitins Molecular Biology 11 Medical and Health Sciences Signal Transduction Transcription Factors Developmental Biology |
| Zdroj: | D'amico, G, Fernandez, I, Gómez-escudero, J, Kim, H, Maniati, E, Azman, M S, Mardakheh, F K, Serrels, B, Serrels, A, Parsons, M, Squire, A, Birdsey, G M, Randi, A M, Bolado-carrancio, A, Gangeswaran, R, Reynolds, L E, Bodrug, N, Wang, Y, Wang, J, Meier, P & Hodivala-dilke, K M 2022, ' ERG activity is regulated by endothelial FAK coupling with TRIM25/USP9x in vascular patterning ', Development, vol. 149, no. 13, dev200528 . https://doi.org/10.1242/dev.200528 |
| ISSN: | 1477-9129 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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