RHOQ is induced by DLL4 and regulates angiogenesis by determining the intracellular route of the Notch intracellular domain

Angiogenesis, the formation of new blood vessels by endothelial cells, is a finely tuned process relying on the balance between promoting and repressing signalling pathways. Among these, Notch signalling is critical in ensuring appropriate response of endothelial cells to pro-angiogenic stimuli. How...

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Bibliographic Details
Published in:Angiogenesis (London) Vol. 23; no. 3; pp. 493 - 513
Main Authors: Bridges, Esther, Sheldon, Helen, Kleibeuker, Esther, Ramberger, Evelyn, Zois, Christos, Barnard, Alun, Harjes, Ulrike, Li, Ji-Liang, Masiero, Massimo, MacLaren, Robert, Harris, Adrian
Format: Journal Article
Language:English
Published: Dordrecht Springer Netherlands 01.08.2020
Springer Nature B.V
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Angiogenesis
Autophagy
Biomedical and Life Sciences
Biomedicine
Blood vessels
Calcium-Binding Proteins - genetics
Calcium-Binding Proteins - metabolism
Cancer Research
Cardiology
Cell Biology
Degradation
Endothelial cells
Guanosine triphosphatases
Human Umbilical Vein Endothelial Cells - metabolism
Humans
Intracellular
Lysosomes
Neovascularization, Physiologic
Notch1 protein
Nuclear transport
Oncology
Ophthalmology
Original Paper
Phagocytosis
Protein Domains
Receptors, Notch - genetics
Receptors, Notch - metabolism
rho GTP-Binding Proteins - genetics
rho GTP-Binding Proteins - metabolism
Route selection
Signal Transduction
Signaling
Translocation
Autophagy pathway
Angiogenesis
DLL4 Notch1 signalling
RHOQ
NICD degradation
ISSN:0969-6970, 1573-7209, 1573-7209
Online Access:Get full text
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Summary:Angiogenesis, the formation of new blood vessels by endothelial cells, is a finely tuned process relying on the balance between promoting and repressing signalling pathways. Among these, Notch signalling is critical in ensuring appropriate response of endothelial cells to pro-angiogenic stimuli. However, the downstream targets and pathways effected by Delta-like 4 (DLL4)/Notch signalling and their subsequent contribution to angiogenesis are not fully understood. We found that the Rho GTPase, RHOQ, is induced by DLL4 signalling and that silencing RHOQ results in abnormal sprouting and blood vessel formation both in vitro and in vivo. Loss of RHOQ greatly decreased the level of Notch signalling, conversely overexpression of RHOQ promoted Notch signalling. We describe a new feed-forward mechanism regulating DLL4/Notch signalling, whereby RHOQ is induced by DLL4/Notch and is essential for the NICD nuclear translocation. In the absence of RHOQ, Notch1 becomes targeted for degradation in the autophagy pathway and NICD is sequestered from the nucleus and targeted for degradation in lysosomes.
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ISSN:0969-6970
1573-7209
1573-7209
DOI:10.1007/s10456-020-09726-w