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@ARTICLE{Manavski:128038,
author = {Y. Manavski and G. Carmona and K. Bennewitz and Z. Tang and
F. Zhang and A. Sakurai and A. M. Zeiher and J. S. Gutkind
and X. Li and J. Kroll$^*$ and S. Dimmeler and E. Chavakis},
title = {{B}rag2 differentially regulates β1- and
β3-integrin-dependent adhesion in endothelial cells and is
involved in developmental and pathological angiogenesis.},
journal = {Basic research in cardiology},
volume = {109},
number = {2},
issn = {0300-8428},
address = {Berlin},
publisher = {Springer65829},
reportid = {DKFZ-2017-04060},
pages = {404},
year = {2014},
abstract = {β1-Integrins are essential for angiogenesis. The
mechanisms regulating integrin function in endothelial cells
(EC) and their contribution to angiogenesis remain elusive.
Brag2 is a guanine nucleotide exchange factor for the small
Arf-GTPases Arf5 and Arf6. The role of Brag2 in EC and
angiogenesis and the underlying molecular mechanisms remain
unclear. siRNA-mediated Brag2-silencing reduced EC
angiogenic sprouting and migration. Brag2-siRNA transfection
differentially affected α5β1- and αVβ3-integrin
function: specifically, Brag2-silencing increased
focal/fibrillar adhesions and adhesion on β1-integrin
ligands (fibronectin and collagen), while reducing the
adhesion on the αVβ3-integrin ligand, vitronectin.
Consistent with these results, Brag2-silencing enhanced
surface expression of α5β1-integrin, while reducing
surface expression of αVβ3-integrin. Mechanistically,
Brag2-mediated αVβ3-integrin-recycling and β1-integrin
endocytosis and specifically of the active/matrix-bound
α5β1-integrin present in fibrillar/focal adhesions (FA),
suggesting that Brag2 contributes to the disassembly of FA
via β1-integrin endocytosis. Arf5 and Arf6 are promoting
downstream of Brag2 angiogenic sprouting, β1-integrin
endocytosis and the regulation of FA. In vivo silencing of
the Brag2-orthologues in zebrafish embryos using morpholinos
perturbed vascular development. Furthermore, in vivo
intravitreal injection of plasmids containing Brag2-shRNA
reduced pathological ischemia-induced retinal and choroidal
neovascularization. These data reveal that Brag2 is
essential for developmental and pathological angiogenesis by
promoting EC sprouting through regulation of adhesion by
mediating β1-integrin internalization and link for the
first time the process of β1-integrin endocytosis with
angiogenesis.},
keywords = {Antigens, CD29 (NLM Chemicals) / Guanine Nucleotide
Exchange Factors (NLM Chemicals) / IQSEC1 protein, human
(NLM Chemicals) / Integrin alphaVbeta3 (NLM Chemicals) /
Integrin beta3 (NLM Chemicals) / RNA, Small Interfering (NLM
Chemicals) / Receptors, Vitronectin (NLM Chemicals) / VEGFA
protein, human (NLM Chemicals) / Vascular Endothelial Growth
Factor A (NLM Chemicals) / integrin alphavbeta1 (NLM
Chemicals) / ADP-Ribosylation Factors (NLM Chemicals) /
ADP-ribosylation factor 6 (NLM Chemicals)},
cin = {A190},
ddc = {610},
cid = {I:(DE-He78)A190-20160331},
pnm = {311 - Signalling pathways, cell and tumor biology
(POF3-311)},
pid = {G:(DE-HGF)POF3-311},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:24522833},
doi = {10.1007/s00395-014-0404-2},
url = {https://inrepo02.dkfz.de/record/128038},
}