Slit2–Robo4 signalling promotes vascular stability by blocking Arf6 activity

Jones, C. E.; Nishiya, Naoyuki; London, Nyall R.; Zhu, Weiquan; Sorensen, Lise K.; Chan, Aubrey C.; Lim, C. J.; Chen, Haoyu; Zhang, Qisheng; Schultz, Peter G.; Hayallah, Alaa M.; Thomas, Kirk R.; Famulok, Michael; Zhang, Kang; Ginsberg, Mark H.; Li, Dean Y.

doi:10.1038/ncb1976

Cited by 200 publications

(300 citation statements)

References 23 publications

(35 reference statements)

Supporting

Mentioning

279

Contrasting

Order By: Relevance

“…Moreover, inhibition of Brag2 seems to be a promising therapeutic target for treatment of pathological angiogenesis. Adhesion to fibronectin and VEGF was shown to stimulate activation of the Arf6 GTPase [18,20,27]. Our present work shows that Brag2 is required for basal and VEGF-induced Arf6 activity in EC.…”

Section: Discussionmentioning

confidence: 53%

“…Moreover, we confirmed that VEGF stimulation rapidly increases the activity of the small GTPase Arf6 in EC (supplemental Figures S1A and S1B) as previously reported [18,20,27]. To address the role of Brag2 as guanine nucleotide exchange factor (GEF) in the VEGFinduced activation of Arf6, we employed siRNA targeting Brag2.…”

Section: Role Of Brag2 In the Vegf-induced Activation Of Arf6mentioning

confidence: 56%

“…These data are consistent with the data of Hashimoto et al [20] demonstrating that VEGF stimulation leads to the association of VEGFR2 to Brag2 thereby mediating Arf6 activation. Interestingly, a pharmacological inhibitor of the Arf6-GEFs cytohesins 1-3, SecinH3, reduced VEGF-induced activation of Arf6 in EC [27], suggesting that not only Brag2, but also Arf6-GEFs of the cytohesin family may contribute to the VEGF-induced stimulation of Arf6 activity.…”

Section: Discussionmentioning

confidence: 99%

“…Several stimuli, such as integrin binding to fibronectin, as well as stimulation with growth factors, cytokines and guidance molecules may induce the activation of Arf6 in EC [18,20,27,44]. Arf6 can be activated by several guanine exchange nucleotide factors (GEFs) [7].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Brag2 differentially regulates β1- and β3-integrin-dependent adhesion in endothelial cells and is involved in developmental and pathological angiogenesis

et al. 2014

View full text Add to dashboard Cite

b1-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 a5b1-and aVb3-integrin function: specifically, Brag2-silencing increased focal/fibrillar adhesions and adhesion on b1-integrin ligands (fibronectin and collagen), while reducing the adhesion on the aVb3-integrin ligand, vitronectin. Consistent with these results, Brag2-silencing enhanced surface expression of a5b1-integrin, while reducing surface expression of aVb3-integrin. Mechanistically, Brag2-mediated aVb3-integrin-recycling and b1-integrin endocytosis and specifically of the active/matrix-bound a5b1-integrin present in fibrillar/focal adhesions (FA), suggesting that Brag2 contributes to the disassembly of FA via b1-integrin endocytosis. Arf5 and Arf6 are promoting downstream of Brag2 angiogenic sprouting, b1-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 b1-integrin internalization and link for the first time the process of b1-integrin endocytosis with angiogenesis.

show abstract

Section: Discussionmentioning

confidence: 53%

Section: Role Of Brag2 In the Vegf-induced Activation Of Arf6mentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Brag2 differentially regulates β1- and β3-integrin-dependent adhesion in endothelial cells and is involved in developmental and pathological angiogenesis

et al. 2014

View full text Add to dashboard Cite

show abstract

“…These observations led us to speculate that Arf6 might be involved in HGF-stimulated tumour angiogenesis. In support of this proposal, Arf6 has recently been shown to be involved in angiogenesis-related cell functions in vitro [23][24][25][26] . However, the in vivo functions of Arf6 in endothelial cells, in particular in relationship to HGF-regulated tumour angiogenesis and growth, have not been explored.…”

mentioning

confidence: 76%

Arf6 regulates tumour angiogenesis and growth through HGF-induced endothelial β1 integrin recycling

et al. 2015

View full text Add to dashboard Cite

Angiogenesis Inhibitors

Shi

2021

Burger's Medicinal Chemistry and Drug Discovery

View full text Add to dashboard Cite

Angiogenesis, the formation of new capillary blood vessels from preexisting vasculature, plays an essential role in organ growth and wound repair. However, pathological angiogenesis is a hallmark of various cancers and a range of nonneoplastic diseases including ischaemic and inflammatory disorders. Angiogenesis is a complicated multistep process that precisely mediated by the balance between pro‐ and antiangiogenic factors. Concentrated efforts in this area of research have led to the discovery of a growing number of angiogenesis‐related molecules and the complex interactions among these molecules. The integrated understanding of molecular mechanism of angiogenesis process involved in tumor growth and metastasis has identified angiogenesis as a promising target for cancer therapy. Over the past two decades, dozens of antiangiogenic drugs have been approved for the treatment of a variety of cancers. So far, hundreds of thousands of cancer patients have benefited from antiangiogenesis treatments but limited efficacy and resistance remain outstanding problems. This article will focus on tumor angiogenesis‐related signaling molecules and pathways, development of antiangiogenic agents for the treatment of various tumors, and challenge of antiangiogenic therapy of tumors.

show abstract

Slit2–Robo4 signalling promotes vascular stability by blocking Arf6 activity

Cited by 200 publications

References 23 publications

Brag2 differentially regulates β1- and β3-integrin-dependent adhesion in endothelial cells and is involved in developmental and pathological angiogenesis

Brag2 differentially regulates β1- and β3-integrin-dependent adhesion in endothelial cells and is involved in developmental and pathological angiogenesis

Arf6 regulates tumour angiogenesis and growth through HGF-induced endothelial β1 integrin recycling

Angiogenesis Inhibitors

Contact Info

Product

Resources

About