BRAG2/GEP100/IQSec1 Interacts with Clathrin and Regulates α5β1 Integrin Endocytosis through Activation of ADP Ribosylation Factor 5 (Arf5)

Moravec, Radim; Conger, Kathryn K.; D’Souza, Ryan S; Allison, Anne; Casanova, James E.

doi:10.1074/jbc.m112.383117

Cited by 48 publications

(64 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Arf6 was shown to contribute via PIP5K and recruitment of AP2 and clathrin to receptor endocytosis [22,29,39]. Moreover, a recent study demonstrated that Brag2 could bind clathrin and AP2 itself and that Arf5, an Arf-GTPase also activated by Brag2, may contribute to b1-integrin endocytosis [33]. In line with these results, we found here that Arf5 and Arf6 mediate downstream of Brag2 angiogenic sprouting and the regulation of focal/fibrillar adhesions containing activated a5b1-integrins in EC.…”

Section: Discussionsupporting

confidence: 79%

“…In line with our results, Dunphy et al [15] demonstrated that silencing of Brag2 in HeLa cells increased surface expression of b1-integrins and cell spreading. Moreover, another study suggested that Brag2 may promote b1-integrin endocytosis [33]. Remarkably in our present work, we demonstrated that Brag2 is involved in the internalization/endocytosis of activated (matrix-bound) a5b1-integrins, as assessed by an activationdependent a5b1-integrin antibody recognizing an active a5b1-integrin conformation present in fibrillar and partly in focal adhesions [12], supporting the idea that Brag2 contributes to the disassembly of focal/fibrillar adhesions by mediating endocytosis of active/matrix-bound a5b1-integrins.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, Brag2 was shown to be involved in trafficking processes such as the endocytosis of synaptic AMPA-receptors, E-Cadherin recycling, and phagocytosis of monocytes [21,46,47]. Silencing of Brag2 in HeLa cells increased the surface expression of b1-integrins [15] and a later study indicated that Brag2 might contribute to b1-integrin endocytosis in HeLa cells [33]. However, the role of Brag2 in the regulation of integrins in EC was not studied thus far.…”

Section: Introductionmentioning

confidence: 99%

“…Arf6 can be activated by several guanine exchange nucleotide factors (GEFs) [7]. Brag2 (GEP100/IQSEC1) is a GEF activating the small ArfGTPases Arf4, Arf5 and Arf6 [33,48] and is expressed in EC [20,45]. Brag2 was found to promote the invasive activity of breast cancer cells [34] and myoblast fusion [11,37].…”

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: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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

“…19 While BRAG2 does indeed activate Arf6 in cell-based assays, we found that it also activates the class II Arf, Arf5, and that knockdown of endogenous BRAG2 reduces the activity of both Arf5 and Arf6. 20 Surprisingly, depletion of Arf5 but not Arf6 phenocopies BRAG2 knockdown; it slows b1 integrin endocytosis and enhances cell spreading. Conversely, the effects of BRAG2 depletion on both surface b1-integrin levels and cell spreading are reversed by expression of a rapid cycling (constitutively active) Arf5T161A mutant, but not by rapid cycling Arf6T157A.…”

Section: Integrin Traffickingmentioning

confidence: 99%

The BRAG/IQSec family of Arf GEFs

D’Souza

Casanova

2016

Small GTPases

Self Cite

View full text Add to dashboard Cite

The IQSec/BRAG proteins are a subfamily of Arf-nucleotide exchange factors. Since their discovery almost 15 y ago, the BRAGs have been reported to be involved in diverse physiological processes from myoblast fusion, neuronal pathfinding and angiogenesis, to pathophysiological processes including X-linked intellectual disability and tumor metastasis. In this review we will address how, in each of these situations, the BRAGs are thought to regulate the surface levels of adhesive and signaling receptors. While in most cases BRAGs are thought to enhance the endocytosis of these receptors, how they achieve this remains unclear. Similarly, while all 3 BRAG proteins contain calmodulin-binding IQ motifs, little is known about how their activities might be regulated by calcium. These are some of the questions that are likely to form the basis of future research.

show abstract

Circular RNA SLTM as a miR‐421‐competing endogenous RNA to mediate HMGB2 expression stimulates apoptosis and inflammation in arthritic chondrocytes

Zhang

Xiang

Zhou

et al. 2023

J Biochem & Molecular Tox

View full text Add to dashboard Cite

Osteoarthritis (OA) is the most common age-related joint disease characterized by chronic inflammation, progressive articular cartilage destruction, and subchondral sclerosis. Accumulating evidence suggests that circular RNAs (circRNAs) play key roles in OA, but the function of circSLTM in OA remains greatly unknown.Therefore, this study focused on interleukin-1β (IL-1β)-treated primary human chondrocytes as well as a rat model to investigate the expression pattern and functional role of circSLTM in OA in vitro and in vivo. CircSLTM and high mobility group protein B2 (HMGB2) were upregulated in IL-1β-induced chondrocytes, whereas miR-421 was downregulated. Knockdown of circSLTM or overexpression of miR-421 ameliorated IL-1β-induced chondrocyte apoptosis and inflammation.The regulatory relationship between circSLTM and miR-421, as well as that between miR-421 and HMGB2, was predicted by bioinformatics and then verified by the RNA immunoprecipitation experiment and dual-luciferase reporter gene assay. Furthermore, silencing of circSLTM increased cartilage destruction and decreased cartilage tissue apoptosis rate and inflammation in a rat model of OA. Taken together, our findings demonstrate the fundamental role of circSLTM in OA progression and provide a potential molecular target for OA therapy.

show abstract

BRAG2/GEP100/IQSec1 Interacts with Clathrin and Regulates α5β1 Integrin Endocytosis through Activation of ADP Ribosylation Factor 5 (Arf5)

Cited by 48 publications

References 34 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

The BRAG/IQSec family of Arf GEFs

Circular RNA SLTM as a miR‐421‐competing endogenous RNA to mediate HMGB2 expression stimulates apoptosis and inflammation in arthritic chondrocytes

Contact Info

Product

Resources

About