GEP ₁₀₀ /BRAG2: Activator of ADP-ribosylation factor 6 for regulation of cell adhesion and actin cytoskeleton via E-cadherin and α-catenin

Abstract

GEP100 (p100) was identified as an ADP-ribosylation factor (ARF) guanine nucleotide-exchange protein (GEP) that partially colocalized with ARF6 in the cell periphery. p100 preferentially accelerated guanosine 5[␥-thio]triphosphate (GTP␥S) binding by ARF6, which participates in protein trafficking near the plasma membrane, including receptor recycling, cell adhesion, and cell migration. Here we report that yeast two-hybrid screening of a human fetal brain cDNA library using p100 as bait revealed specific interaction with ␣-catenin, which is known as a regulator of adherens junctions and actin cytoskeleton remodeling. Interaction of p100 with ␣-catenin was confirmed by coimmunoprecipitation of the endogenous proteins from human HepG2 or CaSki cells, although colocalization was difficult to demonstrate microscopically. ␣-Catenin enhanced GTP␥S binding by ARF6 in vitro in the presence of p100. Depletion of p100 by small interfering RNA (siRNA) treatment in HepG2 cells resulted in E-cadherin content 3-fold that in control cells and blocked hepatocyte growth factorinduced redistribution of E-cadherin, consistent with a known role of ARF6 in this process. F-actin was markedly decreased in normal rat kidney (NRK) cells overexpressing wild-type p100, but not its GEP-inactive mutants, also consistent with the conclusion that p100 has an important role in the activation of ARF6 for its functions in both E-cadherin recycling and actin remodeling.adherens junction ͉ F-actin

Genome-wide association study to identify genetic variants present in Japanese patients harboring intracranial aneurysms

“…ARF-GEP100 protein (ADP-ribosylation factorguanine nucleotide-exchange protein-100 kDa) encoded by this gene activates ADP-ribosylation factor protein, ARF6, and regulates cell adhesion through recycling E-cadherin and remodeling actin cytoskeleton. 24 We speculate that these three products might act in the uniform pathway of actin remodeling with ELN/LIMK 25 in smooth Figure 1 The scatter plot of -log 10 P against all the analysis. The four data sets were plotted in -log 10 P of GWAS.…”

FRMD4A regulates epithelial polarity by connecting Arf6 activation with the PAR complex

“…Another important function of Arf6 is its role in endosome recycling (36). Recently, several lines of evidence indicated that Arf6 is involved in the membrane trafficking of E-cadherin (37,38). Elucidation of the roles of Arf6 at primordial AJs is needed to understand the molecular mechanisms underlying epithelial polarization.…”

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

“…Brag2 was found to promote the invasive activity of breast cancer cells [34] and myoblast fusion [11,37]. 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].…”