Disease relevance of ARFGEF2

• Finally, transfection of a dominant-negative construct of ARFGEF2 in SHSY5Y neuroblastoma cells partially blocked FLNA transport from the Golgi apparatus to the cell membrane [1].
• These phage Ig-like domains fall into three distinct sequence families, which are similar to the classic immunoglobulin domain (I-Set), the fibronectin type 3 repeat (FN3), and the bacterial Ig-like domain (Big2) [2].

High impact information on ARFGEF2

• Here we show that an autosomal recessive condition characterized by microcephaly and periventricular heterotopia maps to chromosome 20 and is caused by mutations in the gene ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2) [3].
• Inhibition of BIG2 by BFA, or by a dominant negative ARFGEF2 cDNA, decreases cell proliferation in vitro, suggesting a cell-autonomous regulation of neural expansion [3].
• Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex [3].
• By northern-blot analysis, we found that mouse Arfgef2 mRNA levels are highest during embryonic periods of ongoing neuronal proliferation and migration, and by in situ hybridization, we found that the mRNA is widely distributed throughout the embryonic central nervous system (CNS) [3].
• By electron microscopy, Golgi membranes in BIG1-depleted cells were less sharply defined than those in mock or BIG2 siRNA-treated cells, with more vesicle-like structures at the transface [4].

Biological context of ARFGEF2

• We show here a requirement for BIG1 (but not BIG2) in glycosylation and function of beta1 [4].

Anatomical context of ARFGEF2

• Here we characterize the expression patterns for ARFGEF2 within the central nervous systems of human and mouse in order to better understand their potential roles in causing PH [1].
• Overlapping expression of ARFGEF2 and Filamin A in the neuroependymal lining of the lateral ventricles: insights into the cause of periventricular heterotopia [1].
• We conclude that in HepG2 cells BIG2 and Exo70 interact in trans-Golgi network and centrosomes, as well as in exocyst structures or complexes that move along microtubules to the plasma membrane, consistent with a functional association in both early and late stages of vesicular trafficking [5].
• By immunofluorescence microscopy, endogenous BIG2 and Exo70 in HepG2 cells were visualized at Golgi membranes and apparently at the microtubule-organizing center (MTOC) [5].
• Association of brefeldin A-inhibited guanine nucleotide-exchange protein 2 (BIG2) with recycling endosomes during transferrin uptake [6].

Associations of ARFGEF2 with chemical compounds

• The Brefeldin A-inhibited Guanine Nucleotide-exchange Protein, BIG2, Regulates the Constitutive Release of TNFR1 Exosome-like Vesicles [7].
• AMY-1 (associate of Myc-1) localization to the trans-Golgi network through interacting with BIG2, a guanine-nucleotide exchange factor for ADP-ribosylation factors [8].
• We have recently shown that BIG2 overexpression blocks BFA-induced redistribution of the AP-1 complex but not TGN membrane tubulation [9].

Regulatory relationships of ARFGEF2

• The BIG2 overexpression blocked BFA-induced redistribution from membranes of ARF1 and the AP-1 complex but not that of the COPI complex [10].

Other interactions of ARFGEF2

• Protein kinase A-anchoring (AKAP) domains in brefeldin A-inhibited guanine nucleotide-exchange protein 2 (BIG2) [11].
• These results suggest that mutations in ARFGEF2 may impair targeted transport of FLNA to the cell surface within neural progenitors along the neuroependyma and that disruption of these cells could contribute to PH formation [1].
• ARFGEF2 encodes for the protein brefeldin-inhibited guanine exchange factor 2 (BIG2) [1].
• Interaction of BIG2, a brefeldin A-inhibited guanine nucleotide-exchange protein, with exocyst protein Exo70 [5].
• These observations indicate that BIG2 is involved in trafficking from the TGN by regulating membrane association of AP-1 and GGA through activating ARF [9].

Analytical, diagnostic and therapeutic context of ARFGEF2

• Furthermore, overlapping BIG2 and FLNA expression was greatest in these same neuroependymal cells of human embryonic brain and was co-expressed in progenitors by Western blot [1].

References