Journal
TRAFFIC
Volume 11, Issue 12, Pages 1537-1551Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1600-0854.2010.01122.x
Keywords
Arf-GEF; GBF1; Golgi; vesicle transport
Categories
Funding
- BBSRC
- MRC
- Assocation pour la Recherche contre le Cancer
- ANR Physique-Chimie du Vivant
- Biotechnology and Biological Sciences Research Council [BB/E012450/1] Funding Source: researchfish
- Medical Research Council [G117/554] Funding Source: researchfish
- BBSRC [BB/E012450/1] Funding Source: UKRI
- MRC [G117/554] Funding Source: UKRI
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Brefeldin A-mediated inhibition of ADP ribosylation factor (Arf) GTPases and their guanine nucleotide exchange factors, Arf-GEFs, has been a cornerstone of membrane trafficking research for many years. Brefeldin A (BFA) is relatively non-selective inhibiting at least three targets in human cells, Golgi brefeldin A resistance factor 1 (GBF1), brefeldin A inhibited guanine nucleotide exchange factor 1 (BIG1) and brefeldin A inhibited guanine nucleotide exchange factor 2 (BIG2). Here, we show that the previously described compound Exo2 acts through inhibition of Arf-GEF function, but causes other phenotypic changes that are not GBF1 related. We describe the engineering of Exo2 to produce LG186, a more selective, reversible inhibitor of Arf-GEF function. Using multiple-cell-based assays and GBF1 mutants, our data are most consistent with LG186 acting by selective inhibition of GBF1. Unlike other Arf-GEF and reported GBF1 inhibitors including BFA, Exo2 and Golgicide A, LG186 induces disassembly of the Golgi stack in both human and canine cells.
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