A Novel Small Molecule Regulator of Guanine Nucleotide Exchange Activity of the ADP-ribosylation Factor and Golgi Membrane Trafficking

An image-based phenotypic screen was developed to identify small molecule regulators of intracellular traffic. Using this screen we found that AG1478, a previously known inhibitor of epidermal growth factor receptor, had epidermal growth factor receptor-independent activity in inducing the disassemb...

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Bibliographic Details
Published in:The Journal of biological chemistry 2008-11, Vol.283 (45), p.31087-31096
Main Authors: Pan, Heling, Yu, Jia, Zhang, Lihong, Carpenter, Anne, Zhu, Hong, Li, Li, Ma, Dawei, Yuan, Junying
Format: Article
Language:English
Subjects:
Biological Transport, Active - drug effects
Biological Transport, Active - genetics
Brefeldin A - pharmacology
Cell Line
Golgi Apparatus - metabolism
Guanine Nucleotide Exchange Factors - antagonists & inhibitors
Guanine Nucleotide Exchange Factors - genetics
Guanine Nucleotide Exchange Factors - metabolism
Humans
Intracellular Membranes - metabolism
Mutation
Protein Structure, Tertiary - genetics
Protein Synthesis Inhibitors - pharmacology
Quinazolines
Tyrphostins - pharmacology
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Summary:An image-based phenotypic screen was developed to identify small molecule regulators of intracellular traffic. Using this screen we found that AG1478, a previously known inhibitor of epidermal growth factor receptor, had epidermal growth factor receptor-independent activity in inducing the disassembly of the Golgi in human cells. Similar to brefeldin A (BFA), a known disrupter of the Golgi, AG1478 inhibits the activity of small GTPase ADP-ribosylation factor. Unlike BFA, AG1478 exhibits low cytotoxicity and selectively targets the cis-Golgi without affecting endosomal compartment. We show that AG1478 inhibits GBF1, a large nucleotide exchange factor for the ADP-ribosylation factor, in a Sec7 domain-dependent manner and mimics the phenotype of a GBF1 mutant that has an inactive mutation. The treatment with AG1478 leads to the recruitment of GBF1 to the vesicular-tubular clusters adjacent to the endoplasmic reticulum exit sites, a step only transiently observed previously in the presence of BFA. We propose that the treatment with AG1478 delineates a membrane trafficking intermediate step that depends upon the Sec7 domain.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M806592200