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J. Biol. Chem., Vol. 283, Issue 45, 31087-31096, November 7, 2008

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

Heling Pan, Jia Yu, Lihong Zhang, Anne Carpenter¹, Hong Zhu^¶, Li Li, Dawei Ma², and Junying Yuan^¶3

From the State Key Laboratory of Bio-organic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China, the Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, and the ^¶Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115

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.

Received for publication, August 25, 2008 , and in revised form, September 15, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R37 AG12859 (to J. Y.). This work was also supported by National Natural Science Foundation of China Grant 20321202 and Chinese Academy of Science Grant KGCX2-SW-209 (to D. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Figs. S1-S3.

¹ Novartis Fellow of the Life Sciences Research Foundation.

² To whom correspondence may be addressed. E-mail: madw{at}pub.sioc.ac.cn.

³ To whom correspondence may be addressed. E-mail: jyuan{at}hms.harvard.edu.

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