title: A novel small molecule regulator of guanine nucleotide exchange activity of the ADP-ribosylation factor and golgi membrane trafficking.
abstract: 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.
authors.affiliation: State Key Laboratory of Bio-organic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
authors.forename: Heling
authors.initials: H
authors.lastname: Pan
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.forename: Lihong
authors.initials: L
authors.lastname: Zhang
authors.forename: Anne
authors.initials: A
authors.lastname: Carpenter
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Dawei
authors.initials: D
authors.lastname: Ma
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
mesh_terms: D001693:Biological Transport, Active / Q000187:drug effects / Q000235:genetics; D020126:Brefeldin A / Q000494:pharmacology; D002460:Cell Line; D006056:Golgi Apparatus / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D009154:Mutation; D017434:Protein Structure, Tertiary / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011799:Quinazolines; D020032:Tyrphostins / Q000494:pharmacology*
chemical_list: C120445:GBF1 protein, human; D020662:Guanine Nucleotide Exchange Factors; D011500:Protein Synthesis Inhibitors; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D020126:Brefeldin A
references.citation: Nature. 2000 Oct 26;407(6807):1022-6
references.pmid: 11069184
references.citation: BMC Genomics. 2005 Feb 17;6:20
references.pmid: 15717927
references.citation: Science. 1991 Nov 22;254(5035):1197-9
references.pmid: 1957170
references.citation: Traffic. 2002 Jul;3(7):483-95
references.pmid: 12047556
references.citation: J Biol Chem. 1994 May 6;269(18):13325-30
references.pmid: 8175763
references.citation: Mol Biol Cell. 2003 Jun;14(6):2250-61
references.pmid: 12808027
references.citation: Biochim Biophys Acta. 2005 Jul 10;1744(3):364-73
references.pmid: 15979507
references.citation: J Biol Chem. 2002 Mar 15;277(11):9468-73
references.pmid: 11777925
references.citation: J Cell Biol. 1991 Jun;113(5):1009-23
references.pmid: 1710224
references.citation: J Cell Sci. 2000 Feb;113 ( Pt 4):587-96
references.pmid: 10652252
references.citation: Mol Biol Cell. 2000 Sep;11(9):3013-30
references.pmid: 10982397
references.citation: Exp Cell Res. 1998 Nov 25;245(1):57-68
references.pmid: 9828101
references.citation: Nat Rev Mol Cell Biol. 2005 Oct;6(10):812-7
references.pmid: 16167055
references.citation: Biotechniques. 2007 Jan;42(1):71-5
references.pmid: 17269487
references.citation: Nature. 2003 Dec 4;426(6966):525-30
references.pmid: 14654833
references.citation: J Biol Chem. 1991 Sep 25;266(27):17729-32
references.pmid: 1917917
references.citation: J Cell Biol. 2001 Nov 12;155(4):557-70
references.pmid: 11706049
references.citation: J Biol Chem. 2007 Sep 28;282(39):28834-28842
references.pmid: 17640864
references.citation: Mol Cell Biol. 1997 Jan;17(1):256-66
references.pmid: 8972206
references.citation: J Cell Sci. 1995 Feb;108 ( Pt 2):789-96
references.pmid: 7769019
references.citation: Science. 1996 Mar 15;271(5255):1526-33
references.pmid: 8599108
references.citation: Cell. 1991 Nov 1;67(3):601-16
references.pmid: 1682055
references.citation: Methods Enzymol. 2005;404:316-32
references.pmid: 16413279
references.citation: Nature. 1998 Mar 5;392(6671):101-5
references.pmid: 9510256
references.citation: Cell. 1998 Feb 6;92(3):415-23
references.pmid: 9476900
references.citation: Mol Cell. 2003 Dec;12(6):1403-11
references.pmid: 14690595
references.citation: J Biol Chem. 1993 May 25;268(15):10820-5
references.pmid: 8496147
references.citation: Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11089-93
references.pmid: 8248213
references.citation: Mol Biol Cell. 2005 Mar;16(3):1213-22
references.pmid: 15616190
references.citation: Nature. 1997 Oct 16;389(6652):758-62
references.pmid: 9338791
references.citation: J Cell Sci. 2006 Sep 15;119(Pt 18):3743-53
references.pmid: 16926190
references.citation: Mol Biol Cell. 2005 Oct;16(10):4495-508
references.pmid: 16030262
references.citation: Nature. 1996 Feb 8;379(6565):557-60
references.pmid: 8596637
references.citation: J Cell Biol. 1999 Jul 12;146(1):71-84
references.pmid: 10402461
references.citation: Mol Biol Cell. 2003 Dec;14(12):5011-8
references.pmid: 14565973
references.citation: Nature. 1994 Nov 3;372(6501):55-63
references.pmid: 7969419
references.citation: J Cell Biol. 1995 Dec;131(6 Pt 2):1715-26
references.pmid: 8557739
references.citation: Proc Natl Acad Sci U S A. 2003 May 27;100(11):6469-74
references.pmid: 12738886
references.citation: Cell. 1991 Nov 1;67(3):591-600
references.pmid: 1657400
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2877-82
references.pmid: 18287014
references.citation: Curr Opin Cell Biol. 2004 Aug;16(4):364-72
references.pmid: 15261668
references.citation: Science. 1995 Mar 24;267(5205):1782-8
references.pmid: 7892601
references.citation: J Cell Sci. 1996 Dec;109 ( Pt 12):2811-21
references.pmid: 9013329
references.citation: Nat Rev Mol Cell Biol. 2006 May;7(5):347-58
references.pmid: 16633337
references.citation: Traffic. 2005 May;6(5):374-85
references.pmid: 15813748
references.citation: Mol Biol Cell. 2000 Aug;11(8):2577-90
references.pmid: 10930455
references.citation: Mol Biol Cell. 2008 Feb;19(2):523-35
references.pmid: 18003980
references.citation: Cancer Res. 2005 Jun 15;65(12):5221-30
references.pmid: 15958567
references.citation: Histochem Cell Biol. 1998 May-Jun;109(5-6):571-90
references.pmid: 9681636
references.citation: Genome Biol. 2006;7(10):R100
references.pmid: 17076895
references.citation: Cell. 1991 Nov 1;67(3):617-27
references.pmid: 1934063
references.citation: Mol Biol Cell. 2008 Aug;19(8):3488-500
references.pmid: 18524849