title: Activation of Gαi at the Golgi by GIV/Girdin imposes finiteness in Arf1 signaling.
abstract: A long-held tenet of heterotrimeric G protein signal transduction is that it is triggered by G protein-coupled receptors (GPCRs) at the PM. Here, we demonstrate that Gi is activated in the Golgi by GIV/Girdin, a non-receptor guanine-nucleotide exchange factor (GEF). GIV-dependent activation of Gi at the Golgi maintains the finiteness of the cyclical activation of ADP-ribosylation factor 1 (Arf1), a fundamental step in vesicle traffic in all eukaryotes. Several interactions with other major components of Golgi trafficking-e.g., active Arf1, its regulator, ArfGAP2/3, and the adaptor protein β-COP-enable GIV to coordinately regulate Arf1 signaling. When the GIV-Gαi pathway is selectively inhibited, levels of GTP-bound Arf1 are elevated and protein transport along the secretory pathway is delayed. These findings define a paradigm in non-canonical G protein signaling at the Golgi, which places GIV-GEF at the crossroads between signals gated by the trimeric G proteins and the Arf family of monomeric GTPases.
authors: Departments of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors: I-Chung
authors: IC
authors: Lo
authors: Departments of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Vijay
authors: V
authors: Gupta
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Krishna K
authors: KK
authors: Midde
authors: Departments of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Vanessa
authors: V
authors: Taupin
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Inmaculada
authors: I
authors: Lopez-Sanchez
authors: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Irina
authors: I
authors: Kufareva
authors: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Ruben
authors: R
authors: Abagyan
authors: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors: Paul A
authors: PA
authors: Randazzo
authors: Departments of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: mfarquhar@ucsd.edu.
authors: Marilyn G
authors: MG
authors: Farquhar
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: prghosh@ucsd.edu.
authors: Pradipta
authors: P
authors: Ghosh
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000378:metabolism*; D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019556:COS Cells; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D020756:Coatomer Protein / Q000378:metabolism; D004789:Enzyme Activation; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D022161:Transport Vesicles / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: C503240:ARFGAP3 protein, human; C502451:CCDC88A protein, human; D020756:Coatomer Protein; D020690:GTPase-Activating Proteins; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; D033921:Vesicular Transport Proteins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020823:ADP-Ribosylation Factor 1; D020727:ADP-Ribosylation Factors; C525860:ARFGAP2 protein, human