title: ADP-ribosylation factor 4 small GTPase mediates epidermal growth factor receptor-dependent phospholipase D2 activation.
abstract: The epidermal growth factor receptor (EGFR) plays a critical role in the development, proliferation, and differentiation of cells of epithelial and mesenchymal origin. These EGFR-dependent cellular processes are mediated by a repertoire of intracellular signaling pathways triggered by the activation of the EGFR cytoplasmic domain, which originates from ligand binding of its extracellular domain. To understand the molecular mechanisms by which the intracellular domain of EGFR transmits mitogenic messages to the downstream signaling pathways, we used the cytoplasmic region of EGFR as bait in yeast two-hybrid screening. We found that ADP-ribosylation factor 4 (ARF4) interacts with the intracellular part of EGFR and mediates the EGF-dependent cellular activation of phospholipase D2 (PLD2) but does not mediate the activation of PLD1. In addition, ARF4-mediated PLD2 activation leads to dramatic activation of the transcription factor activator protein 1 (AP-1), and, importantly, ARF4 activity is required for EGF-induced activation of cellular AP-1. Our findings indicate that ARF4 is a critical molecule that directly regulates cellular PLD2 activity and that this ARF4-mediated PLD2 activation stimulates AP-1-dependent transcription in the EGF-induced cellular response.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Sung-Woo
authors.initials: SW
authors.lastname: Kim
authors.forename: Masaaki
authors.initials: M
authors.lastname: Hayashi
authors.forename: Jeng-Fan
authors.initials: JF
authors.lastname: Lo
authors.forename: Young
authors.initials: Y
authors.lastname: Yang
authors.forename: Jin-San
authors.initials: JS
authors.lastname: Yoo
authors.forename: Jiing-Dwan
authors.initials: JD
authors.lastname: Lee
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D002460:Cell Line; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004072:Digitonin / Q000494:pharmacology; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D015723:Gene Library; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D006133:Growth Substances / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D010739:Phospholipase D / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques
chemical_list: D018076:DNA, Complementary; D006133:Growth Substances; D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; D049452:Green Fluorescent Proteins; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D004815:Epidermal Growth Factor; D004247:DNA; C105606:phospholipase D2; D010739:Phospholipase D; D020558:GTP Phosphohydrolases; D020727:ADP-Ribosylation Factors; C116688:ARF4 protein, human; D004072:Digitonin