title: The mechanism and function of mitogen-activated protein kinase activation by ARF1.
abstract: Mitogen-activated protein kinases (MAPK) can be activated by a number of biochemical pathways through distinct signaling molecules. We have recently revealed a novel function for the Ras-like small GTPase ADP-ribosylation factor 1 (ARF1) in mediating the activation of Raf1-MEK-ERK1/2 pathway by G protein-coupled receptors [Dong C, Li C and Wu G (2011) J Biol Chem 286, 43,361-43,369]. Here, we have further defined the underlying mechanism and the possible function of ARF1-mediated MAPK pathway. We demonstrated that the blockage of ARF1 activation and the disruption of ARF1 localization to the Golgi by mutating Thr48, a highly conserved residue involved in the exchange of GDP for GTP, and the myristoylation site Gly2 abolished ARF1's ability to activate ERK1/2. In addition, treatment with Golgi structure disrupting agents markedly attenuated ARF1-mediated ERK1/2 activation. Furthermore, ARF1 significantly promoted cell proliferation. More interestingly, ARF1 activated 90kDa ribosomal S6 kinase 1 (RSK1) without influencing Elk-1 activation and ERK2 translocation to the nuclei. These data demonstrate that, once activated, ARF1 activates the MAPK pathway likely using the Golgi as a main platform, which in turn activates the cytoplasmic RSK1, leading to cell proliferation.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112, United States.
authors.forename: Fuguo
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112, United States.
authors.forename: Chunmin
authors.initials: C
authors.lastname: Dong
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Blvd., Augusta, GA 30912, United States.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Davis
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Blvd., Augusta, GA 30912, United States.
authors.forename: William H
authors.initials: WH
authors.lastname: Wu
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Blvd., Augusta, GA 30912, United States.
authors.forename: Kristen
authors.initials: K
authors.lastname: Surrao
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112, United States.|Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Blvd., Augusta, GA 30912, United States.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Wu
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000502:physiology*; D000595:Amino Acid Sequence; D049109:Cell Proliferation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006056:Golgi Apparatus / Q000201:enzymology; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D021381:Protein Transport; D043704:Receptor, Adenosine A2B / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
chemical_list: C494112:ELK1 protein, human; D043704:Receptor, Adenosine A2B; D050807:ets-Domain Protein Elk-1; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048049:Extracellular Signal-Regulated MAP Kinases; D020823:ADP-Ribosylation Factor 1
keywords: ARF1; Cell proliferation; ERK1/2; G protein; G protein-coupled receptor; MAPK; RSK1