title: Activation and nuclear translocation of ERK1/2 by the formyl peptide receptor is regulated by G protein and is not dependent on beta-arrestin translocation or receptor endocytosis.
abstract: G protein-coupled receptors (GPCRs) transmit diverse cellular signals in response to a large number of stimuli such as chemoattractants, lipids, neurotransmitters, odorants and light. The classical signaling pathway is through heterotrimeric G proteins, but GPCRs can also transmit signals through mechanisms that are not dependent on G proteins. In mammalian cells, the key component for this type of signaling is the family of scaffolding molecules called beta-arrestins. They can function as scaffolds for activation of mitogen-activated protein kinases, including extracellular signal-regulated kinases 1 and 2 (ERK1/2). In this study we examined the role of G protein and beta-arrestin in formyl peptide receptor (FPR)-mediated activation of chemotaxis, receptor endocytosis and ERK1/2 activation using wild type and mutant receptors. Our findings suggest that, unlike certain other GPCRs that can activate ERK1/2 without the involvement of G protein, FPR requires signaling through a G protein-mediated pathway. Previous observations have shown that ERK1/2, activated through G protein, translocates to the nucleus where it stimulates transcription factors. In contrast, the scaffolding protein beta-arrestin retains the activated ERK1/2 in the cytoplasm to allow phosphorylation of cytoplasmic targets. Our experimental data show that both wild-type FPR and a mutant FPR, defective in beta-arrestin binding, induce nuclear translocation of activated ERK1/2 with similar ligand concentration dependence as seen for activation of cytosolic ERK1/2. We propose that FPR-mediated activation of ERK1/2 takes place primarily through G protein and is physiologically important to ensure transcriptional activation of myeloid immunomodulators, such as cytokines.
authors.affiliation: Department of Microbiology, Montana State University, 109 Lewis Hall, Bozeman, MT 59717-3520, USA.
authors.forename: Jeannie M
authors.initials: JM
authors.lastname: Gripentrog
authors.forename: Heini M
authors.initials: HM
authors.lastname: Miettinen
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D003600:Cytosol / Q000378:metabolism; D004705:Endocytosis; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009154:Mutation / Q000502:physiology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D044042:Receptors, Formyl Peptide / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D044042:Receptors, Formyl Peptide; D000071557:beta-Arrestins; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009240:N-Formylmethionine Leucyl-Phenylalanine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019204:GTP-Binding Proteins; D002118:Calcium