title: FcgammaRI coupling to phospholipase D initiates sphingosine kinase-mediated calcium mobilization and vesicular trafficking.
abstract: Aggregation of receptors specific for the constant region of immunoglobulin G activates a repertoire of monocyte responses that can lead ultimately to targeted cell killing via antibody-directed cellular cytotoxicity. The high affinity receptor, FcgammaRI, contains no recognized signaling motif in its cytoplasmic tail but rather utilizes the gamma-chain of FcepsilonRI as an accessory molecule to recruit tyrosine kinases for signal transduction. We show here that, in a human monocytic cell line primed with interferon-gamma, FcgammaRI mobilizes intracellular calcium stores using a novel pathway that involves tyrosine kinase coupling to phospholipase D and resultant downstream activation of sphingosine kinase. Moreover, FcgammaRI is not coupled to phospholipase C; hence, calcium release from intracellular stores occurred in the absence of any measurable rise in inositol triphosphate. Finally, as this novel activation pathway is also shown to be responsible for mediating the vesicular trafficking of internalized immune complexes for degradation, it is likely to play a key role in controlling intracellular events triggered by FcgammaRI.
authors.affiliation: Department of Medicine and Therapeutics and Division of Biochemistry and Molecular Biology, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Melendez
authors.forename: R A
authors.initials: RA
authors.lastname: Floto
authors.forename: D J
authors.initials: DJ
authors.lastname: Gillooly
authors.forename: M M
authors.initials: MM
authors.lastname: Harnett
authors.forename: J M
authors.initials: JM
authors.lastname: Allen
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002451:Cell Compartmentation; D002460:Cell Line; D003432:Cross-Linking Reagents; D004075:Diglycerides / Q000378:metabolism; D004705:Endocytosis; D004789:Enzyme Activation; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D007700:Kinetics; D008246:Lysophospholipids; D015388:Organelles / Q000502:physiology; D010739:Phospholipase D / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017452:Receptors, IgG / Q000502:physiology*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000911:Antibodies, Monoclonal; D002118:Calcium; D003432:Cross-Linking Reagents; D004075:Diglycerides; D019833:Genistein; D015544:Inositol 1,4,5-Trisphosphate; D007371:Interferon-gamma; D008246:Lysophospholipids; D010739:Phospholipase D; D017853:Phosphotransferases (Alcohol Group Acceptor); D011505:Protein-Tyrosine Kinases; D017452:Receptors, IgG; D013110:Sphingosine; D010738:Type C Phospholipases; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate