title: Dynamic interactions of Fc gamma receptor IIB with filamin-bound SHIP1 amplify filamentous actin-dependent negative regulation of Fc epsilon receptor I signaling.
abstract: The engagement of high affinity receptors for IgE (FcepsilonRI) generates both positive and negative signals whose integration determines the intensity of mast cell responses. FcepsilonRI-positive signals are also negatively regulated by low affinity receptors for IgG (FcgammaRIIB). Although the constitutive negative regulation of FcepsilonRI signaling was shown to depend on the submembranous F-actin skeleton, the role of this compartment in FcgammaRIIB-dependent inhibition is unknown. We show in this study that the F-actin skeleton is essential for FcgammaRIIB-dependent negative regulation. It contains SHIP1, the phosphatase responsible for inhibition, which is constitutively associated with the actin-binding protein, filamin-1. After coaggregation, FcgammaRIIB and FcepsilonRI rapidly interact with the F-actin skeleton and engage SHIP1 and filamin-1. Later, filamin-1 and F-actin dissociate from FcR complexes, whereas SHIP1 remains associated with FcgammaRIIB. Based on these results, we propose a dynamic model in which the submembranous F-actin skeleton forms an inhibitory compartment where filamin-1 functions as a donor of SHIP1 for FcgammaRIIB, which concentrate this phosphatase in the vicinity of FcepsilonRI and thereby extinguish activation signals.
authors.affiliation: Laboratoire d'Immunologie Cellulaire et Clinique, Institut National de la Santé et de la Recherche Médicale, Unité 255, Institut Biomédical des Cordeliers, Paris, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Lesourne
authors.forename: Wolf H
authors.initials: WH
authors.lastname: Fridman
authors.forename: Marc
authors.initials: M
authors.lastname: Daëron
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism* / Q000502:physiology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D045744:Cell Line, Tumor; D003285:Contractile Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000276:immunology*; D064448:Filamins; D007073:Immunoglobulin E / Q000502:physiology; D000072181:Inositol Polyphosphate 5-Phosphatases; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D008970:Molecular Weight; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding / Q000276:immunology; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D011940:Receptor Aggregation / Q000276:immunology; D017455:Receptors, IgE / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D017452:Receptors, IgG / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines; D013997:Time Factors
chemical_list: D000199:Actins; D015703:Antigens, CD; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003285:Contractile Proteins; C080571:Fc gamma receptor IIB; D064448:Filamins; D008840:Microfilament Proteins; D020033:Protein Isoforms; D017455:Receptors, IgE; D017452:Receptors, IgG; D013844:Thiazoles; D053778:Thiazolidines; D007073:Immunoglobulin E; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; C037068:latrunculin B