Dynamic interactions of Fc gamma receptor IIB with filamin-bound SHIP1 amplify filamentous actin-dependent negative regulation of Fc epsilon receptor I signaling

J Immunol. 2005 Feb 1;174(3):1365-73. doi: 10.4049/jimmunol.174.3.1365.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / antagonists & inhibitors
  • Actins / metabolism
  • Actins / physiology*
  • Animals
  • Antigens, CD / metabolism*
  • Antigens, CD / physiology
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cell Line, Tumor
  • Contractile Proteins / metabolism*
  • Down-Regulation / immunology*
  • Filamins
  • Immunoglobulin E / physiology
  • Inositol Polyphosphate 5-Phosphatases
  • Mast Cells / drug effects
  • Mast Cells / enzymology
  • Mast Cells / metabolism
  • Membrane Microdomains / metabolism
  • Mice
  • Microfilament Proteins / metabolism*
  • Molecular Weight
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
  • Phosphoric Monoester Hydrolases / metabolism*
  • Phosphoric Monoester Hydrolases / physiology
  • Protein Binding / immunology
  • Protein Isoforms / metabolism
  • Rats
  • Receptor Aggregation / immunology
  • Receptors, IgE / antagonists & inhibitors*
  • Receptors, IgE / metabolism
  • Receptors, IgE / physiology*
  • Receptors, IgG / antagonists & inhibitors
  • Receptors, IgG / metabolism*
  • Receptors, IgG / physiology
  • Resting Phase, Cell Cycle / immunology
  • Signal Transduction / immunology*
  • Thiazoles / pharmacology
  • Thiazolidines
  • Time Factors

Substances

  • Actins
  • Antigens, CD
  • Bridged Bicyclo Compounds, Heterocyclic
  • Contractile Proteins
  • Fc gamma receptor IIB
  • Filamins
  • Microfilament Proteins
  • Protein Isoforms
  • Receptors, IgE
  • Receptors, IgG
  • Thiazoles
  • Thiazolidines
  • Immunoglobulin E
  • Phosphoric Monoester Hydrolases
  • Inositol Polyphosphate 5-Phosphatases
  • Inpp5d protein, mouse
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
  • latrunculin B