Dynamic Interactions of Fcγ Receptor IIB with Filamin-Bound SHIP1 Amplify Filamentous Actin-Dependent Negative Regulation of Fcε Receptor I Signaling

Abstract

The engagement of high affinity receptors for IgE (FcεRI) generates both positive and negative signals whose integration determines the intensity of mast cell responses. FcεRI-positive signals are also negatively regulated by low affinity receptors for IgG (FcγRIIB). Although the constitutive negative regulation of FcεRI signaling was shown to depend on the submembranous F-actin skeleton, the role of this compartment in FcγRIIB-dependent inhibition is unknown. We show in this study that the F-actin skeleton is essential for FcγRIIB-dependent negative regulation. It contains SHIP1, the phosphatase responsible for inhibition, which is constitutively associated with the actin-binding protein, filamin-1. After coaggregation, FcγRIIB and FcεRI 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 FcγRIIB. 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 FcγRIIB, which concentrate this phosphatase in the vicinity of FcεRI and thereby extinguish activation signals.