IgG-Independent Co-aggregation of Fc?RI and Fc?RIIB Results in LYN- and SHIP1-Dependent Tyrosine Phosphorylation of Fc?RIIB in Murine Bone Marrow-Derived Mast Cells.

ABSTRACT: Activation of the high-affinity receptor for IgE (Fc?RI) follows a bell-shaped dose-response curve. Upon supra-optimal stimulation, mast cell effector responses are down-regulated by inhibitory molecules like the SH2-containing inositol-5'-phosphatase SHIP1 and the SRC-family-kinase LYN. To identify further molecules involved in a negative regulatory signalosome, we screened for proteins showing the same pattern of tyrosine phosphorylation as SHIP1, which is tyrosine-phosphorylated strongest upon supra-optimal antigen (Ag) stimulation. The low-affinity IgG receptor, Fc?RIIB, was found to be most strongly phosphorylated under supra-optimal conditions. This phosphorylation is the consequence of passive, Ag/IgE-dependent and progressive co-localization of Fc?RI and Fc?RIIB, which is not dependent on IgG. Upon supra-optimal Fc?RI cross-linking, Fc?RIIB phosphorylation is executed by LYN and protected from dephosphorylation by SHIP1. Analysis of Fc?RIIB-deficient bone marrow-derived mast cells revealed an ambiguous phenotype upon Fc?RI cross-linking. Absence of Fc?RIIB significantly diminished the level of SHIP1 phosphorylation and resulted in augmented Ca2+ mobilization. Though, degranulation and IL-6 production were only weakly altered. Altogether our data establish the LYN/Fc?RIIB/SHIP1 signalosome in the context of Fc?RI activation, particularly at supra-optimal Ag concentrations. The fact that SHIP1 tyrosine phosphorylation/activation not only depends on Fc?RIIB, highlights the necessity for its tight backup control.

SUBMITTER: Gast M 

PROVIDER: S-EPMC6119721 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature