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The low-affinity receptor for IgG, FcγRIIB, functions broadly in the immune system, blocking mast cell degranulation, dampening the humoral immune response, and reducing the risk of autoimmunity. Previous studies concluded that inhibitory signal transduction by FcγRIIB is mediated solely by its immunoreceptor tyrosine-based inhibition motif (ITIM) that, when phosphorylated, recruits the SH2-containing inositol 5′- phosphatase SHIP and the SH2-containing tyrosine phosphatases SHP-1 and SHP-2. The mutational analysis reported here reveals that the receptor’s C-terminal 16 residues are also required for detectable FcγRIIB association with SHIP in vivo and for FcγRIIB-mediated phosphatidylinositol 3-kinase hydrolysis by SHIP. Although the ITIM appears to contain all the structural information required for receptor-mediated tyrosine phosphorylation of SHIP, phosphorylation is enhanced when the C-terminal sequence is present. Additionally, FcγRIIB-mediated dephosphorylation of CD19 is independent of the cytoplasmic tail distal from residue 237, including the ITIM. Finally, the findings indicate that tyrosines 290, 309, and 326 are all sites of significant FcγRIIB1 phosphorylation following coaggregation with B cell Ag receptor. Thus, we conclude that multiple sites in FcγRIIB contribute uniquely to transduction of FcγRIIB-mediated inhibitory signals.

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FcγRIIB are low-affinity receptors for IgG whose intracytoplasmic domain contains an immunoreceptor tyrosine-based inhibition motif (ITIM). FcγRIIB inhibit cell activation triggered by receptors that signal via immunoreceptor tyrosine-based activation motifs. This inhibition requires ITIM tyrosyl phosphorylation and is correlated with the binding of SH2 domain-containing phosphatases that may mediate the inhibitory signal. In the present work, we investigated the mechanism of FcγRIIB phosphorylation and its consequences in mast cells. We demonstrate that the phosphorylation of FcγRIIB requires coaggregation with FcεRI and that, once phosphorylated, FcγRIIB selectively recruit the inositol polyphosphate 5 phosphatase SHIP, in vivo. In vitro, however, the phosphorylated FcγRIIB ITIM binds not only SHIP, but also the two protein tyrosine phosphatases, SHP-1 and SHP-2. We show that the coaggregation of FcγRIIB with FcεRI does not prevent FcεRI-mediated activation of lyn and syk. Both kinases can phosphorylate FcγRIIB in vitro. However, when coaggregated with FcεRI, FcγRIIB was in vivo phosphorylated in syk-deficient mast cells, but not in lyn-deficient mast cells. When FcεRI are coaggregated with FcγRIIB by immune complexes, FcεRI-associated lyn may thus phosphorylate FcγRIIB. By this mechanism, FcεRI initiate ITIM-dependent inhibition of intracellular propagation of their own signals.

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