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FcγRIIB Signaling in B Lymphocytes

Fc-γ-RIIB is critical for the regulation of antibody-mediated immune responses, and is the only IgG receptor expressed on B-Cells. Antigenic stimulation of BCR is a central event in the immune response. Antigen bound to IgG negatively regulates signals from the BCR by cross-linking it to the inhibitory receptor Fc-γ-RIIB. Expression of Fc-γ-RIIB on B-Cells provides a mechanism for the suppressive effects of immune complexes on antibody production, particularly during the germinal center reaction. The inhibitory ITIM motif is both necessary and sufficient to mediate the inhibition of BCR-generated Ca2+ mobilization and cellular proliferation...

FcγRIIB Signaling in B Lymphocytes

Pathway Summary

Fc-γ-RIIB is critical for the regulation of antibody-mediated immune responses, and is the only IgG receptor expressed on B-Cells. Antigenic stimulation of BCR is a central event in the immune response. Antigen bound to IgG negatively regulates signals from the BCR by cross-linking it to the inhibitory receptor Fc-γ-RIIB. Expression of Fc-γ-RIIB on B-Cells provides a mechanism for the suppressive effects of immune complexes on antibody production, particularly during the germinal center reaction. The inhibitory ITIM motif is both necessary and sufficient to mediate the inhibition of BCR-generated Ca2+ mobilization and cellular proliferation.Signaling through BCR is critical for differentiation, proliferation, maturation and effector functions of B lymphocytes. The cytoplasmic tail of BCR contains ITAMs with associated tyrosine kinases such as Lyn and Syk. The ITAMs become phosphorylated on tyrosine residues, which activates the tyrosine kinases and initiates intracellular signaling. These kinases coordinately phosphorylate downstream substrates that include adaptors such as BLNK and effectors such as PLC-γ2. Ultimately, a cascade of signaling events involving Ras, PI3K and calcium leads to transcription of target genes, resulting in differentiation and proliferation of antigen-specific B-Cells.In B-Cells, phosphorylation of the tyrosine of the ITIM motif occurs upon BCR coligation and is required for its inhibitory activity. This modification generates an SH2 recognition domain that is the binding site for the inhibitory signaling molecule SHIP that leads to the abrogation of ITAM activation signaling by hydrolyzing the membrane inositol phosphate PIP3. In B-Cells, Fc-γ-RIIB displays three separable inhibitory activities, two of which are dependent on the ITIM motif and one that is independent of this motif. Co-engagement of Fc-γ-RIIB to the ITAM-containing BCR leads to tyrosine phosphorylation of the ITIM by the Lyn kinase, recruitment of SHIP, and the inhibition of ITAM-triggered Ca2+ mobilization and cellular proliferation. These two inhibitory activities result from different signaling pathways, with Ca2+ inhibition requiring the phosphatase activity of SHIP to hydrolyze PIP3 and the ensuing dissociation of PH domain-containing proteins like BTK and PLC-γ2 from the membrane. Inhibition of PLC-γ2 results in inhibition of the process of conversion of PIP2. The net effect is to block Ca2+ influx through the capacitance-coupled Ca2+ channel (CaCn) and prevent sustained calcium signaling, which prevents calcium-dependent processes such as degranulation, phagocytosis, ADCC, cytokine release and proinflammatory response. SHIP can affect proliferation in several ways: 1) Through its catalytic phosphatase domain, SHIP can prevent recruitment of the PH domain survival factor Akt by hydrolysis of PIP3. Hydrolysis of PIP3 also blocks the PIP3-PDK1-Akt pathway, thus affecting B-cell survival. 2) SHIP also contains PTB domains that can recruit DOK1 to the plasma membrane where DOK1 is activated by Lyn kinase.Arrest of proliferation in B-Cells is also dependent on the ITIM pathway, through the activation of the adaptor protein DOK1 and subsequent inactivation of MAPKs. DOK1 is involved in the negative regulation of the MAPK pathway activated by antigen stimulation of BCR through SYK, SHC, GRB2, SOS, and Ras. The third inhibitory activity displayed by Fc-γ-RIIB is independent of the ITIM sequence and is displayed upon homoaggregation of the receptor in germinal center B-Cells. Under these conditions of Fc-γ-RIIB clustering, a pro-apoptotic signal is generated through the transmembrane sequence in a BTK-dependent manner by JNK activation.

FcγRIIB Signaling in B Lymphocytes Genes list

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