Fc gamma receptor IIb modulates the molecular Grb2 interaction network in activated B cells |
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Authors: | Neumann Konstantin Oellerich Thomas Heine Ines Urlaub Henning Engelke Michael |
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Institution: | a Georg August University of Göttingen, Institute of Cellular and Molecular Immunology, Humboldtallee 34, 37073 Göttingen, Germanyb Max Planck Institute of Biophysical Chemistry, Bioanalytical Mass Spectrometry, Am Fassberg 11, 37077 Göttingen, Germany |
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Abstract: | B cells require signals transduced by the B cell antigen receptor (BCR) to provide humoral adaptive immunity. These signals are modulated by co-receptors like the Fcγ receptor IIb (FcγRIIb) that prevents activation of B cells after co-ligation with the BCR. Positive and negative effectors need to be precisely organized into signaling complexes, which requires adapter proteins like the growth factor receptor-bound protein 2 (Grb2). Here, we address the question how Grb2-mediated signal integration is affected by FcγRIIb. Our data reveal that concomitant engagement of BCR and FcγRIIb leads to markedly increased Grb2-mediated formation of ternary protein complexes comprising downstream of kinase-3 (Dok-3), Grb2, and the SH2 domain-containing inositol phosphatase (SHIP). Consistently, we found Grb2 to be required for full FcγRIIb-mediated negative regulation. To investigate how FcγRIIb influences the entire Grb2 interactions, we utilized quantitative mass spectrometry to make a differential interactome analysis. This approach revealed a shift of Grb2 interactions towards negative regulators like Dok-3, SHIP and SHP-2 and reduced binding to other proteins like CD19. Hence, we provide evidence that Grb2-mediated signal integration is a dynamic process that is important for the crosstalk between the BCR and its co-receptor FcγRIIb. |
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Keywords: | FcγRIIb fragment crystalline of gamma chain receptor IIb Grb2 growth factor receptor-bound protein 2 Dok-3 downstream of kinase-3 SHIP SH2 domain-containing inositol phosphatase SILAC stable isotope labeling of amino acids in cell culture |
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