Human type II Fcgamma receptors inhibit B cell activation by interacting with the p21(ras)-dependent pathway.
Co-ligation of antigen receptors and type II Fcgamma receptors (FcgammaRIIb) on B cells interrupts signal transduction and ultimately inhibits antibody production. We have identified p52 Shc in the FcgammaRIIb1-specific immunoprecipitates isolated from the membrane fraction of BL41 Burkitt lymphoma cells following B cell receptor-FcgammaRIIb1 co-ligation. The insolubilized synthetic peptide representing the phosphorylated form of the tyrosine-based inhibitory motif of FcgammaRIIb also binds Shc from the lysates of activated but not from resting BL41 cells. This suggests that the binding does not depend on the interaction of FcgammaRIIb1-phosphotyrosine with the SH2 domain of Shc. Tyr phosphorylation of FcgammaRIIb1-associated Shc is low, indicating an impaired function. Shc is implicated in regulating p21(ras) activation; thus, we have compared p21(ras) activities in BL41 cells treated in different ways. p21(ras) activity is reduced when B cell receptor and FcgammaRIIb1 are co-ligated. p21(ras) couples protein-tyrosine kinase-dependent events to the Ser/Thr kinase-mediated signaling pathway leading to the activation of mitogen-activated protein kinases (MAPK). Our results show that B cell receptor-FcgammaRIIb1 co-cross-linking partially inhibits mitogen-activated protein kinase activity. We conclude that FcgammaRIIb1-dependent inhibition of human B cell activation may be based on interrupting signal transduction between protein-tyrosine kinases and the p21(ras)/mitogen-activated protein kinase-dependent activation pathway.
Sármay
G
G
Laboratory of Immunoregulation, Vienna International Research Cooperation Center at SFI, Vienna, Austria.
Koncz
G
G
Gergely
J
J
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D015703:Antigens, CD / Q000502:physiology*; D001402:B-Lymphocytes / Q000276:immunology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D011506:Proteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D017452:Receptors, IgG / Q000276:immunology / Q000502:physiology*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D015703:Antigens, CD; C080571:Fc gamma receptor IIB; D011506:Proteins; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)