Abstract
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.
Highlights
The low affinity, IgG Fc-binding, type IIb receptors (Fc␥RIIb)1 expressed on B cells may down-regulate cell activation when cross-linked with the antigen receptor, membrane immunoglobulin [1]
Neither Fc␥RIIb1 nor Fc␥RIIb2 transduce activation signals for human B cells; we have previously demonstrated that protein-tyrosine kinase Fyn and several unidentified Tyr-phosphorylated polypeptides as well as Ser/ Thr kinase activities associate with Fc␥RII isolated from BCRcross-linked BL41 Burkitt lymphoma cells [6, 7]
The best documented role for G proteins in B cells is the activation of p21ras, the low molecular mass G protein, since (i) co-localization of p21ras and membrane immunoglobulin (mIg) was observed after mIg cross-linking [9], (ii) the p21ras signaling pathway has been shown to be operative in both human and murine B cells connecting protein-tyrosine kinase activation and the regulation of gene transcription [10], and (iii) it has recently been reported that activation of the p21ras pathway couples antigen receptor stimulation to the induction of the primary response gene egr-1 in B cells [11]
Summary
The low affinity, IgG Fc-binding, type IIb receptors (Fc␥RIIb) expressed on B cells may down-regulate cell activation when cross-linked with the antigen receptor, membrane immunoglobulin (mIg) [1]. Neither Fc␥RIIb1 nor Fc␥RIIb2 transduce activation signals for human B cells; we have previously demonstrated that protein-tyrosine kinase Fyn and several unidentified Tyr-phosphorylated polypeptides as well as Ser/ Thr kinase activities associate with Fc␥RII isolated from BCRcross-linked BL41 Burkitt lymphoma cells [6, 7]. It was recently demonstrated that a Tyr-containing motif of the adapter molecule Shc becomes phosphorylated by the Lyn-activated Syk protein-tyrosine kinases in B cells following mIg cross-linking [13]. The primary response gene egr-1 encodes a sequence-specific transcription factor, the expression of which is necessary for antigen receptor-stimulated activation of B cells, and it has been demonstrated that induction of egr-1 after BCR cross-linking is mediated by activation of the p21ras/MAPK-signaling pathway [11]
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