B-cell antigen receptor motifs have redundant signalling capabilities and bind the tyrosine kinases PTK72, Lyn and Fyn (original) (raw)
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Signal transduction by immunoglobulin is mediated through Ig alpha and Ig beta
Journal of Experimental Medicine, 1993
Immunoglobulin (Ig) antigen receptors are composed of a noncovalently-associated complex of Ig and two other proteins, Igo~ and Ig3. The cytoplasmic domain of both of these Ig associated proteins contains a consensus sequence that is shared with the signaling proteins of the T cell and Fc receptor. To test the idea that Igc~-IgB heterodimers are the signaling components of the Ig receptor, we have studied Ig mutations that interfere with signal transduction. We find that specific mutations in the transmembrane domain of Ig that inactivate Ca 2+ and phosphorylation responses also uncouple IgM from Igoe-Ig/3. These results define amino acid residues that are essential for the assembly of the Ig receptor. Further, receptor activity can be fully reconstituted in Ca 2+ flux and phosphorylation assays by fusing the cytoplasmic domain of Igct with the mutant Igs. In contrast, fusion of the cytoplasmic domain of Ig~ to the inactive Ig reconstitutes only Ca z+ responses. Thus, Igor and IgB are both necessary and sufficient to mediate signal transduction by the Ig receptor in B cells. In addition, our results suggest that IgoL and IgB can activate different signaling pathways.
Functional Reconstitution of an Immunoglobulin Antigen Receptor in T Cells
1992
Humoral immune responses are initiated by binding of antigen to the immunoglobulins (Igs) on the plasma membrane of B lymphocytes. On the cell surface, Ig forms a complex with several other proteins, two of which, MB-1 and B29, have been implicated in ~eceptor assembly. We have reconstituted Ig receptor function in T lymphocytes by transfection of cloned receptor components. We found that efficient transport of IgM to the surface of T cells required coexpression of B29. Furthermore, IgM and B29 alone were sufficient to reconstitute antigen-specific signal transduction by Ig in the transfected T cells. Crosslinking of IgM with either antireceptor antibodies or antigen induced a calcium flux, phosphoinositol turnover, and interleukin secretion in T cells. These experiments establish a requirement for B29 in Ig receptor function, and suggest that the signaling apparatus of T and B cells is structurally homologous.
European Journal of Immunology, 1992
To characterize the signal transduction through the antigen receptor (AgR) on human B lymphocytes, we analyzed its association with other molecular components. The surface IgM (sIgM) complex isolated in digitonin contains two surface expressed polypeptides - the previously described Igα and Igβ proteins - covalently linked to each other in a 48/39-kDa heterodimer. We show herein that the human sIgM complex isolated from the Burkitt's lymphoma cell line, Ramos, or from dense tonsillar B cells contains additional molecules −160 kDa and 75 kDa in size — and enzymatic activities able to phosphorylate on tyrosine as well as serine/threonine residues the 39−, 48−, 75− and 160-kDa polypeptides. By specific immunoprecipitation with antibodies to src-family kinases, we consistently detected p56lyn in the sIgM complex. In the Ramos cell line, both p56lck and p59fyn activity were also observed, although to a much lesser extent than p56lyn. These kinases are associated with sIgM before cell stimulation. As shown by two-dimensional electrophoresis, they interact in a tight complex with multimeric forms of the Igα and Igβ components. The kinases are active in vitro but must be highly regulated in vivo: Western blotting with anti-phosphotyrosine antibodies revealed that stimulation of the AgR on viable B cells increased detectable phosphotyrosine residues on the components present in the sIgM complex. Based on these phosphorylation changes, the 39−, 48−, 75− and 160-kDa molecules are likely to be functionally active elements in an IgM complex crucial for the transduction of the antigenic signal.
Molecular and cellular biology, 1996
Human B cells express four immunoglobulin G receptors, FcgammaRIIa, FcgammaRIIb1, FcgammaRIIb2, and FcgammaRIIc. Coligation of either FcgammaRII isoform with the B-cell antigen receptor (BCR) results in the abrogation of B-cell activation, but only the FcgammaRIIa/c and FcgammaIIb1 isoforms become phosphorylated. To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point mutants. While each PTK phosphorylated FcgammaRIIa/c, FcgammaRIIb1 was phosphorylated by Lyn and Blk whereas FcgammaRIIb2 became phosphorylated only by Blk. Mutants lacking both tyrosine residues of the immune receptor tyrosine-based activation...
Journal of Experimental Medicine, 2007
ginal zone B cell formation, was not due to diminished CD22 phosphorylation or inhibitory function. Microarray profi ling showed no evidence for enhanced signaling by the IgG tail for calcium/calcineurin, ERK, or nuclear factor κB response genes and little evidence for any enhanced gene induction. Instead, almost half of the antigen-induced gene response in IgM B cells was diminished 50-90% by the IgG tail segment. These fi ndings suggest a novel "less-is-more" hypothesis to explain how switching to IgG enhances B cell memory responses, whereby decreased BCR signaling to genes that oppose marginal zone and plasma cell differentiation enhances the formation of these key cell types. CORRESPONDENCE Christopher C. Goodnow: Chris.Goodnow@anu.edu.au Abbreviations used: BCR, B cell antigen receptor; ERK, extracellular signal-related kinase; HEL, hen egg lysozyme; ITAM, immunoreceptor tyrosine-based activation motif; MAP, mitogen-activated protein; MEK, MAP kinase/ ERK kinase; SHP-1, Src homology domain 2-containing protein tyrosine phosphatase.