A B cell's response to antigen, whether it be proliferation, differentiation, anergy, or deletion, is dependent upon recognition of that antigen by the B cell antigen receptor (BCR) 1 (1-3). The receptor is a multimeric complex consisting of the antigenrecognition substructure, membrane-bound immunoglobulin non-covalently associated with heterodimer(s) of Ig-␣ and Ig- (4 -6). Present evidence indicates that the cytoplasmic tails of Ig-␣ and  (7) translate antigen engagement into cytoplasmic signaling events that initiate cellular responses (8 -12). Most proximally in the signaling cascade, one or more tyrosine kinases, including Syk and members of the Src family, are activated (13-15). These in turn activate a variety of pathways whose constituents include Ras, phosphatidylinositol 3-kinase, and phospholipase C (1). Embedded within the cytoplasmic tails of both Ig-␣ and  is a sequence common to other multichain immune recognition receptor (MIRR) subunits including CD3␦, CD3␥, TCR, Fc␥RIII␥, and Fc⑀RI␥, termed the immunoreceptor tyrosine-based activation motif (ITAM) (16,17). The motif contains two tyrosines, both of which are critical for initiating tyrosine kinase activation (10, 18). Phosphorylation of these tyrosines facilitates the recruitment and activation of tyrosine kinases which contain SH2 domains, such as . Substrates for these kinases may also be recruited (22). The presence of the ITAM in all MIRR chains involved in signal transduction has led some to suggest that apparently heterologous chains such as CD3⑀ and TCR are functionally redundant and the presence of multiple ITAMs within each MIRR serve to increase the strength of signal which can be generated via the receptor. Evidence for this assertion has been obtained in studies of both the B and T cell antigen receptors (8,12,23,24). In contrast, we and others have provided evidence indicating that each heterologous ITAM containing chain has a distinct function (10,11,19,25,26).Many of the above studies utilized chimeras in which irrelevant extracellular and transmembrane domains were fused to the single cytoplasmic domain under study (18,27,28). Although this approach has yielded considerable insight into ITAM-containing chains, it assumes that functions observed in the isolated circumstance of a single chimera are reflective of the function of that cytoplasmic domain within the intact receptor complex. This might not be true since most ITAM-containing chains, such as Ig-␣ and Ig-, are expressed on cell surfaces as heterodimers (29 -32). Therefore, we postulated that within the context of a heterodimer, Ig-␣ and Ig- would have new, complementary or even synergistic functions, not predicted from studies of single chain chimeras.As demonstrated in this report, Ig-␣ and  have new and unpredicted functions in the context of a heterodimer. Using a novel chimera system, which allowed us to form either heteroor homodimers of the cytoplasmic domains of Ig-␣ and Ig-, we observed that when Ig- is ligated independently it is able to activate tyrosine...
Stimulation of the B cell Ag receptor (BCR), a multimeric complex containing heterodimers of Ig-alpha and Ig-beta, initiates a cascade of tyrosine phosphorylation that results in cellular activation. One of the earliest substrates phosphorylated is Ig-alphabeta, and it appears that kinase activation emanates from this structure with the most proximal kinases themselves, and some of their immediate substrates, associating with the heterodimer. To identify other molecules that may be involved in proximal BCR signaling, we examined the substrates that were tyrosine phosphorylated following stimulation with either anti-IgG Abs or pervanadate in the murine B cell lymphoma A20 IIA1.6 and in resting splenic B cells. Immunoblotting with anti-phosphotyrosine Abs revealed that a doublet of 40 and 42 kDa was phosphorylated within 1 min of stimulation with either agonist. The phosphorylation of p40/42 in A20 cells induced by anti-IgG was rapid and transient, peaking at 2 min after stimulation and becoming almost undetectable after 10 min. Furthermore, at least 25% of phosphorylated p40/42 co-immunoprecipitated with Ig-alphabeta, but none precipitated with MHC II, CD40, Fc(gamma)RII, Fyn, HS-1, or Syk, suggesting that this protein complex specifically associates with the Ig-alphabeta heterodimer. p40/42 did not react with Abs to Ig-alpha, Ig-beta, mitogen-activated protein kinase, or Lnk. Furthermore, and in contrast to Ig-alphabeta, p40/42 was highly acidic and not part of a disulfide-linked complex. Finally, p40/42 was demonstrated to be a glycosylated surface protein that was constitutively associated with Ig-alphabeta. These results suggest that p40/42 is a novel constituent of the resting B cell Ag receptor complex.
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