We have exploited the paradigm of positive/negative signaling in B cells to dissect critical biochemical signaling events that promote B cell activation. Thus, in the earlier funding period, we identified the inositol 5-phosphatase SHIP as a primary contributor in the B cell negative signaling process. First, SHIP acts as a SHIP domain competitor for GRB2 binding to phospho-Shc, thereby blocking induction of the Ras pathway. Second, although as yet unexplored in any receptor system, SHIP consumes 3-phosphorylated phosphoinositides and thus blocks signaling pathways downstream of PtdIns 3-kinase. PtdIns 3-kinase plays an important but largely undefined role in a wide variety of biological processes, including transformation and proliferation, antigen uptake, phagocytosis, and cellular invasion by pathogens. Our paradigm of B cell positive/negative signaling may be ideal to investigate the precise role of 3-phosphorylated phosphoinositides in these processes, because of the enzymatic specificity of SHIP towards PtdIns 3-kinase products and because only small changes in the stimulating reagent [F(ab')2 or intact anti-Ig] are necessary to promote or prevent SHIP action. Here, we propose experiments to better understanding signaling pathways of B cell activation and the negative influence of SHIP on the associated downstream biochemical events. Such information may reveal novel therapeutic targets in a variety of pathologic conditions and contribute to the etiology of such diseases.
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