The B-cell antigen receptor (BCR) produces a calcium-dependent signal which is required for both B-cell proliferation and apoptotic receptor editing during antigen driven humoral immune responses. This calcium signal is generated by a mechanism which involves inositol-1,4,5- trisphosphate (IP3) production driven at least in part by the D3- phosphoinositide PtdIns-3,4,5-P3 through the action of TEC family tyrosine kinases. The importance of the PtdIns-3,4,5-P3/TEC kinase pathway is underscored by the modulation of this pathway negatively by the inhibitory receptor Fc[gamma]RIIb l for the purpose of feedback control of B-cell proliferation and antibody production, and by the interruption of this pathway by mutations in BTK which cause the inherited B-cell irnmunodeficiency X-linked agammglobulinemia (XLA). Tec kinase signaling mechanisms have been shown in two different systems to involve a direct interaction between TEC PH domains and PtdIns-3,4,5-P3, and phosphorylation of PLCgamma2 by the kinase domains. However two other TEC domains also appear to be required for TEC signaling function: the Tec homology (TH) doman and the SH2 domain, and what these domains do during TEC signaling is currently unknown. This grant will use the B-cell predominant TEC kinase BTK as a prototype to pursue two lines of investigation aimed at extending and refining our understanding of the mechanisms of TEC kinase function during the B-cell receptor calcium signal: I) Analysis of the role of the BTK TH domain in BTK-dependent PLC- activation; and II) Analysis of the role of the BTK SH2 domain in BTK-dependent PLCgamma2 activation.
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