Regulation of the phospholipase C-gamma 2 pathway in B cells

In B lymphocytes, a signaling complex that contributes to cell fate decisio ns is the B-cell antigen receptor (BCR), with different extents of receptor engagement leading to such outcomes as cell death, survival, or proliferat ion. Here, based upon the available genetic and biochemical data of the BCR signal components, we discuss several mechanisms by which BCR signals are propagated and modified, with specific emphasis on the phospholipase C (PLC )-gamma 2-calcium pathway. Gene-targeting experiments in DT40 chicken B cells highlighted the importan ce of the intracellular protein tyrosine kinases Syk and Btk in PLC-gamma 2 activation. Until recently, the molecular mechanism underlying the double requirement for Syk and Btk in PLC-gamma 2 activation remained unclear, but new data suggest that an adapter molecule, B-cell Linker protein (alternat ively named SLP-65 or BASH), phosphorylated by Syk, provides docking sites for Btk SH2 domain as well as PLC-gamma 2 SH2 domains, thus bringing Btk in to close proximity with PLC-gamma 2. The activated Btk then phosphorylates PLC-gamma 2, leading to its activation. The activated PLC-gamma 2 converts phosphatidylinositol 4,5-bisphosphate into the second messenger inositol 1, 4,5-trisphosphate (IP3), which in turn binds to IF, receptors located on th e endoplasmic reticulum (ER). Binding of IP3 to the IP3 receptors is essent ial for triggering a calcium release from the ER and subsequent entry of ex tracellular calcium. Balancing these activation signals in the PLC-gamma 2-calcium pathway are t he inhibitory receptors expressed on B cells, Fc gamma RII and paired immun oglobin-like receptor (PIR)-B. Although both Fc gamma RII and PIR-B inhibit s the BCR-mediated [Ca2+](i) increase, the inhibitory mechanisms of these r eceptors are distinct. The Fc gamma RII-mediated inhibitory signal is depen dent on lipid phosphatase SHIP, whereas the PIR-B requires redundant functi ons of protein phosphatases SHP-1 and SHP-2. Thus, PIR-B and Fc gamma RII i nhibit calcium signals by utilizing two distinct signaling molecules, there by contributing to setting threshold levels for activation signals as well as terminating activation responses.