Kurosaki T, Maeda A, Ishiai M, Hashimoto A, Inabe K, Takata M
Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, Moriguchi, Japan.
Immunol Rev. 2000 Aug;176:19-29. doi: 10.1034/j.1600-065x.2000.00605.x.
In B lymphocytes, a signaling complex that contributes to cell fate decisions is the B-cell antigen receptor (BCR), with different extents of receptor engagement leading to such outcomes as cell death, survival, or proliferation. 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)-gamma2-calcium pathway Gene-targeting experiments in DT40 chicken B cells highlighted the importance of the intracellular protein tyrosine kinases Syk and Btk in PLC-gamma2 activation. Until recently, the molecular mechanism underlying the double requirement for Syk and Btk in PLC-gamma2 activation remained unclear, but new data suggest that an adapter molecule, B-cell linker protein (alternatively named SLP-65 or BASH), phosphorylated by Syk, provides docking sites for Btk SH2 domain as well as PLC-gamma2 SH2 domains, thus bringing Btk into close proximity with PLC-gamma2. The activated Btk then phosphorylates PLC-gamma2, leading to its activation. The activated PLC-gamma2 converts phosphatidylinositol 4,5-bisphosphate into the second messenger inositol 1,4,5-trisphosphate (IP3), which in turn binds to IP3 receptors located on the endoplasmic reticulum (ER). Binding of IP3 to the IP3 receptors is essential for triggering a calcium release from the ER and subsequent entry of extracellular calcium. Balancing these activation signals in the PLC-gamma2-calcium pathway are the inhibitory receptors expressed on B cells, FcyRII and paired immunoglobin-like receptor (PIR)-B. Although both FcyRII and PIR-B inhibits the BCR-mediated [Ca2+]i increase, the inhibitory mechanisms of these receptors are distinct. The FcyRII-mediated inhibitory signal is dependent on lipid phosphatase SHIP, whereas the PIR-B requires redundant functions of protein phosphatases SHP-1 and SHP-2. Thus, PIR-B and FcgammaRII inhibit calcium signals by utilizing two distinct signaling molecules, thereby contributing to setting threshold levels for activation signals as well as terminating activation responses.
在B淋巴细胞中，一种有助于细胞命运决定的信号复合物是B细胞抗原受体（BCR），不同程度的受体结合会导致细胞死亡、存活或增殖等结果。在此，基于BCR信号成分的现有遗传和生化数据，我们讨论了BCR信号传导和修饰的几种机制，特别强调磷脂酶C（PLC）-γ2-钙途径。DT40鸡B细胞中的基因靶向实验突出了细胞内蛋白酪氨酸激酶Syk和Btk在PLC-γ2激活中的重要性。直到最近，Syk和Btk在PLC-γ2激活中的双重需求背后的分子机制仍不清楚，但新数据表明，一种由Syk磷酸化的衔接分子B细胞连接蛋白（也称为SLP-65或BASH）为Btk SH2结构域以及PLC-γ2 SH2结构域提供对接位点，从而使Btk与PLC-γ2紧密靠近。然后，活化的Btk使PLC-γ2磷酸化，导致其激活。活化的PLC-γ2将磷脂酰肌醇4,5-二磷酸转化为第二信使肌醇1,4,5-三磷酸（IP3），IP3继而与位于内质网（ER）上的IP3受体结合。IP3与IP3受体的结合对于触发内质网钙释放以及随后细胞外钙的进入至关重要。在PLC-γ2-钙途径中平衡这些激活信号的是B细胞上表达的抑制性受体FcyRII和配对免疫球蛋白样受体（PIR）-B。虽然FcyRII和PIR-B都抑制BCR介导的[Ca2+]i增加，但这些受体的抑制机制不同。FcyRII介导的抑制信号依赖于脂质磷酸酶SHIP，而PIR-B需要蛋白磷酸酶SHP-1和SHP-2的冗余功能。因此，PIR-B和FcγRII通过利用两种不同的信号分子抑制钙信号，从而有助于设定激活信号的阈值水平以及终止激活反应。
