Grb2 and the non-T cell activation linker NTAL constitute a Ca2+-regulating signal circuit in B lymphocytes
Grb2 and the non-T cell activation linker NTAL constitute a Ca2+-regulating signal circuit in B lymphocytes
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DOI：
10.1016/j.immuni.2004.09.007
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发表时间：
2004-11-01
期刊：
影响因子：
32.4
通讯作者：
Wienands, J
中科院分区：
文献类型：
--
作者：
Stork, B;Engelke, M;Wienands, J
B细胞抗原受体的活化分别触发胞质和跨膜衔接蛋白如SLP-65和NTAL的磷酸化。SLP-65中的特异性磷酸受体位点作为Ca 2+动员酶Btk和PLC-γ 2的对接位点。磷酸化的NTAL募集Grb 2接头，但下游信号级联尚不清楚。我们现在表明，受体诱导的NTAL酪氨酸磷酸化和伴随的Grb 2复合物的形成，关键调节钙离子反应，而不影响SLP-65和PLC-γ 2磷酸化。Grb 2被证明发挥负调节作用，其似乎在与NTAL结合后被消除。这允许细胞内Ca 2+的持续释放，并且对于随后从细胞外来源进入Ca 2+是强制性的。因此，Ca 2+的升高受至少两种信号传导模块调节，即包含SLP-65、Btk和PLC-γ 2的B细胞特异性Ca 2+起始复合物和更普遍表达的NTAL/Grb 2复合物，其通过关闭抑制元件而充当放大器。
Activation of the B cell antigen receptor triggers phosphorylation of cytoplasmic and transmembrane adaptor proteins such as SLP-65 and NTAL, respectively. Specific phosphoacceptor sites in SLP-65 serve as docking sites for Ca2+-mobilizing enzymes Btk and PLC-gamma2. Phosphorylated NTAL recruits the Grb2 linker, but downstream signaling cascades are unclear. We now show that receptor-induced tyrosine phosphorylation of NTAL and concomitant Grb2 complex formation critically modulate the Ca2+ response without affecting SLP-65 and PLC-gamma2 phosphorylation. Grb2 turned out to play a negative regulatory role, which appears to be eliminated upon binding to NTAL. This allows for a sustained release of intracellular Ca2+ and is mandatory for subsequent entry of Ca2+ from extracellular sources. Thus, elevation of Ca2+ is regulated by at least two signaling modules, the B cell-specific Ca2+ initiation complex comprising SLP-65, Btk, and PLC-gamma2 and the more ubiquitously expressed NTAL/Grb2 complex, which acts as an amplifier by switching off inhibitory elements.