Synergistic B cell activation by CD40 and the B cell antigen receptor - Role of B lymphocyte antigen receptor-mediated kinase activation and tumor necrosis factor receptor-associated factor regulation
Synergistic B cell activation by CD40 and the B cell antigen receptor - Role of B lymphocyte antigen receptor-mediated kinase activation and tumor necrosis factor receptor-associated factor regulation
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DOI：
10.1074/jbc.m310628200
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发表时间：
2004-01-23
影响因子：
4.8
通讯作者：
Bishop, GA
中科院分区：
文献类型：
--
作者：
Haxhinasto, SA;Bishop, GA
B 淋巴细胞的最佳激活取决于各种细胞表面受体的表达和信号通路的充分整合。这需要 B 淋巴细胞抗原受体 (BCR) 识别抗原时产生的信号，以及与 T 辅助细胞的同源相互作用（包括 CD40-CD154 相互作用）提供的附加信号。 BCR 和 CD40 的结合导致 B 细胞协同激活。先前的研究发现 CD40 信号通路中的肿瘤坏死因子受体相关因子 (TRAF)-2 和 TRAF3 以及 BCR 激活蛋白激酶 D (PKD) 是这种协同作用中的重要协同因素。为了更好地了解这些因素在桥接 BCR 和 CD40 信号通路中的作用，我们检查了 TRAF 功能的 BCR 信号调节。结果表明，BCR 参与时 TRAF2 的磷酸化增加，但 CD40 参与时不增加，并且 TRAF2 的潜在磷酸化残基酪氨酸 484 对于 BCR-CD40 协同作用至关重要。此外，野生型或组成型活性布鲁顿酪氨酸激酶 (Btk) 增强了 BCR-CD40 协同作用，而 Btk 的 xid 突变形式则阻止了 BCR-CD40 协同作用。这些作用取决于 TRAF2 和 PKD 活性。这些发现提出了一个模型，其中 Btk 以 PKD 依赖性方式有助于增强 TRAF2 的 CD40 反应。
Optimal activation of B-lymphocytes depends both upon expression of various cell surface receptors and adequate integration of signaling pathways. This requires signals generated upon recognition of antigen by the B lymphocyte antigen receptor (BCR) as well as additional signals provided by cognate interaction with T helper cells, including the CD40-CD154 interaction. Engagement of both the BCR and CD40 results in synergistic activation of B cells. Previous studies identified tumor necrosis factor receptor-associated factor (TRAF)-2 and TRAF3 in the CD40-signaling pathway together with BCR-activated protein kinase D (PKD) as important cooperative factors in this synergy. To better understand the role of these factors in bridging the BCR and CD40 signaling pathways, BCR signal regulation of TRAF function was examined. Results show that phosphorylation of TRAF2 is increased upon BCR but not CD40 engagement and that of the potentially phosphorylated residues of TRAF2, tyrosine 484 is crucial for BCR-CD40 synergy. Additionally, wild type or constitutively active Bruton's tyrosine kinase (Btk) enhanced, whereas the xid mutant form of Btk prevented, BCR-CD40 synergy. These effects were dependent upon TRAF2 and PKD activity. These findings suggest a model in which Btk contributes to the enhancement of the CD40 response by TRAF2 in a PKD-dependent manner.