Vav1 transduces T cell receptor signals to the activation of phospholipase C-gamma1 via phosphoinositide 3-kinase-dependent and -independent pathways.
Vav1 transduces T cell receptor signals to the activation of phospholipase C-gamma1 via phosphoinositide 3-kinase-dependent and -independent pathways.
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DOI：
10.1084/jem.20011663
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发表时间：
2002-05-06
期刊：
影响因子：
--
通讯作者：
Tybulewicz VL
中科院分区：
文献类型：
--
作者：
Reynolds LF;Smyth LA;Norton T;Freshney N;Downward J;Kioussis D;Tybulewicz VL
Vav1是T细胞受体(TCR)信号所需的信号转导蛋白，TCR信号驱动胸腺的正负选择。此外，Vav1缺乏的胸腺细胞显示TCR诱导的细胞内钙通量显著降低。利用一种新的遗传系统，可以研究高度丰富的CD4+CD8+双阳性胸腺细胞群中的信号传递，我们研究了Vav1调节TCR诱导的钙离子通量的机制。我们发现，在Vav1缺乏的双阳性胸腺细胞中，磷脂酶C-γ1(PLCγ1)的磷酸化和激活是有缺陷的。此外，我们还证明了Vav1至少通过两条不同的途径调节PLCγ1的磷酸化。首先，在没有Vav1的情况下，Tec家族的激酶ITK和Tec不再被激活，很可能是由于磷脂酰肌醇3-激酶(PI3K)激活的缺陷。其次，缺乏Vav1的胸腺细胞显示出一个信号复合体的组装有缺陷，该复合体包含PLCγ1和适配分子Src Homology 2结构域，包含白细胞磷蛋白76。我们证明了后一种函数独立于PI3K。
Vav1 is a signal transducing protein required for T cell receptor (TCR) signals that drive positive and negative selection in the thymus. Furthermore, Vav1-deficient thymocytes show greatly reduced TCR-induced intracellular calcium flux. Using a novel genetic system which allows the study of signaling in highly enriched populations of CD4+CD8+ double positive thymocytes, we have studied the mechanism by which Vav1 regulates TCR-induced calcium flux. We show that in Vav1-deficient double positive thymocytes, phosphorylation, and activation of phospholipase C-γ1 (PLCγ1) is defective. Furthermore, we demonstrate that Vav1 regulates PLCγ1 phosphorylation by at least two distinct pathways. First, in the absence of Vav1 the Tec-family kinases Itk and Tec are no longer activated, most likely as a result of a defect in phosphoinositide 3-kinase (PI3K) activation. Second, Vav1-deficient thymocytes show defective assembly of a signaling complex containing PLCγ1 and the adaptor molecule Src homology 2 domain–containing leukocyte phosphoprotein 76. We show that this latter function is independent of PI3K.
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影响因子：
9.2
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