The N-terminal 20-Amino Acid Region of Guanine Nucleotide Exchange Factor Vav1 Plays a Distinguished Role in T Cell Receptor-mediated Calcium Signaling
The N-terminal 20-Amino Acid Region of Guanine Nucleotide Exchange Factor Vav1 Plays a Distinguished Role in T Cell Receptor-mediated Calcium Signaling
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鸟嘌呤核苷酸交换因子 Vav1 的 N 端 20 个氨基酸区域在 T 细胞受体介导的钙信号转导中发挥着重要作用
DOI：
10.1074/jbc.m112.426221
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发表时间：
2013-02-08
影响因子：
4.8
通讯作者：
Cao, YouJia
中科院分区：
文献类型：
--
作者：
Li, Shi-Yang;Du, Ming-Juan;Cao, YouJia
Vav 1是一种特异性表达于造血细胞的鸟嘌呤核苷酸交换因子（GEF）。它由多个结构域组成，在T细胞活化中起重要作用。Vav家族的其他高度保守的同种型Vav 2和Vav 3在包括淋巴细胞在内的人体组织中广泛表达。所有三种Vav蛋白都激活Rho家族小GTP酶，其参与T细胞活化期间的各种生物学过程。大量的研究表明，Vav 1是T细胞受体（TCR）介导的信号转导所不可或缺的，而Vav 2和Vav 3作为GEFs与Vav 1重叠，在TCR诱导的细胞骨架重组中发挥作用。缺乏Vav 1的T细胞在TCR介导的钙升高中表现出严重缺陷，表明共存的Vav 2和Vav 3不能补偿Vav 1的钙信号传导。Vav 1在淋巴细胞中的功能特性是什么？在这项研究中，我们确定了N-末端20个氨基酸的Vav 1的钙调蛋白同源（CH）域是必不可少的，它与钙调蛋白（CaM），导致TCR诱导的钙动员的相互作用。将Vav 1的1-20个氨基酸替换为Vav 2或Vav 3的氨基酸，可消除与CaM的结合，并且Vav 1的N端突变不能增强正常TCR诱导的钙动员，这反过来又会暂停活化T细胞核因子（NFAT）的活化和IL-2的产生。这项研究突出了Vav 1的N-末端20 aa对CaM结合的重要性，并为Vav 1在T细胞活化和信号转导中的独特和不可替代的作用提供了新的见解。
Vav1 is a guanine nucleotide exchange factor (GEF) specifically expressed in hematopoietic cells. It consists of multiple structural domains and plays important roles in T cell activation. The other highly conserved isoforms of Vav family, Vav2 and Vav3, are ubiquitously expressed in human tissues including lymphocytes. All three Vav proteins activate Rho family small GTPases, which are involved in a variety of biological processes during T cell activation. Intensive studies have demonstrated that Vav1 is indispensable for T cell receptor (TCR)-mediated signal transduction, whereas Vav2 and Vav3 function as GEFs that overlap with Vav1 on TCR-induced cytoskeleton reorganization. T cells lacking Vav1 exhibited severe defect in TCR-mediated calcium elevation, indicating that the co-existing Vav2 and Vav3 did not compensate Vav1 in calcium signaling. What is the functional particularity of Vav1 in lymphocytes? In this study, we identified the N-terminal 20 amino acids of Vav1 in the calponin homology (CH) domain to be essential for its interaction with calmodulin (CaM) that leads to TCR-induced calcium mobilization. Substitution of the 1-20 amino acids of Vav1 with those of Vav2 or Vav3 abolished the association with CaM, and the N-terminal mutations of Vav1 failed to potentiate normal TCR-induced calcium mobilization, that in turn, suspended nuclear factor of activated T cells (NFAT) activation and IL-2 production. This study highlights the importance of the N-terminal 20 aa of Vav1 for CaM binding, and provides new insights into the distinguished and irreplaceable role of Vav1 in T cell activation and signal transduction.