Tyrosine-phosphorylated Vav1 as a point of integration for T-cell receptor- and CD28-mediated activation of JNK, p38, and interleukin-2 transcription
Tyrosine-phosphorylated Vav1 as a point of integration for T-cell receptor- and CD28-mediated activation of JNK, p38, and interleukin-2 transcription
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DOI：
10.1074/jbc.275.24.18160
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发表时间：
2000-06-16
影响因子：
4.8
通讯作者：
Schmitz, ML
中科院分区：
文献类型：
--
作者：
Hehner, SP;Hofmann, TG;Schmitz, ML
在这项研究中，Re确定酪氨酸磷酸化的Vav 1是人类T细胞白血病细胞中T细胞受体和CD 28触发的信号通路之间的早期整合点。与单独的T细胞受体激活相比，共刺激导致Vav 1的长期和持续的磷酸化和膜定位。T细胞刺激诱导Vav 1在质膜上募集到可诱导的多蛋白T细胞活化信号复合物。Vav 1激活丝裂原活化蛋白激酶JNK和p38。Vav 1介导的JNK激活采用了涉及Rac、HPK 1、MLK 3和MKK 7的途径。Vav 1、Pac和MKK 6的显性负性形式抑制了共刺激诱导的p38激活。在这里，我们表明，Vav 1也诱导转录因子结合到CD 28 RE/AP元件中所含的白细胞介素-2启动子。对Vav 1的详细突变分析揭示了Vav 1的一系列组成性活性和非功能性形式。几乎所有的失活版本都在其Dbl同源结构域中发生突变，并表现为显性负突变体，其损害了共刺激诱导的JNK，p38和CD 28 RE/AP依赖性转录的激活。与NF-AT依赖性转录相反，Vav 1介导的白细胞介素-a启动子中的CD 28 RE/AP元件的转录诱导只能被环孢菌素A部分抑制，这表明Vav 1控制Ca 2+依赖性和非依赖性事件的双重作用。
In this study Re identified tyrosine-phosphorylated Vav1 as an early point of integration between the signaling routes triggered by the T-cell receptor and CD28 in human T-cell leukemia cells. Costimulation resulted in a prolonged and sustained phosphorylation and membrane localization of Vav1 in comparison to T-cell receptor activation alone. T-cell stimulation induced the recruitment of Vav1 to an inducible multiprotein T-cell activation signaling complex at the plasma membrane. Vav1 activated the mitogen-activated protein kinases JNK and p38. The Vav1-mediated activation of JNK employed a pathway involving Rac, HPK1, MLK3, and MKK7. The costimulation-induced activation of p38 was inhibited by dominant negative forms of Vav1, Pac, and MKK6. Here we show that Vav1 also induces transcription factors that bind to the CD28RE/AP element contained in the interleukin-2 promoter. A detailed mutational analysis of Vav1 revealed a series of constitutively active and nonfunctional forms of Vav1. Almost all inactive versions were mutated in their Dbl homology domain and behaved as dominant negative mutants that impaired costimulation-induced activation of JNK, p38, and CD28RE/AP-dependent transcription. In contrast to NF-AT-dependent transcription, Vav1-mediated transcriptional induction of the CD28RE/AP element in the interleukin-a promoter could only partially be inhibited by cyclosporin A, suggesting a dual role of Vav1 for controlling Ca2+-dependent and -independent events.