A functional T-cell receptor signaling pathway is required for p95vav activity.
A functional T-cell receptor signaling pathway is required for p95vav activity.
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p95vav 活性需要功能性 T 细胞受体信号传导通路。
DOI：
10.1128/mcb.15.8.4337
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发表时间：
1995
影响因子：
5.3
通讯作者：
Weiss,A
中科院分区：
文献类型：
--
作者：
Wu,J;Katzav,S;Weiss,A
t细胞抗原受体（TCR）的刺激诱导多种酪氨酸激酶的激活，导致许多细胞内底物的磷酸化。其中一种底物是p95vav，仅在造血细胞和滋养细胞中表达。它包含许多结构基序，包括Src同源性2、Src同源性3、pleckstrin同源结构域和一个假定的鸟嘌呤核苷酸交换结构域。p95vavin在tcr介导的信号传导过程中的作用尚不清楚。在这里，我们发现p95vavalone在Jurkat T细胞中的过表达导致核因子的激活，包括NFAT，参与白细胞介素-2的表达。此外，p95vav与TCR刺激协同诱导NFAT-和白细胞介素-2依赖性转录。相反，g蛋白偶联受体的NFAT激活不受p95vav过表达的调节，这表明这种作用是TCR信号通路所特有的。尽管去除p95vav的前67个氨基酸激活了其在NIH 3T3细胞中的转化潜力，但该区域似乎是其在T细胞中的功能所必需的。我们进一步证明p95vav诱导的NFAT激活不会被Ras激活模仿，尽管其功能依赖于Ras和Raf。此外，p95vin的激活功能被FK506阻断，提示其活性也依赖于钙调神经磷酸酶。为了进一步分析p95vavto参与TCR信号传导，我们分析了各种缺乏TCR信号功能或TCR表达的Jurkat突变体，并发现p95vavto的功能需要一个完整的TCR信号通路。然而，p95vavs的过表达似乎不会影响tcr诱导的蛋白酪氨酸磷酸化或细胞质游离钙的增加。综上所述，我们的数据表明p95vav在TCR信号级联的近端位置发挥重要作用，但尚未确定。
Stimulation of the T-cell antigen receptor (TCR) induces activation of multiple tyrosine kinases, resulting in phosphorylation of numerous intracellular substrates. One substrate is p95vav, which is expressed exclusively in hematopoietic and trophoblast cells. It contains a number of structural motifs, including Src homology 2, Src homology 3, and pleckstrin homology domains and a putative guanine nucleotide exchange domain. The role of p95vavin TCR-mediated signaling processes is unclear. Here, we show that overexpression of p95vavalone in Jurkat T cells leads to activation of the nuclear factors, including NFAT, involved in interleukin-2 expression. Furthermore, p95vavsynergizes with TCR stimulation in inducing NFAT- and interleukin-2-dependent transcription. In contrast, NFAT activation by a G-protein-coupled receptor is not modulated by p95vavoverexpression, suggesting that the effect is specific to the TCR signaling pathways. Although removal of the first 67 amino acids of p95vavactivates its transforming potential in NIH 3T3 cells, this region appears to be required for its function in T cells. We further demonstrate that the p95vav-induced NFAT activation is not mimicked by Ras activation, though its function is dependent upon Ras and Raf. Furthermore, the activating function of p95vavis blocked by FK506, suggesting that its activity also depends on calcineurin. To further dissect p95vavinvolvement in TCR signaling, we analyzed various Jurkat mutants deficient in TCR signaling function or TCR expression and showed that an intact TCR signaling pathway is required for p95vavto function. However, overexpression of p95vavdoes not appear to influence TCR-induced protein tyrosine phosphorylation or increases in cytoplasmic free calcium. Taken together, our data suggest that p95vavplays an important role at an yet unidentified proximal position in the TCR signaling cascade.