Vav links the T cell antigen receptor to the actin cytoskeleton and T cell activation independently of intrinsic Guanine nucleotide exchange activity.
Vav links the T cell antigen receptor to the actin cytoskeleton and T cell activation independently of intrinsic Guanine nucleotide exchange activity.
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DOI：
10.1371/journal.pone.0006599
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发表时间：
2009-08-12
期刊：
影响因子：
3.7
通讯作者：
Swat W
中科院分区：
文献类型：
--
作者：
Miletic AV;Graham DB;Sakata-Sogawa K;Hiroshima M;Hamann MJ;Cemerski S;Kloeppel T;Billadeau DD;Kanagawa O;Tokunaga M;Swat W
T细胞受体（TCR）参与导致形成信号微簇并诱导肌动蛋白细胞骨架的快速和动态变化，尽管TCR启动肌动蛋白聚合的确切机制尚不完全清楚。鸟嘌呤核苷酸交换因子（GEF）的Vav家族与TCR信号的产生和免疫突触形成有关，然而，目前尚不清楚Vav的GEF活性是否通常在TCR的T细胞活化中，特别是在TCR下游的肌动蛋白聚合中是必需的。在这里，我们报告说，Vav1组装成信号微簇在TCR接触位点，是TCR启动的肌动蛋白聚合的关键。令人惊讶的是，Vav 1功能TCR信号和Ca++动员通过一种机制，似乎并不严格依赖于内在的GEF活性。我们在这里提出了一个模型，其中Vav功能主要是作为一个酪氨酸磷酸化的接头蛋白的TCR活化的T细胞。我们的研究结果表明，与先前发表的研究（包括我们自己的实验室）的预期相反，药理学抑制Vav 1的内在GEF活性可能不是T细胞定向免疫抑制治疗的有效策略。
T cell receptor (TCR) engagement leads to formation of signaling microclusters and induction of rapid and dynamic changes in the actin cytoskeleton, although the exact mechanism by which the TCR initiates actin polymerization is incompletely understood. The Vav family of guanine nucleotide exchange factors (GEF) has been implicated in generation of TCR signals and immune synapse formation, however, it is currently not known if Vav's GEF activity is required in T cell activation by the TCR in general, and in actin polymerization downstream of the TCR in particular. Here, we report that Vav1 assembles into signaling microclusters at TCR contact sites and is critical for TCR-initiated actin polymerization. Surprisingly, Vav1 functions in TCR signaling and Ca++ mobilization via a mechanism that does not appear to strictly depend on the intrinsic GEF activity. We propose here a model in which Vav functions primarily as a tyrosine phosphorylated linker-protein for TCR activation of T cells. Our results indicate that, contrary to expectations based on previously published studies including from our own laboratory, pharmacological inhibition of Vav1's intrinsic GEF activity may not be an effective strategy for T cell-directed immunosuppressive therapy.
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DOI：
10.1084/jem.20030976
发表时间：
2004-01-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Badour K;Zhang J;Shi F;Leng Y;Collins M;Siminovitch KA
通讯作者：
Siminovitch KA
影响因子：
5.4
作者：
Ardouin, L;Bracke, M;Tybulewicz, VLJ
通讯作者：
Tybulewicz, VLJ
影响因子：
30.5
作者：
Faure, S;Salazar-Fontana, LI;Delon, J
通讯作者：
Delon, J
影响因子：
64.8
作者：
BUSTELO, XR;LEDBETTER, JA;BARBACID, M
通讯作者：
BARBACID, M
影响因子：
30.5
作者：
Barda-Saad, M;Braiman, A;Samelson, LE
通讯作者：
Samelson, LE