Fischer K D, Kong Y Y, Nishina H, Tedford K, Marengère L E, Kozieradzki I, Sasaki T, Starr M, Chan G, Gardener S, Nghiem M P, Bouchard D, Barbacid M, Bernstein A, Penninger J M
Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), University of Wuerzburg, Germany.
Curr Biol. 1998 May 7;8(10):554-62. doi: 10.1016/s0960-9822(98)70224-6.
Vav is a guanine-nucleotide exchange factor for the Rho-like small GTPases RhoA, Rac1 and Cdc42, which regulate cytoskeletal reorganization and activation of stress-activated protein kinases (SAPK/JNKs). Vav is expressed in hematopoietic cells and is phosphorylated in T and B cells following activation of various growth factor or antigen receptors. Vav interacts with several signaling molecules in T cells, but the functional relevance of these interactions is established only for Slp76: they cooperate to induce activity of the transcription factor NF-AT and interleukin-2 expression. We have investigated the role of Vav in T cells by generating vav-/- mice.
Mice deficient for vav were viable and healthy, but had impaired T-cell development. In vav-/- T cells, in response to activation of the T-cell receptor (TCR), cell cycle progression, induction of NF-ATc1 activity, downregulation of the cell-cycle inhibitor p27Kip1, interleukin-2 production, actin polymerization and the clustering of TCRs into patches and caps--a cytoskeletal reorganization process--were defective. TCR-mediated activation of mitogen-activated protein kinase and SAPK/JNK was unaffected. Ca2+ mobilization was impaired in vav-/- thymocytes and T cells. In wild-type cells, Vav constitutively associated with the cytoskeletal membrane anchors talin and vinculin. In the absence of Vav, phosphorylation of Slp76, Slp76-talin interactions, and recruitment of the actin cytoskeleton to the CD3 zeta chain of the TCR co-receptor were impaired.
Vav is a crucial regulator of TCR-mediated Ca2+ flux, cytoskeletal reorganization and TCR clustering, and these are required for T-cell maturation, interleukin-2 production and cell cycle progression.
Vav是一种鸟嘌呤核苷酸交换因子，作用于Rho样小GTP酶RhoA、Rac1和Cdc42，这些酶调节细胞骨架重组以及应激激活蛋白激酶（SAPK/JNKs）的激活。Vav在造血细胞中表达，在各种生长因子或抗原受体激活后，T细胞和B细胞中的Vav会发生磷酸化。Vav与T细胞中的多种信号分子相互作用，但这些相互作用的功能相关性仅在与Slp76的相互作用中得以明确：它们协同诱导转录因子NF-AT的活性以及白细胞介素-2的表达。我们通过培育vav基因敲除小鼠研究了Vav在T细胞中的作用。
vav基因缺陷的小鼠存活且健康，但T细胞发育受损。在vav基因敲除的T细胞中，对T细胞受体（TCR）激活的反应中，细胞周期进程、NF-ATc1活性的诱导、细胞周期抑制剂p27Kip1的下调、白细胞介素-2的产生、肌动蛋白聚合以及TCRs聚集成斑块和帽状结构（一种细胞骨架重组过程）均存在缺陷。TCR介导的丝裂原活化蛋白激酶和SAPK/JNK的激活未受影响。vav基因敲除的胸腺细胞和T细胞中Ca2+动员受损。在野生型细胞中，Vav与细胞骨架膜锚定蛋白踝蛋白和纽蛋白组成性结合。在缺乏Vav的情况下，Slp76的磷酸化、Slp76与踝蛋白的相互作用以及肌动蛋白细胞骨架向TCR共受体CD3ζ链的募集均受损。
Vav是TCR介导的Ca2+通量、细胞骨架重组和TCR聚集的关键调节因子，而这些对于T细胞成熟、白细胞介素-2的产生和细胞周期进程是必需的。
