Vav1 phosphorylation is induced by β2 integrin engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization
Vav1 phosphorylation is induced by β2 integrin engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization
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DOI：
10.1084/jem.20021995
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发表时间：
2003-08-04
影响因子：
15.3
通讯作者：
Long, EO
中科院分区：
文献类型：
--
作者：
Riteau, B;Barber, DF;Long, EO
鸟嘌呤核苷酸交换因子Vav 1调节肌动蛋白聚合，并有助于自然杀伤（NK）细胞的细胞毒性。一个悬而未决的问题是Vav 1如何被激活，以及什么受体可以在NK细胞与靶细胞接触时在肌动蛋白细胞骨架重排的上游发出信号。使用表达人NK细胞受体配体的转染昆虫细胞，我们表明，参与NK细胞上的β 2整合素LFA-1的细胞间粘附分子（ICAM）-1导致Vav 1的酪氨酸磷酸化，这是不敏感的胆固醇消耗和抑制肌动蛋白聚合。Vav 1磷酸化被Src家族激酶的抑制剂阻断，并且与其下游效应器PAK的激活相关。活化受体2134与其配体CD 48的结合不足以使Vav 1磷酸化。然而，2134与LFA-1的共同参与导致Vav 1磷酸化的增强，这对胆固醇消耗和肌动蛋白聚合的抑制是敏感的。只有当2B 4和LFA-1共同接合时，Vav 1才被招募到耐洗涤剂膜（DRM）部分，但在LFA-1接合后则没有。因此，LFA-1与靶细胞上的ICAM-1结合可能通过激活Vav 1在NK细胞中启动早期信号级联，导致细胞骨架重组和来自其他激活受体的信号放大。
The guanine nucleotide exchange factor Vav1 regulates actin polymerization and contributes to cytotoxicity by natural killer (NK) cells. An open question is how Vav1 becomes activated and what receptor can signal upstream of actin cytoskeleton rearrangement upon NK cell contact with target cells. Using transfected insect cells that express ligands of human NK cell receptors, we show that engagement of the beta2 integrin LFA-1 on NK cells by intercellular adhesion molecule (ICAM)-1 led to a tyrosine phosphorylation of Vav1 that was not sensitive to cholesterol depletion and to inhibition of actin polymerization. Vav1 phosphorylation was blocked by an inhibitor of Src-family kinases, and correlated with activation of its downstream effector PAK. Binding of activation receptor 2134 to its ligand CD48 was not sufficient for Vav1 phosphorylation. However, coengagement of 2134 with LFA-1 resulted in an enhancement of Vav1 phosphorylation that was sensitive to cholesterol depletion and to inhibition of actin polymerization. Vav1 was recruited to a detergent-resistant membrane (DRM) fraction only when 2B4 and LFA-1 were coengaged, but not after LFA-1 engagement. Therefore, binding of LFA-1 to ICAM-1 on target cells may initiate an early signaling cascade in NK cells through activation of Vav1, leading to cytoskeleton reorganization and amplification of signals from other activation receptors.