Defects in actin-cap formation in Vav-deficient mice implicate an actin requirement for lymphocyte signal transduction
Defects in actin-cap formation in Vav-deficient mice implicate an actin requirement for lymphocyte signal transduction
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DOI：
10.1016/s0960-9822(98)70225-8
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发表时间：
1998-05-07
期刊：
影响因子：
9.2
通讯作者：
Crabtree, GR
中科院分区：
文献类型：
--
作者：
Holsinger, LJ;Graef, IA;Crabtree, GR
背景资料：淋巴细胞上的抗原-受体相互作用导致肌动蛋白、受体和信号分子局部聚集成称为帽的不对称膜结构。虽然已知肌动蛋白聚合是必需的，但帽形成的机制尚不清楚。我们已经研究了事件的帽子形成使用小鼠轴承无效突变的vav（vav（-/-）），一个基因，编码的鸟嘌呤核苷酸交换因子的GTTPac.Results：淋巴细胞从vav（-/-）小鼠未能形成T细胞受体帽激活后，有缺陷的肌动蛋白细胞骨架。vav（-/-）细胞缺乏白细胞介素-2（IL-2）的产生和增殖，Ca ~（2+）动员峰值降低，但持续时间正常。Jun N-末端激酶或应激激活激酶（JNK或SAPK）和丝裂原激活蛋白激酶（MAPK）的激活以及转录因子NF-ATc 1和NF-κ B-1基因的诱导是正常的。尽管Ca 2+动员减少，但胞质NF-ATc向细胞核的移位是正常的，反映了vav（-/-）细胞中较低水平的Ca 2+仍足以激活钙调神经磷酸酶。用细胞松弛素D处理淋巴细胞，可以阻断肌动蛋白聚合，抑制帽形成，并产生信号传导和IL-2转录诱导缺陷，以响应抗原受体信号传导，这与在vav（-/-）细胞中观察到的几乎相同。在转染研究中，无论是组成型活性的Vav或Rac可以补充组成型活性的钙调神经磷酸酶激活NF-AT依赖的transcription.Conclusions：这些结果表明，Vav是所需的帽形成在淋巴细胞，此外，帽形成，IL-2的生产和增殖之间的相关性支持的假设，肌动蛋白依赖的途径是一个专门的生长调节信号的来源。(C)Current Biology Ltd ISSN 0960-9822。
Background: Antigen-receptor interactions on lymphocytes result in local clustering of actin, receptors and signaling molecules into an asymmetric membrane structure termed a cap. Although actin polymerization is known to be required, the mechanisms underlying cap formation are unclear. We have studied the events underlying cap formation using mice bearing a null mutation in vav (vav(-/-)), a gene that encodes a guanine-nucleotide exchange factor for the GTPase Pac.Results: Lymphocytes from vav(-/-) mice failed to form T-cell receptor caps following activation and had a defective actin cytoskeleton. The vav(-/-) cells were deficient in interleukin-2 (IL-2) production and proliferation, and the peak of Ca2+ mobilization was reduced although of normal duration. Activation of Jun N-terminal kinase or stress-activated kinase (JNK or SAPK) and mitogen-activated protein kinase (MAPK) and the induction of the transcription factor NF-ATc1 and egr-1 genes was normal. Despite the reduced Ca2+ mobilization, translocation of cytoplasmic NF-ATc to the nucleus was normal, reflecting that the lower levels of Ca2+ in vav(-/-) cells were still sufficient to activate calcineurin. Treatment of lymphocytes with cytochalasin D, which blocks actin polymerization, inhibited cap formation and produced defects in signaling and IL-2 transcriptional induction in response to antigen-receptor signaling that were nearly identical to those seen in vav(-/-) cells. In transfection studies, either constitutively active Vav or Rac could complement constitutively active calcineurin to activate NF-AT-dependent transcription.Conclusions: These results indicate that Vav is required for cap formation in lymphocytes, Furthermore, the correlation between cap formation, IL-2 production and proliferation supports the hypothesis that an actin-dependent pathway is a source of specialized growth regulatory signals. (C) Current Biology Ltd ISSN 0960-9822.