Negative regulation of mast cell signaling and function by the adaptor LAB/NTAL.
Negative regulation of mast cell signaling and function by the adaptor LAB/NTAL.
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DOI：
10.1084/jem.20041213
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发表时间：
2004-10-18
影响因子：
15.3
通讯作者：
Dráber, P
中科院分区：
文献类型：
--
作者：
Volná, P;Lebduska, P;Dráberová, L;Símová, R;Heneberg, P;Boubélik, M;Bugajev, V;Malissen, B;Wilson, BS;Horejsi, V;Malissen, M;Dráber, P
Fcɛ受体I(FcɛRI)与肥大细胞和嗜碱性粒细胞的结合启动了导致脱颗粒的信号通路。早期激活事件包括两个跨膜接头蛋白的酪氨酸磷酸化，即T细胞激活连接物(LAT)和非T细胞激活连接物(NTAL；也称为LAB，Wbscr5基因的产物)。以往的研究表明，LAT缺陷小鼠的骨髓源性肥大细胞(BMMCs)的分泌反应受到部分抑制。为了阐明NAL在肥大细胞脱颗粒中的作用，我们比较了NAL缺陷小鼠和野生型小鼠BMMC中FcɛRI介导的信号转导事件。尽管NTAL在结构上与LAT相似，但在NTAL缺陷的肥大细胞中，抗原介导的脱颗粒反应出人意料地增加。最早受到影响的事件是抗原激活细胞中LAT的酪氨酸磷酸化增强。伴随着酪氨酸磷酸化和磷脂酶Cγ1和磷脂酶Cγ2活性的增强，导致三磷酸肌醇水平和细胞内游离钙离子水平升高。NTAL缺陷的BMMCs还表现出磷脂酰肌醇3-羟基激酶和含Src同源2结构域的蛋白酪氨酸磷酸酶-2的活性增强。虽然LAT和NTAL都被认为定位于膜筏中，但免疫金电子显微镜在分离的膜片上显示了它们独立的聚集。综合数据显示，NAT在功能和地形上与LAT不同。
Engagement of the Fcɛ receptor I (FcɛRI) on mast cells and basophils initiates signaling pathways leading to degranulation. Early activation events include tyrosine phosphorylation of two transmembrane adaptor proteins, linker for activation of T cells (LAT) and non–T cell activation linker (NTAL; also called LAB; a product of Wbscr5 gene). Previous studies showed that the secretory response was partially inhibited in bone marrow–derived mast cells (BMMCs) from LAT-deficient mice. To clarify the role of NTAL in mast cell degranulation, we compared FcɛRI-mediated signaling events in BMMCs from NTAL-deficient and wild-type mice. Although NTAL is structurally similar to LAT, antigen-mediated degranulation responses were unexpectedly increased in NTAL-deficient mast cells. The earliest event affected was enhanced tyrosine phosphorylation of LAT in antigen-activated cells. This was accompanied by enhanced tyrosine phosphorylation and enzymatic activity of phospholipase C γ1 and phospholipase C γ2, resulting in elevated levels of inositol 1,4,5-trisphosphate and free intracellular Ca2+. NTAL-deficient BMMCs also exhibited an enhanced activity of phosphatidylinositol 3-OH kinase and Src homology 2 domain–containing protein tyrosine phosphatase-2. Although both LAT and NTAL are considered to be localized in membrane rafts, immunogold electron microscopy on isolated membrane sheets demonstrated their independent clustering. The combined data show that NTAL is functionally and topographically different from LAT.
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影响因子：
8
作者：
Wu, CJ;O'Rourke, DM;Greene, MI
通讯作者：
Greene, MI
影响因子：
32.4
作者：
Finco, TS;Kadlecek, T;Weiss, A
通讯作者：
Weiss, A
影响因子：
15.3
作者：
Brdicka, T;Imrich, M;Horejsí, V
通讯作者：
Horejsí, V
影响因子：
32.4
作者：
Saitoh, S;Arudchandran, R;Samelson, LE
通讯作者：
Samelson, LE
影响因子：
20.3
作者：
Tkaczyk, C;Horejsi, V;Gilfillan, AM
通讯作者：
Gilfillan, AM