Phospholipid scramblase 1 modulates a selected set of IgE receptor-mediated mast cell responses through LAT-dependent pathway
Phospholipid scramblase 1 modulates a selected set of IgE receptor-mediated mast cell responses through LAT-dependent pathway
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DOI：
10.1074/jbc.m705320200
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发表时间：
2008-09-12
影响因子：
4.8
通讯作者：
Benhamou, Marc
中科院分区：
文献类型：
--
作者：
Amir-Moazami, Omid;Alexia, Catherine;Benhamou, Marc
肥大细胞上的 IgE 受体 (Fc epsilon RI) 的结合导致预先形成的和新形成的介质以及细胞因子的释放。负责这些反应的信号传导途径涉及多种蛋白质的酪氨酸磷酸化。我们之前报道了 Fc epsilon RI 聚集后磷脂扰乱酶 1 (PLSCR1) 酪氨酸的磷酸化。在这里，使用短发夹 RNA 敲低 RBL-2H3 肥大细胞系中的 PLSCR1 表达。敲除 PLSCR1 表达会导致 Fc epsilon RI 聚集和血管内皮生长因子释放后的脱颗粒反应显着受损，而 MCP-1 的释放受到的影响最小。敲低 PLSCR1 不会改变白三烯 C4 和前列腺素 D2 的释放。对 Fc epsilon RI 依赖性信号通路的分析表明，虽然 ERK 和 Akt 的酪氨酸磷酸化不受影响，但在 PLSCR1 敲低的细胞中，LAT 的酪氨酸磷酸化显着降低。在这些细胞中，磷脂酶 C gamma 1 的酪氨酸磷酸化以及由此导致的钙动员也显着减少。在未激活的肥大细胞中，PLSCR1 部分存在于脂筏中，在细胞激活后进一步募集，并与 Lyn 和 Syk 组成型相关，但与 LAT 或 Fyn 不相关。总而言之，这些数据将 PLSCR1 确定为 Fc epsilon RI 信号传导的新型放大器，选择性地作用于 Lyn 启动的 LAT/磷脂酶 C gamma 1/钙轴，从而增强一组选定的肥大细胞反应。
Engagement of the IgE receptor (Fc epsilon RI) on mast cells leads to the release of preformed and newly formed mediators as well as of cytokines. The signaling pathways responsible for these responses involve tyrosine phosphorylation of multiple proteins. We previously reported the phosphorylation on tyrosine of phospholipid scramblase 1 (PLSCR1) after Fc epsilon RI aggregation. Here, PLSCR1 expression was knocked down in the RBL-2H3 mast cell line using short hairpin RNA. Knocking down PLSCR1 expression resulted in significantly impaired degranulation responses after Fc epsilon RI aggregation and release of vascular endothelial growth factor, whereas release of MCP-1 was minimally affected. The release of neither leukotriene C4 nor prostaglandin D2 was altered by knocking down of PLSCR1. Analysis of Fc epsilon RI-dependent signaling pathways revealed that whereas tyrosine phosphorylation of ERK and Akt was unaffected, tyrosine phosphorylation of LAT was significantly reduced in PLSCR1 knocked down cells. Tyrosine phosphorylation of phospholipase C gamma 1 and consequently the mobilization of calcium were also significantly reduced in these cells. In nonactivated mast cells, PLSCR1 was found in part in lipid rafts where it was further recruited after cell activation and was constitutively associated with Lyn and Syk but not with LAT or Fyn. Altogether, these data identify PLSCR1 as a novel amplifier of Fc epsilon RI signaling that acts selectively on the Lyn-initiated LAT/phospholipase C gamma 1/calcium axis, resulting in potentiation of a selected set of mast cell responses.