Signal Transduction in Mast Cells

肥大细胞通过释放一系列介质在许多炎症和免疫反应中发挥重要作用。 我们研究的目的是了解导致这些分子释放的细胞内信号转导途径。 在先前的研究中，我们观察到蛋白酪氨酸磷酸化是FceRI诱导的脱粒的早期和关键信号。 蛋白酪氨酸激酶Syk被发现是酪氨酸磷酸化和激活后，受体聚集。还鉴定了RBL-2 H3肥大细胞的变体，其没有可检测的Syk，并证明Syk对于受体诱导的炎症介质释放是必需的。对这些细胞中信号通路的分析表明，大多数FceRI诱导的细胞蛋白质酪氨酸磷酸化位于Syk的下游，并且需要具有酶活性的Syk。用Syk阴性肥大细胞检测Syk在免疫受体诱导的细胞活化中的作用。 CD 45对于ZAP-70而不是Syk重建肥大细胞中抗原受体启动的脱粒信号是必需的。 SH 2结构域介导的Syk膜转位对于免疫受体介导的Syk激活下游信号传导事件是必不可少的，并且Syk自身在富含鞘糖脂的微结构域中的定位不足以产生或增强信号传导事件。 发现Syk调节包括蛋白酪氨酸激酶Btk和鸟嘌呤核苷酸交换因子Vav的分子。 这两种蛋白与蛋白酪氨酸磷酸酶SHP-1一起调节c-Jun N-末端激酶（JNK）途径，导致细胞因子基因的转录激活。

Mast Cells play an important role in many inflammatory and immunological reactions by releasing an array of mediators. The goal of our studies is to understand the intracellular signal transduction pathways that lead to the release of these molecules. In previous studies we observed that protein tyrosine phosphorylation is an early and critical signal for FceRI induced degranulation. The protein tyrosine kinase Syk was found to be tyrosine phosphorylated and activated after receptor aggregation. A variant of the RBL-2H3 mast cells that has no detectable Syk was also identified and demonstrated that Syk is essential for the receptor-induced release of inflammatory mediators. Analysis of signaling pathways in these cells indicate that most of the FceRI-induced cellular protein tyrosine phosphorylation is downstream of Syk and requires enzymatically active Syk. The Syk negative mast cells were used to examine the role of Syk in immune receptor induced activation of cells. CD45 was essential for ZAP-70, but not for Syk, to reconstitute antigen receptor-initiated degranulation signals in mast cells. The SH2 domain-mediated membrane translocation of Syk was essential for immune receptor mediated activation of Syk for downstream signaling events and the localization of Syk in glycosphingolipid-enriched microdomains by itself was not enough to generate or enhance signaling events. Syk was found to regulate molecules including the protein tyrosine kinase Btk and the guanine nucleotide exchange factor Vav. Both of these proteins together with the protein tyrosine phosphatase SHP-1 regulate the c-Jun N-terminal kinase (JNK) pathway that leads to transcriptional activation of cytokine genes.