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。在之前的研究中，我们观察到蛋白酪氨酸磷酸化是FceRI诱导脱颗粒的早期和关键信号。酪氨酸蛋白激酶Syk在受体聚集后被酪氨酸磷酸化并被激活。Syk也被证明是受体诱导的炎症介质释放所必需的。在最近的研究中发现，SH2结构域介导的膜易位对于免疫受体介导的Syk下游信号事件的激活至关重要，Syk本身定位于鞘糖脂富集微结构域并不足以产生或增强信号事件。对Syk激活的结构基础的研究表明，激活环中相邻的两个酪氨酸是下游信号传递所必需的。Syk的激酶活性在体内和体外磷酸化这些酪氨酸中起主要作用。对大鼠嗜碱性白血病细胞系变体的研究表明，Cdc42和/或Rac1 GTPase的激活在免疫受体介导的早期信号传导中起重要作用，导致钙动员和脱颗粒。

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. Syk was also shown to be essential for the receptor-induced release of inflammatory mediators. In recent studies the SH2 domain-mediated membrane translocation was found to be critical for this 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. Studies on the structural basis of the activation of Syk demonstrated that the two adjacent tyrosines in the activation loop were required for downstream signaling. The kinase activity of Syk played the major role in phosphorylating these tyrosines both in vivo and in vitro. Studies with a variant of the rat basophilic leukemia cell line demonstrated that activation of the Cdc42 and/or Rac1 GTPase plays an essential role in immune receptor mediated early signaling that leads to calcium mobilization and degranulation.