Adaptor molecules in lymphocyte signaling

T和B细胞上抗原受体的结合导致一系列信号级联反应的激活， 包括细胞蛋白的磷酸化、Ras-MAPK通路和钙离子通量的激活。在T中 细胞，膜相关的适配器分子，LAT(激活细胞的连接物)起着至关重要的作用。 通过招募Grb2、Gads和Gads将TCR参与与RAS-MAPK激活和钙通量联系起来 PLC-y1到膜上。然而，目前还不清楚BCR参与如何与RAS-MAPK相结合 激活和钙离子通量。在B细胞中还没有发现LAT样分子。最近，我们克隆了一本小说 编码膜相关接头蛋白的基因。我们将这个基因命名为Lab(激活B的链接器 单元格)。我们的初步数据显示，LAB与LAT有许多相似之处。我们假设，在 B细胞，LAB功能将BCR参与与下游Ras-MAPK激活和钙离子通量偶联 通过将Grb2募集到膜上。这项建议旨在进一步研究LAB在B细胞激活中的作用 和发展。为了检验这一假说，我们设计了三个具体目标。在特定目标1中，Lab基因将被 在鸡DT40B细胞系中被破坏。该基因缺失导致的信号缺陷将是 特色化的。在具体目标2中，我们将检查LAB和LAT之间的功能差异 转基因小鼠。在特定目标3中，将在小鼠中干扰Lab基因，以研究B细胞中Lab的功能 发展。我们还将研究实验室在血小板和NK细胞中的功能。

Engagement of antigen receptors on T and B cells leads to activation of a series of signaling cascades, including phosphorylation of cellular proteins and activation of the Ras-MAPK pathway and Ca 2+ flux. In T cells, the membrane-associated adaptor molecule, LAT (Linker for activation ofT cells), plays a crucial role in connecting the TCR engagement to Ras-MAPK activation and Ca 2+ flux by recruiting Grb2, Gads, and PLC-y1 to the membrane. However, it is not clear how the BCR engagement is coupled to Ras-MAPK activation and Ca 2¿ flux. A LAT-like molecule has not been found in B cells. Recently, we cloned a novel gene encoding a membrane-associated adaptor protein. We named this gene, LAB (Linker for activation of B cells). Our preliminary data showed that LAB shares many characteristics with LAT. We hypothesize that, in B cells, LAB functions to couple the BCR engagement to downstream Ras-MAPK activation and Ca 2+ flux by recruiting Grb2 to the membrane. This proposal aims to further study LAB function in B cell activation and development. Three specific aims are designed to test this hypothesis. In specific aim 1, LAB gene will be disrupted in the chicken DT40 B cell line. Signaling defects caused by deletion of this gene will be characterized. In specific aim 2, we will examine the functional differences between LAB and LAT using transgenic mice. In specific aim 3, LAB gene will be disrupted in mice to study LAB function in B cell development. We will also study LAB function in platelets and NK cells.