Signal Transduction of Paired Inhibitory Receptors of NK

Ly49和KIR家族由抑制性和激活性受体组成，后者通过DAP12相互作用并发出信号。在回顾期间，我们继续对与DAP12信号相关的近端事件进行剖析。这项工作的结果包括定义了129/Sv背景的小鼠中DAP12信号的明显缺陷，可以深刻影响基因靶标小鼠的分析，描绘了CD45调节DAP12信号的两个水平(DAP-12本身的信号启动和去磷酸化)，以及最近对用于激活T细胞的非催化适配蛋白连接物(LAT)和用于激活B细胞的连接物(LAB)的重叠使用的剖析。TREM-1调节脓毒症，而TREM-2控制DC、小胶质细胞和破骨细胞的发育。我们对TREM簇的研究已发表了以下文献：1)鉴定了TREM样转录本-1(TLT-1)，这是一种不与DAP-12偶联而是与SHP-1相互作用的蛋白质；2)TLT-1是一种隔离在阿尔法颗粒中的血小板特异性受体；以及3)鉴定了血清中可溶的TLT-1，以及细胞外域的晶体结构。我们还在小鼠身上定位了TLT-1，展示了它在体外对血小板聚集的作用，并定义了一些与其相互作用的蛋白质。尽管血小板和血栓可以调节炎症、肿瘤生长和转移以及获得性免疫，但我们选择不在我们的基础分配下提出进一步的TLT-1研究。然而，如果有足够的资源，我们将继续TLT-1的生化研究。我们目前正在与我们实验室的一位前同事合作，评估我们的TLT-1-/-小鼠。

The Ly49 and KIR families are comprised of both inhibitory and activating receptors; the latter interacting and signaling through DAP12. We have continued our dissection of the proximal events associated with DAP12 signaling over the review period. The result of this work includes the definition of an apparent defect in DAP12 signaling in mice of the 129/Sv background that can profoundly effect the analysis of gene targeted mice, delineation of two levels of regulation of DAP12 signaling by CD45 (signal initiation and dephosphorylation of DAP-12 itself), and most recently, dissection of the overlapping use of the non-catalytic adaptor proteins Linker for Activation of T cells (LAT) and the Linker for Activation of B cells (LAB). TREM-1 regulates sepsis whereas TREM-2 can control the development of DC, microglia and osteoclasts. Our studies of the TREM cluster have led to publications regarding; 1) the identification of TREM-like transcript-1 (TLT-1), a protein that does not couple to DAP-12 but instead interacts with SHP-1; 2) characterization of TLT-1 as a platelet specific receptor sequestered in alpha granules; and 3) identification of soluble TLT-1 in serum, and solution of the crystal structure of the extracellular domain. We have also targeted TLT-1 in mice, shown its role in platelet aggregation in vitro, and defined some proteins that interact with it. Although platelets and thrombosis can regulate inflammation, cancer growth and metastasis, and adaptive immunity, we have chosen not to propose further TLT-1 studies under our base allocation here. If however, sufficient resources were available, we would continue biochemical study of TLT-1. We are currently, evaluating our TLT-1-/- mice in collaboration with a former fellow from our lab.