INTEGRIN ASSOCIATED PROTEIN IS A THROMBOSPONDIN RECEPTOR

血小板反应蛋白-1（TS 1）是一种多结构域糖蛋白，参与了血小板活化过程。 伤口愈合、炎症、血管生成、癌症和发育。 我们已经发现整合素相关蛋白或IAP（CD 47）是一种免疫调节因子， TS 1的C-末端细胞结合结构域（CBD）受体。 抗 IAP单克隆抗体可阻断整合素依赖性功能，需要IAP 整合素启动的信号转导。 我们的初步数据显示 TS 1-IAP相互作用共刺激或增强β 1，β 2 和白细胞，血小板，内皮细胞， 成纤维细胞和黑色素瘤细胞，导致趋化，增强细胞 扩散、血小板活化和白细胞整合素活化 是内皮细胞粘附和迁移所必需的。 所有这些 百日咳毒素特异性阻断TS 1/IAP的功能 表明需要异源三聚体Gi蛋白连接IAP 通过TS 1激活下游信号传导事件 为： 1. 对CBD进行诱变以确定其结构特征 重要的是结合和激活IAP。 整个TS 1的突变将 其中其他细胞结合位点已被“敲除”， 与CBD的结合。 2. 测定TS 1、IAP、其 IAP信号传导所必需的伴侣干扰素和Gi蛋白。 3. 评估TS 1/CBD作为α I共刺激因子的作用 血小板粘附和聚集中的iota β 3。 4. TS 1/IAP激活与炎症相关的作用将被测试 在白细胞趋化性、β 2整联蛋白活化、白细胞趋化性、β 2整联蛋白活化和β 2整联蛋白活化的模型中， 内皮细胞单层的迁移和 通过巨噬细胞使炎性细胞凋亡。 我们现在有一个新的范式TS 1功能在许多生物学 其中整合素的亲和性和信号传导功能被 调制的最好的例子是血小板 激活/聚集和炎症反应，其中循环 白细胞迅速活化，粘附在发炎的内皮上 并侵入组织 这项工作可能会产生信息， 具有止血和血栓形成、创伤治疗价值的化合物 愈合、血管生成和炎性疾病如关节炎。

Thrombospondin-1 (TS1) is a multidomain glycoprotein involved in wound healing, inflammation, angiogenesis, cancer and development. We have found that integrin associated protein or IAP (CD47) is a receptor for the C-terminal cell binding domain (CBD) of TS1. Anti- IAP mAbs block may integrin-dependent functions and IAP is required for integrin-initiated signal transduction. Our preliminary data indicate that the TS1-IAP interaction costimulates or augments beta 1, beta 2 and beta 3 integrins in leukocytes, platelets, endothelial cells, fibroblasts and melanoma cells leading to chemotxis, enhanced cell spreading, platelet activation and activation of leukocyte integrins required for endothelial adhesion and transmigration. All of these functions of TS1/IAP are blocked specifically by pertussis toxin indicating a requirement for a heterotrimeric Gi protein to link IAP activation by TS1 to downstream signaling events The proposed aim are: 1. To mutagenize the CBD to determine its structural features important for binding and activating IAP. Mutations of whole TS1 will be created in which other cell binding sites have been 'knocked out' in combination with those in the CBD. 2. Determination of the molecular interactions among TS1, IAP, its partner intefrins and Gi proteins necessary for IAP signaling. 3. Assessment of the role of TS1/CBD as a costimulator of alpha iota iota beta3 in platelet adhesion and aggregation. 4. Roles of TS1/IAP activation relevant to inflammation will be tested in models of leukocyte chemotaxis, beta2 integrin activation, leukocyte transmigration of endothelial monolayers and the phagocytosis of apoptotic inflammatory cells by macrophages. We now have a novel paradigm for TS1 function in many biological systems in which the affinity and signaling functions of integrins are modulated. Some of the best examples of this are in platelet activation/aggregation and the inflammatory response where circulating leukocytes become rapidly activated to adhere to inflamed endothelium and invade tissues. This work can potentially yield information and compounds of therapeutic value in hemostasis and thrombosis, wound healing, angiogenesis and inflammatory diseases such as arthritis.