INTEGRIN ASSOCIATED PROTEIN IS A THROMBOSPONDIN RECEPTOR

凝血酶原蛋白-1(TS1)是一种多结构域糖蛋白，参与多种蛋白的表达。 伤口愈合、炎症、血管生成、癌症和发展。 我们发现整合素相关蛋白或IAP(CD47)是一种 TS1的C末端细胞结合域(CBD)的受体。反- IAP单抗阻断可能依赖整合素的功能，需要IAP 用于整合素启动的信号转导。我们的初步数据显示 TS1-IAP相互作用共刺激或增强β1，β2 以及白细胞、血小板、内皮细胞中的β3整合素， 成纤维细胞和黑色素瘤细胞导致趋化，增强细胞 扩散、血小板活化与白细胞整合素的激活 内皮细胞黏附和移行所必需的。所有这些都是 百日咳毒素特异性阻断TS1/IAP的功能 表明需要异源三聚体Gi蛋白连接IAP TS1激活下游信令事件达到建议的目标 包括： 1.对CBD进行诱变以确定其结构特征 对于绑定和激活IAP很重要。整个TS1的突变将 被创建，其中其他细胞结合位点已被“敲除” 与CBD中的那些结合。 2.TS1、IAP、ITS间分子相互作用的测定 IAP信号转导所必需的伙伴干扰素和Gi蛋白。 3.评估TS1/CBD作为αIOTA共刺激因子的作用 IOTAβ3在血小板黏附和聚集中的作用。 4.将测试与炎症相关的TS1/IAP激活的作用 在白细胞趋化模型中，β2整合素活化，白细胞 血管内皮细胞单层移位与吞噬功能 巨噬细胞引起的炎性细胞凋亡。 我们现在有了一种新的TS1功能范例，在许多生物学中 整合素的亲和力和信号功能是 调制过的。这方面的一些最好的例子是血小板 活化/聚集与循环部位的炎症反应 白细胞迅速激活，与炎症的内皮细胞黏附 并侵入组织。这项工作可能会产生信息和 止血、血栓、创面有治疗价值的化合物 治疗、血管生成和炎症性疾病，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.