CELL BIOLOGY OF TISSUE FACTOR

有令人信服的实验证据表明，转铁蛋白的生物学功能不仅仅是作为凝血级联的启动、促凝血的辅助因子。对实验性血源性肿瘤细胞转移的分析表明，细胞外依赖转铁蛋白的促凝活性与转铁蛋白胞浆结构域的信号功能协同作用，提示细胞内结合信号通路将转铁蛋白与细胞的迁移功能联系起来。该项目基于这样的总体假设，即TF细胞生物学功能的复杂性是配体在细胞内的募集和具有催化活性的TF.VIIa复合体的特定细胞外相互作用的相互作用的结果。目的1研究Tf依赖的TF.VIIa复合体中胞质结构域的功能。目的1研究胞浆结构域在肿瘤细胞转移中的作用。通过定点定位研究胞浆结构域在肿瘤细胞转移中的作用。通过定点突变和使用缺乏ABP-280的细胞系，这些实验将检验Tf细胞质结构域与ABP-280的相互作用是否在Tf的促转移功能中发挥重要作用。目的2研究转铁蛋白VIIa复合体与基质相关的转铁蛋白途径特异性抑制物之间的相互作用及其在依赖转铁蛋白的细胞迁移功能中的作用。这些实验将阐明在肿瘤细胞侵袭和血管生成过程中非常重要的分子途径，其中血管的高通透性导致在体内血管外位置形成TF.VIIa复合体。在目标3中，实验表征了转铁蛋白胞质结构域与新发现的可能解释转铁蛋白细胞类型特异性功能的替代细胞内配体的相互作用。在定义这些配体与Tf的功能相互作用时，这些研究是基于这样的假设，即这些配体与Tf的功能相互作用是基于这样的假设，即与Tf细胞质区域的复杂的细胞内大分子组装受可能同时与ABP-280结合的辅助分子的调节。该项目将新的分子通路的体外分析与在适当的体内模型中对这些通路的严格测试相结合的方法，为了解双功能蛋白酶受体Tf的基本细胞生物学提供了基础和新的见解。

There is compelling experimental evidence that the biological functions of TF go beyond an exclusive role as the initiating, procoagulent co-factor of the coagulation cascade. Analysis of experimental hematogenous tumor cell metastasis has demonstrated a cooperation of extracellular TF-dependent procoagulent activity with signaling functions of the TF cytoplasmic domain suggests an intracellular binding signaling pathway that links TF to migratory functions of cells. This project is based on the overall hypothesis that the complexity of TF's cell biological functions results from an interplay of intracellular recruitment of ligands and specific extracellular interactions of the catalytically competent TF.VIIa complex. Aim 1 is to characterize the function of the cytoplasmic domain in TF-dependent TF.VIIa complex. Aim 1 is to characterize the function of the cytoplasmic domain in TF-dependent tumor cell metastasis. By site directed characterize the function of the cytoplasmic domain in TF-dependent tumor cell metastasis. By site directed mutagenesis and the use of ABP-280 deficient cell lines, these experiments will examine whether the interaction of the TF cytoplasmic domain with ABP-280 plays an essential role in TF's pro-metastatic functions. Aim 2 is to characterize the interaction of the TF.VIIa complex with matrix associated specific inhibitors of the TF pathway and their role in TF-dependent migratory functions of cells. These experiments will elucidate molecular pathways that are highly significant during tumor cell invasion and angiogenesis, in which the vascular hyperpermeability leads to the formation of the TF.VIIa complex at extra-vascular locations in vivo. In Aim 3, experiment characterize the interaction of the TF cytoplasmic domain with newly identified, alternative intracellular ligands that may account for cell-type specific functions of TF. In defining the functional interactions of these ligands with TF, these studies are based on the hypothesis that the complex the functional interaction of these ligands with TF, these studies are based on the hypothesis that the complex intracellular macromolecular assemblies with TF cytoplasmic domain re regulated by accessory molecules that may bind simultaneously with ABP-280. The approach of this project to combine in vitro analysis of novel molecular pathways with the rigorous testing of these pathways in appropriate in vivo models promises fundamental and novel insight into the basic cell biology of the dual function protease receptor TF.