CELL BIOLOGY OF TISSUE FACTOR

有令人信服的实验证据表明，TF的生物学功能不仅仅是作为凝血级联的启动、促凝辅助因子。对实验性血源性肿瘤细胞转移的分析表明，细胞外TF依赖的促凝活性与TF细胞质结构域的信号功能之间存在合作关系，这表明细胞内结合信号通路将TF与细胞的迁移功能联系起来。这个项目是基于这样一个假设，即TF的细胞生物学功能的复杂性是由配体的细胞内招募和催化能力强的TF的特异性细胞外相互作用的相互作用引起的。VIIa复杂。目的1是表征TF依赖性TF的细胞质结构域的功能。VIIa复杂。目的1是表征细胞质结构域在tf依赖性肿瘤细胞转移中的功能。通过定点定向的方法表征肿瘤细胞转移过程中细胞质结构域的功能。通过定点诱变和使用ABP-280缺陷细胞系，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的促转移功能中起重要作用。目的2是表征TF的相互作用。与基质相关的TF通路特异性抑制剂复合物及其在TF依赖性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TF的形成。体内血管外部位的复合体。在Aim 3中，实验表征了TF细胞质结构域与新发现的可选择的细胞内配体的相互作用，这些配体可能解释了TF的细胞类型特异性功能。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的功能相互作用是复杂的，这些研究是基于这样的假设，即与TF细胞质结构域的复杂细胞内大分子组装被可能同时与ABP-280结合的附属分子重新调节。该项目将新型分子途径的体外分析与在适当的体内模型中对这些途径的严格测试相结合，为双重功能蛋白酶受体TF的基本细胞生物学提供了基础和新颖的见解。

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.