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.
Showing the most recent 10 out of 329 publications
