Role of tissue factor in metastasis: Functions of the cytoplasmic and extracellular domains of the molecule

Tissue factor (TF) is a transmembrane glycoprotein that complexes with fact or VIIa to initiate blood coagulation. It was reported in an earlier study that expression of high levels of TF in a human melanoma cell line promotes metastasis, and that the cytoplasmic domain of TF is required for this met astatic effect. To analyze the functions of the cytoplasmic and extracellul ar domains of TF in metastasis, two TF mutants were constructed; in one mut ant alanine was substituted for each of the three serine residues in the cy toplasmic domain, preventing phosphorylation; in the other mutant alanine w as substituted for four key residues in the extracellular domain, preventin g binding of factor VIIa and consequently eliminating the initiation of blo od coagulation by the TF-VIIa complex. Melanoma lines expressing high level s of either mutant form of TF were weakly metastatic in SCID mice; indicati ng that phosphorylation of the cytoplasmic domain and formation of a comple x with VIIa by the extracellular domain are required for the full metastati c effect of TF. It was also found that increasing TF expression in human me lanoma cells does not increase expression of vascular endothelial growth fa ctor or promote growth and vascularization of tumors derived from the melan oma cells, suggesting that TF acts by a mechanism other than angiogenesis t o promote metastasis.