REQUIREMENT FOR BINDING OF CATALYTICALLY ACTIVE FACTOR VIIA IN TISSUEFACTOR-DEPENDENT EXPERIMENTAL METASTASIS

Tissue factor (TF), the initiating cell surface receptor of the coagul ation cascade, plays important roles in embryogenesis, angiogenesis, a nd tumor cell metastasis, It is controversial whether proteolytic func tion of TF complexed with its serine protease ligand VIIa is required for metastatic tumor dissemination, We show here in a model for TF-dep endent: experimental hematogenous metastasis, that TF supports metasta sis by both proteolytic activity of the TF-VIIa complex and currently undefined functions of the cytoplasmic domain, We demonstrate that lig and binding of VIIa to TF is required for metastasis, Antimetastatic p roperties of covalently inactivated VIIa provide evidence that ligand binding is insufficient per se to support metastasis, emphasizing that proteolytic activity is necessary for the metastatic process, Ala or Asp mutations of cytoplasmic serine residues were introduced to preclu de of mimic phosphorylation. In vivo analysis of these mutants suggest s that local protease generation on the tumor cell surface does not se rve simply to activate the cytoplasmic domain of TF by serine phosphor ylation. Thus, extracellular functions of the catalytically active TF- VIIa complex cooperate with specific functions of the TF cytoplasmic d omain to support the complex process of hematogenous tumor cell dissem ination.