A ROLE FOR TISSUE-FACTOR IN CELL-ADHESION AND MIGRATION MEDIATED BY INTERACTION WITH ACTIN-BINDING PROTEIN-280

Tissue factor (TF), the protease receptor initiating the coagulation s ystem, functions in vascular development, angiogenesis, and tumor cell metastasis by poorly defined molecular mechanisms, We demonstrate tha t immobilized ligands for TF specifically support cell adhesion, migra tion, spreading, and intracellular signaling, which are not inhibited by RGD peptides, Two-hybrid screening identified actin-binding protein 280 (ABP-280) as ligand for the TF cytoplasmic domain, Extracellular ligation of TF is necessary for ABP-280 binding, ABP-280 recruitment t o TF adhesion contacts is associated with reorganization of actin fila ments, but cytoskeletal adaptor molecules typically found in integrin- mediated focal contacts are not associated with TF, Chimeric molecules of the TF cytoplasmic domain and an unrelated extracellular domain su pport cell spreading and migration, demonstrating that the extracellul ar domain of TF is not involved in the recruitment of accessory molecu les that influence adhesive functions. Replacement of TF's cytoplasmic Ser residues with Asp to mimic phosphorylation enhances the interacti on with ABP-280, whereas Ala mutations abolish coprecipitation of ABP- 280 with immobilized TF cytoplasmic domain, and severely reduce cell s preading, The specific interaction of the TF cytoplasmic domain with A BP-280 provides a molecular pathway by which TF supports tumor cell me tastasis and vascular remodeling.