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J. Cell Biol.,
Volume 140, Number 5, March 9, 1998 1241-1253
Departments of Immunology and Vascular Biology, IMM-17, The Scripps Research Institute, La Jolla, California 92037
Tissue factor (TF), the protease receptor initiating the coagulation system, functions in vascular development, angiogenesis, and tumor cell metastasis by
poorly defined molecular mechanisms. We demonstrate that immobilized ligands for TF specifically support cell adhesion, migration, 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 to TF adhesion contacts is associated with reorganization of actin filaments, 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 support cell spreading and migration, demonstrating that
the extracellular domain of TF is not involved in the recruitment of accessory molecules that influence adhesive functions. Replacement of TF's cytoplasmic Ser
residues with Asp to mimic phosphorylation enhances
the interaction with ABP-280, whereas Ala mutations
abolish coprecipitation of ABP-280 with immobilized
TF cytoplasmic domain, and severely reduce cell
spreading. The specific interaction of the TF cytoplasmic domain with ABP-280 provides a molecular pathway by which TF supports tumor cell metastasis and
vascular remodeling.
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