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© The Rockefeller University Press, 0021-9525/1998//1241 $5.00
The Journal of Cell Biology, Volume 140, Number 5, , 1998 1241-1253

Article

A Role for Tissue Factor in Cell Adhesion and Migration Mediated by Interaction with Actin-binding Protein 280



Ilka Ott, Edgar G. Fischer, Yohei Miyagi, Barbara M. Mueller, and Wolfram Ruf

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.

Abbreviations used in this paper: ABP-280, actin-binding protein 280; FAK, focal adhesion kinase; GPI, glycosol phosphatidylinositol; IL-2, interleukin 2; sTF, soluble tissue factor; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TNF{alpha}, tumor necrosis factor {alpha}; VEGF, vascular endothelial cell growth factor.

W. Ruf and B.M. Mueller were supported by National Institutes of Health grants HL16411 and CA59692, respectively. W. Ruf is an Established Investigator of the American Heart Association, B.M. Mueller is the recipient of a Junior Faculty Research Award from the American Cancer Society. Fellowship support was provided by the Deutsche Forschungsgemeinschaft to I. Ott and E.G. Fischer, and by the American Heart Association to I. Ott and Y. Miyagi.

Address all correspondence to Wolfram Ruf, Departments of Immunology and Vascular Biology, IMM-17, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. Tel.: (619) 784-2748. Fax: (619) 784-8480. E-mail: ruf{at}scripps.edu

Edgar G. Fischer's current address is Department of Pathology, University of Erlangen-Nürnberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany.

Yohei Miyagi's current address is Department of Pathology, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236 Japan.


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