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Vol. 15, Issue 10, 4416-4425, October 2004

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Cross-talk of Integrin 31 and Tissue Factor in Cell Migration

Andrea Dorfleutner ^*  , Edith Hintermann  , Takehiko Tarui , Yoshikazu Takada  ^||, and Wolfram Ruf ^* ¶

^* Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037; Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037

Submitted September 3, 2003; Revised July 2, 2004; Accepted July 6, 2004
Monitoring Editor: Martin A. Schwartz

In cancer and angiogenesis, coagulation-independent roles of tissue factor (TF) in cell migration are incompletely understood. Immobilized anti-TF extracellular domain antibodies induce cell spreading, but this phenomenon is epitope specific and is not induced by anti-TF 5G9. Spreading on anti-TF is 1 integrin–dependent, indicating functional interactions of the TF extracellular domain 5G9 epitope (a presumed integrin-binding site) and integrins. Recombinant TF extracellular domain supports adhesion of cells expressing v3 or certain 1 integrin heterodimers (31, 41, 51, 61, 91) and adhesion is blocked by specific anti-integrin antibodies or mutations in the integrin ligand-binding site. Although several studies have linked TF to cell migration, we here demonstrate that TF specifically regulates 31-dependent migration on laminin 5. Expression of TF suppresses 31-dependent migration, but only when the TF cytoplasmic domain is not phosphorylated. Suppression of migration can be reversed by 5G9, presumably by disrupting integrin interaction, or by the protease ligand VIIa, known to induce PAR-2–dependent phosphorylation of TF. In both cases, release of 31 inhibition is prevented by mutation of critical phosphorylation sites in the TF cytoplasmic domain. Thus, TF influences integrin-mediated migration through cooperative intra- and extracellular interactions and phosphorylation regulates TF's function in cell motility.

Abbreviations used: mAB, monoclonal antibody; PAR, protease-activated receptor; PKC, protein kinase C; TF, tissue factor; TFLZ, recombinant TF extracellular domain with a carboxyl-terminal leucine zipper domain; TFPI, TF pathway inhibitor; uPAR, urokinase receptor; VIIa, coagulation factor VIIa.

Present address: The Mary Babb Randolph Cancer Center and the Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506-9300

These authors contributed equally to this work.

^|| Present address: University of California Davis Medical Center, Research III, Suite 3300, 4645 2nd Avenue, Sacramento, CA 95817.

^¶ Corresponding author. E-mail address: ruf{at}scripps.edu.

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