Download PDF
Thromb Haemost 2005; 93(01): 27-34
DOI: 10.1160/TH04-07-0405
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Regulation of chemotaxis by the cytoplasmic domain of tissue factor

Agneta Siegbahn
1   Department of Medical Sciences, Clinical Chemistry, Akademiska Hospital and Ludwig Institute for Cancer Research, Biomedical Centre, Uppsala Sweden, Haemostasis Biology, Health Care Discovery, Novo Nordisk A/S, Maaloev, Denmark
,
Matilda Johnell
1   Department of Medical Sciences, Clinical Chemistry, Akademiska Hospital and Ludwig Institute for Cancer Research, Biomedical Centre, Uppsala Sweden, Haemostasis Biology, Health Care Discovery, Novo Nordisk A/S, Maaloev, Denmark
,
Brit B. Sorensen
1   Department of Medical Sciences, Clinical Chemistry, Akademiska Hospital and Ludwig Institute for Cancer Research, Biomedical Centre, Uppsala Sweden, Haemostasis Biology, Health Care Discovery, Novo Nordisk A/S, Maaloev, Denmark
,
Lars C. Petersen
1   Department of Medical Sciences, Clinical Chemistry, Akademiska Hospital and Ludwig Institute for Cancer Research, Biomedical Centre, Uppsala Sweden, Haemostasis Biology, Health Care Discovery, Novo Nordisk A/S, Maaloev, Denmark
,
Carl-Henrik Heldin
1   Department of Medical Sciences, Clinical Chemistry, Akademiska Hospital and Ludwig Institute for Cancer Research, Biomedical Centre, Uppsala Sweden, Haemostasis Biology, Health Care Discovery, Novo Nordisk A/S, Maaloev, Denmark
› Author AffiliationsFinancial support: Supported by Swedish Research Council, Swedish Cancer Foundation, Swedish Heart and Lung Foundation and King Gustav V and Queen Victoria Foundation
Further Information

Publication History

Received 02 July 2004

Accepted after revision 21 October 2004

Publication Date:
14 December 2017 (online)

   Permissions and Reprints

Summary

We previously demonstrated that FVIIa bound to tissue factor (TF) induces a hyperchemotactic response towards PDGF-BB. The aim of the present study was to investigate the role of the cytoplasmic domain of TF in cell migration. Porcine aortic endothelial (PAE) cells expressing human PDGF β -receptors (PAE/ PDGFR β ) were transfected for expression of human wildtype TF (PAE/PDGFRβ ,TF), a construct lacking the cytoplasmic domain (PAE/PDGFRβ ,TF ∆ cyto), a construct with alanine replacement of serine 258 (PAE/PDGFRβ ,TFS258A), or a construct with alanine replacement of serine 253, 258 and 263 in the cytoplasmic domain (PAE/PDGFRβ ,TF3SA). All stably transfected cell lines expressed functional TF. Chemotaxis was analyzed in a modified Boyden chamber assay. PAE/PDGFRβ ,TF cells stinulated with FVIIa migrated towards a 100-fold lower concentration of PDGF-BB than in the absence of FVIIa,however,hyperchemotaxis was not seen in PAE/PDGFRβ ,TF ∆ cyto cells. PAE/ PDGFR β /TFS258A and PAE/PDGFRβ ,TF3SA cells responded to low levels of PDGF-BB, but migrated a significantly shorter distance than PAE/PDGFRβ ,TF cells. Thus, hyperchemotaxis towards PDGF-BB is likely to depend in part on phosphorylation of the cytoplasmic domain of TF.We conclude that the cytoplasmic domain of TF plays a pivotal role in modulating cellular migration response.Our results suggest that the FVIIa/TF complex mediates intracellular signaling by alternative signal transduction pathway(s).

Keywords

Tissue factor - platelet-derived growth factor - intracellular signaling - cell migration
 

  • References

  • 1 Camerer E, Kolsto AB, Prydz H. Cell biology of tissue factor, the principal initiator of blood coagulation. Thromb Res 1996; 81: 1-41.
    CrossrefPubMedGoogle Scholar
  • 2 Rao LV. Tissue factor as a tumor procoagulant. Cancer Metastasis Rev 1992; 11: 249-66.
    CrossrefPubMedGoogle Scholar
  • 3 Hamada K, Kuratsu J, Saitoh Y. et al Expression of tissue factor correlates with grade of malignancy in human glioma. Cancer 1996; 77: 1877-83.
    CrossrefPubMedGoogle Scholar
  • 4 Shigemori C, Wada H, Matsumoto K. et al Tissue factor expression and metastatic potential of colorectal cancer. Thromb Haemost 1998; 80: 894-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Siegbahn A. Cellular consequences upon factor VIIa binding to tissue factor. Haemostasis 2000; 30 S2: 41-7.
    Google Scholar
  • 6 Morrissey JH. Tissue factor: an enzyme cofactor and a true receptor. Thromb Haemost 2001; 86: 66-74.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Chen J. et al Tissue factor – A receptor involved in the control of cellular properties, including angiogenesis. Thromb Haemost 2001; 86: 334-45.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Sorensen BB. et al Antiapoptotic effect of coagulation factor VIIa. Blood 2003; 102: 1708-15.
    CrossrefPubMedGoogle Scholar
  • 9 Bazan JF. Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci U S A 1990; 87: 6934-8.
    CrossrefPubMedGoogle Scholar
  • 10 Camerer E, Rottingen JA, Iversen JG. et al Coagulation factors VII and X induce Ca2+ oscillations in Madin-Darby canine kidney cells only when proteolytically active. J Biol Chem 1996; 271: 29034-42.
    CrossrefPubMedGoogle Scholar
  • 11 Poulsen LK, Jacobsen N, Sorensen BB. et al Signal transduction via the mitogen-activated protein kinase pathway induced by binding of coagulation factor VIIa to tissue factor. J Biol Chem 1998; 273: 6228-32.
    CrossrefPubMedGoogle Scholar
  • 12 Sorensen BB, Freskgard PO, Nielsen LS. et al Factor VIIa-induced p44/42 mitogen-activated protein kinase activation requires the proteolytic activity of factor VIIa and is independent of the tissue factor cytoplasmic domain. J Biol Chem 1999; 274: 21349-54.
    CrossrefPubMedGoogle Scholar
  • 13 Camerer E. et al Coagulation factors VIIa and Xa induce cell signaling leading to up-regulation of the egr-1 gene. J Biol Chem 1999; 274: 32225-33.
    CrossrefPubMedGoogle Scholar
  • 14 Pendurthi UR. et al Binding of factor VIIa to tissue factor induces alterations in gene expression in human fibroblast cells: up-regulation of poly(A) polymerase. Proc Natl Acad Sci U S A 1997; 94: 12598-603.
    CrossrefPubMedGoogle Scholar
  • 15 Pendurthi UR, Allen KE, Ezban M. et al Factor VIIa and thrombin induce the expression of Cyr61 and connective tissue growth factor, extracellular matrix signaling proteins that could act as possible downstream mediators in factor VIIa x tissue factor-induced signal transduction. J Biol Chem 2000; 275: 14632-41.
    CrossrefPubMedGoogle Scholar
  • 16 Versteeg HH, Sorensen BB, Slofstra SH. et al VIIa/ tissue factor interaction results in a tissue factor cytoplasmic domain-independent activation of protein synthesis, p70, and p90 S6 kinase phosphorylation. J Biol Chem 2002; 277: 27065-72.
    CrossrefPubMedGoogle Scholar
  • 17 Camerer E, Huang W, Coughlin SR. Tissue factorand factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc Natl Acad Sci U S A 2000; 97: 5255-60.
    CrossrefPubMedGoogle Scholar
  • 18 Ruf W. et al Specificity of coagulation factor signaling. J Thromb Haemost 2003; 1: 1495-503.
    CrossrefPubMedGoogle Scholar
  • 19 Yang YH, Hall P, Milenkovski G. et al Reduction in arthritis severity and modulation of immune function in tissue factor cytoplasmic domain mutant mice. Am J Pathol 2004; 164: 109-17.
    CrossrefPubMedGoogle Scholar
  • 20 Mueller BM, Reisfeld RA, Edgington TS. et al Expression of Tissue Factor by Melanoma-Cells Promotes Efficient Hematogenous Metastasis. Proc Natl Acad Sci U S A 1992; 89: 11832-6.
    CrossrefPubMedGoogle Scholar
  • 21 Mueller BM, Ruf W. Requirement for binding of catalytically active factor VIIa in tissue factor-dependent experimental metastasis. J Clin Invest 1998; 101: 1372-8.
    CrossrefPubMedGoogle Scholar
  • 22 Bromberg ME, Konigsberg WH, Madison JF. et al Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation. Proc Natl Acad Sci U S A 1995; 92: 8205-9.
    CrossrefPubMedGoogle Scholar
  • 23 Bromberg ME, Sundaram R, Homer RJ. et al Role of tissue factor in metastasis: functions of the cytoplasmic and extracellular domains of the molecule. Thromb Haemost 1999; 82: 88-92.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Abe K, Shoji M, Chen J. et al Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor. Proc Natl Acad Sci U S A 1999; 96: 8663-8.
    CrossrefPubMedGoogle Scholar
  • 25 Siegbahn A. et al Binding of factor VIIa to tissue factor on human fibroblasts leads to activation of phospholipase C and enhanced PDGF-BB-stimulated chemotaxis. Blood 2000; 96: 3452-8.
    PubMedGoogle Scholar
  • 26 Ronnstrand L. et al Overactivation of phospholipase C-gamma 1 renders platelet-derived growth factor beta-receptor-expressing cells independent of the phosphatidylinositol 3-kinase pathway for chemotaxis. J Biol Chem 1999; 274: 22089-94.
    CrossrefPubMedGoogle Scholar
  • 27 Sorensen BB. et al Incorporation of an active site inhibitor in factor VIIa alters the affinity for tissue factor. J Biol Chem 1997; 272: 11863-8.
    CrossrefPubMedGoogle Scholar
  • 28 Siegbahn A. et al Differential effects of the various isoforms of platelet-derived growth factor on chemotaxis of fibroblasts, monocytes, and granulocytes. J Clin Invest 1990; 85: 916-20.
    CrossrefPubMedGoogle Scholar
  • 29 Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Phys Rev 1999; 79: 1283-316.
    PubMedGoogle Scholar
  • 30 Petersen LC. et al Exclusion of known protease-activated receptors in factor VIIa-induced signal transduction. Thromb Haemost 2000; 83: 571-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Riewald M, Ruf W. Mechanistic coupling of protease signaling and initiation of coagulation by tissue factor. Proc Natl Acad Sci U S A 2001; 98: 7742-7.
    CrossrefPubMedGoogle Scholar
  • 32 Ahamed J, Ruf W. Protease-activated receptor 2-dependent phosphorylation of the tissue factor cytoplasmic domain. J Biol Chem 2004; 279: 23038-44.
    CrossrefPubMedGoogle Scholar
  • 33 Malarstig A, Tenno T, Jossan S. et al A quantitative real-time PCR method for tissue factor mRNA. Thromb Res 2003; 112: 175-83.
    CrossrefPubMedGoogle Scholar
  • 34 Zioncheck TF, Roy S, Vehar GA. The cytoplasmic domain of tissue factor is phosphorylated by a protein kinase C-dependent mechanism. J Biol Chem 1992; 267: 3561-4.
    PubMedGoogle Scholar
  • 35 Dorfleutner A, Ruf W. Regulation of tissue factor cytoplasmic domain phosphorylation by palmitoylation. Blood 2003; 102: 3998-4005.
    CrossrefPubMedGoogle Scholar
  • 36 Melis E, Moons L, De Mol M. et al Targeted deletion of the cytosolic domain of tissue factor in mice does not affect development. Biochem Biophys Res Commun 2001; 286: 580-6.
    CrossrefPubMedGoogle Scholar
  • 37 Sharma L. et al The cytoplasmic domain of tissue factor contributes to leukocyte recruitment and death in endotoxemia. Am J Pathol 2004; 165: 331-40.
    CrossrefPubMedGoogle Scholar
  • 38 Camerer E, Gjernes E, Wiiger M. et al Binding of factor VIIa to tissue factor on keratinocytes induces gene expression. J Biol Chem 2000; 275: 6580-5.
    CrossrefPubMedGoogle Scholar
  • 39 Belting M, Dorrell MI, Sandgren S. et al Regulation of angiogenesis by tissue factor cytoplasmic domain signaling. Nat Med 2004; 10: 502-9.
    CrossrefPubMedGoogle Scholar
  • 40 Kamath L. et al Signaling from protease-activated receptor-1 inhibits migration and invasion of breast cancer cells. Cancer Res 2001; 61: 5933-40.
    PubMedGoogle Scholar
  • 41 Jiang X, Bailly MA, Panetti TS. et al Formation of tissue factor-factor VIIa-factor Xa complex promotes cellular signaling and migration of human breast cancer cells. J Thromb Haemost 2004; 2: 93-101.
    CrossrefPubMedGoogle Scholar
  • 42 Ott I. et al A role for tissue factor in cell adhesion and migration mediated by interaction with actin-binding protein 280. J Cell Biol 1998; 140: 1241-53.
    CrossrefPubMedGoogle Scholar
  • 43 Cunningham CC, Gorlin JB, Kwiatkowski DJ. et al Actin-binding protein requirement for cortical stability and efficient locomotion. Science 1992; 255: 325-7.
    CrossrefPubMedGoogle Scholar
  • 44 Stossel TP, Condeelis J, Cooley L. et al Filamins as integrators of cell mechanics and signalling. Nat Rev Molecular Cell Biol 2001; 2: 138-45.
    PubMedGoogle Scholar
  • 45 Ilic D, Furuta Y, Kanazawa S. et al Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 1995; 377: 539-44.
    CrossrefPubMedGoogle Scholar
  • 46 Goldmann WH. p56(lck) controls phosphorylation of filamin (ABP-280) and regulates focal adhesion kinase (pp125(FAK)). Cell Biol Int 2002; 26: 567-71.
    CrossrefPubMedGoogle Scholar
  • 47 Lauffenburger DA, Horwitz AF. Cell migration: a physically integrated molecular process. Cell 1996; 84: 359-69.
    CrossrefPubMedGoogle Scholar
  • 48 Manske M, Bade EG. Growth factor-induced cellmigration – biology and methods of analysis. Int Rev Cytol 1994; 155: 49-96.
    PubMedGoogle Scholar
  • 49 Marutsuka K, Hatakeyama K, Sato Y. et al Protease- activated receptor 2 (PAR2) mediates vascular smooth muscle cell migration induced by tissue factor/ factor VIIa complex. Thromb Res 2002; 107: 271-6.
    CrossrefPubMedGoogle Scholar
  • 50 Hjortoe GM. et al Tissue factor-factor VIIa specific up-regulation of IL-8 expression in MDAMB- 231 cells is mediated via PAR-2 and results in increased cell migration. Blood 2004; 103: 3029-3.
    CrossrefPubMedGoogle Scholar