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Binding of factor VIIa to tissue factor on human fibroblasts leads to activation of phospholipase C and enhanced PDGF-BB-stimulated chemotaxis

Siegbahn, Agneta; Johnell, Matilda; Rorsman, Charlotte; Ezban, Mirella; Heldin, Carl-Henrik and Rönnstrand, Lars LU (2000) In Blood 96(10). p.3452-3458
Abstract
Tissue factor (TF) is the cellular receptor for factor FVIIa (FVIIa), and the complex is the principal initiator of blood coagulation. The effects of FVIIa binding to TF on cell migration and signal transduction of human fibroblasts, which express high amounts of TF, were studied. Fibroblasts incubated with FVIIa migrated toward a concentration gradient of PDGF-BB at approximately 100 times lower concentration than do fibroblasts not ligated with FVIIa. Anti-TF antibodies inhibited the increase in chemotaxis induced by FVIIa/TF. Moreover, a pronounced suppression of chemotaxis induced by PDGF-BB was observed with active site-inhibited FVIIa (FFR-FVIIa). The possibility that hyperchemotaxis was induced by a putative generation of FXa and... (More)
Tissue factor (TF) is the cellular receptor for factor FVIIa (FVIIa), and the complex is the principal initiator of blood coagulation. The effects of FVIIa binding to TF on cell migration and signal transduction of human fibroblasts, which express high amounts of TF, were studied. Fibroblasts incubated with FVIIa migrated toward a concentration gradient of PDGF-BB at approximately 100 times lower concentration than do fibroblasts not ligated with FVIIa. Anti-TF antibodies inhibited the increase in chemotaxis induced by FVIIa/TF. Moreover, a pronounced suppression of chemotaxis induced by PDGF-BB was observed with active site-inhibited FVIIa (FFR-FVIIa). The possibility that hyperchemotaxis was induced by a putative generation of FXa and thrombin activity was excluded. FVIIa/TF did not induce increased levels of PDGF beta-receptors on the cell surface. Thus, the hyperchemotaxis was not a result of this mechanism. FVIIa induced the production of inositol-1,4, 5-trisphosphate to the same extent as PDGF-BB; the effects of FVIIa and PDGF-BB were additive. FFR-FVIIa did not induce any release of inositol-1,4,5,-trisphosphate. Thus, binding of catalytically active FVIIa to TF can, independent of coagulation, modulate cellular responses, such as chemotaxis. (Less)
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@article{f4512c26-c7d6-481c-98cb-ef44f8144929,
  abstract     = {Tissue factor (TF) is the cellular receptor for factor FVIIa (FVIIa), and the complex is the principal initiator of blood coagulation. The effects of FVIIa binding to TF on cell migration and signal transduction of human fibroblasts, which express high amounts of TF, were studied. Fibroblasts incubated with FVIIa migrated toward a concentration gradient of PDGF-BB at approximately 100 times lower concentration than do fibroblasts not ligated with FVIIa. Anti-TF antibodies inhibited the increase in chemotaxis induced by FVIIa/TF. Moreover, a pronounced suppression of chemotaxis induced by PDGF-BB was observed with active site-inhibited FVIIa (FFR-FVIIa). The possibility that hyperchemotaxis was induced by a putative generation of FXa and thrombin activity was excluded. FVIIa/TF did not induce increased levels of PDGF beta-receptors on the cell surface. Thus, the hyperchemotaxis was not a result of this mechanism. FVIIa induced the production of inositol-1,4, 5-trisphosphate to the same extent as PDGF-BB; the effects of FVIIa and PDGF-BB were additive. FFR-FVIIa did not induce any release of inositol-1,4,5,-trisphosphate. Thus, binding of catalytically active FVIIa to TF can, independent of coagulation, modulate cellular responses, such as chemotaxis.},
  author       = {Siegbahn, Agneta and Johnell, Matilda and Rorsman, Charlotte and Ezban, Mirella and Heldin, Carl-Henrik and Rönnstrand, Lars},
  issn         = {1528-0020},
  keyword      = {Cultured
Chemotaxis/*drug effects
Dose-Response Relationship,Drug
Endothelium,Vascular/drug effects
Enzyme Activation
Factor VIIa/*metabolism/pharmacology
Factor Xa/pharmacology
Fibroblasts/chemistry/*metabolism
Humans
Isoenzymes/drug effects/metabolism
Muscle,Amino Acid Chloromethyl Ketones/pharmacology
Binding Sites
Cells,Smooth,Vascular/cytology
Phospholipase C gamma
Phosphorylation/drug effects
Platelet-Derived Growth Factor/*pharmacology
Protein Binding
Serine Proteinase Inhibitors/pharmacology
Signal Transduction
Thrombin/pharmacology
Thromboplastin/*metabolism
Type C Phospholipases/drug effects/*metabolism},
  language     = {eng},
  number       = {10},
  pages        = {3452--3458},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Binding of factor VIIa to tissue factor on human fibroblasts leads to activation of phospholipase C and enhanced PDGF-BB-stimulated chemotaxis},
  volume       = {96},
  year         = {2000},
}