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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:135.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

TF/FVIIa Transactivate PDGFRβ to Regulate PDGF-BB–Induced Chemotaxis in Different Cell Types

Involvement of Src And PLC

Agneta Siegbahn; Matilda Johnell; Anna Nordin; Mikael Åberg; Teet Velling

From the Department of Medical Sciences, Clinical Chemistry, Uppsala University, Sweden.

Correspondence to Agneta Siegbahn or Teet Velling, Department of Medical Sciences, Clinical Chemistry, Academic Hospital, SE-751 85 Uppsala, Sweden. E-mail agneta.siegbahn{at}medsci.uu.se or teet.velling@medsci.uu.se

Abstract

Background— We have previously reported the potentiation of PDGF-BB–induced chemotaxis of fibroblasts, vascular smooth muscle cells, and endothelial cells by FVIIa. Here we studied the role of TF/FVIIa and the induced signaling pathways in regulation of chemotaxis of human monocytes, fibroblasts, and porcine aorta endothelial cells.

Methods and Results— Human monocytes were obtained by using Ficoll-Paque gradient and the MACS system (for highly purified population), fibroblasts and PAE cells have been characterized previously. Inhibitors of selected signaling intermediates were used, and the effect of TF/FVIIa on the migratory response of all cells to chemotactic agents was analyzed. The induced signaling was studied by immunoprecipitation and Western blotting. TF/FVIIa complex selectively enhanced PDGF-BB–induced chemotaxis in a Src-family, PLC, and PAR-2–dependent manner. Using PAE cells we identified c-Src and c-Yes as the Src-family members activated by TF/FVIIa. We report for the first time the PAR-2 and Src family-dependent transactivation of PDGFRβ by TF/FVIIa involving phosphorylation of a subset of PDGFRβ tyrosines.

Conclusions— The described transactivation is a likely mechanism of TF/FVIIa-mediated regulation of PDGF-BB–induced chemotaxis. Similar behavior of 3 principally different cell types in our experimental setup may reflect a general function of TF in regulation of cell migration.

TF/FVIIa was found to selectively potentiate the PDGF-BB–induced chemotaxis of 3 principally different cell types. We provide data concerning the signaling pathways involved in this potentiation, and describe the TF/FVIIa-induced, PAR-2, c-Src, and c-Yes–dependent transactivation of PDGFRβ as a likely mechanism of its regulation.

Key Words: TF/FVIIa • PDGFRβ • transactivation • cell signaling • chemotaxis

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