on November 8, 2007
Published online before print November 8, 2007, doi: 10.1161/ATVBAHA.107.155754
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Submitted on July 2, 2007
Accepted on October 28, 2007
TF/FVIIa Transactivate PDGFR
to Regulate PDGF-BB–Induced Chemotaxis in Different Cell Types. Involvement of Src And PLC
Agneta Siegbahn *;
From the Department of Medical Sciences, Clinical Chemistry, Uppsala University, Sweden.
* To whom correspondence should be addressed. E-mail: agneta.siegbahn{at}medsci.uu.se or teet.velling{at}medsci.uu.se.
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 PDGFR
by TF/FVIIa involving phosphorylation of a subset of PDGFR 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.
Key words: TF/FVIIa • PDGFR
•
transactivation •
cell signaling •
chemotaxis
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