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TF/FVIIa transactivate PDGFRbeta to regulate PDGF-BB-induced chemotaxis in different cell types: involvement of Src and PLC
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
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2008 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 28, no 1, 135-41 p.Article in journal (Refereed) Published
Abstract [en]

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 PDGFRbeta by TF/FVIIa involving phosphorylation of a subset of PDGFRbeta 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.

Place, publisher, year, edition, pages
2008. Vol. 28, no 1, 135-41 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97675DOI: 10.1161/ATVBAHA.107.155754ISI: 000252159500020PubMedID: 17991872OAI: oai:DiVA.org:uu-97675DiVA: diva2:172706
Available from: 2008-10-30 Created: 2008-10-30 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Tissue Factor Biological Functions: Coagulation Activity in Microparticles and Signaling with Focus On Migration and Apoptosis
Open this publication in new window or tab >>Tissue Factor Biological Functions: Coagulation Activity in Microparticles and Signaling with Focus On Migration and Apoptosis
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Tissue factor (TF) is a 47 kDa transmembrane glycoprotein known as the main initiator of blood coagulation. TF is over-expressed on many malignant cells and apart from increasing the risk of thrombosis, the presence of TF/FVIIa also promotes the progression of cancer and metastasis by intracellular signaling. TF expressing microparticles (MP) are, moreover, often found in the circulation of cancer patients.

Aim: The aim of this thesis was to study different aspects of TF activity, e.g. the importance of procoagulant MP and TF-induced intracellular signaling pathways, with focus on cell migration (chemotaxis) and apoptosis.

Results: The TF signaling complexes were shown to prevent apoptosis induced by serum starvation and TRAIL in cancer cells by reduced activation of caspase-8 in a PI3k/AKT-dependent manner. FVIIa also decreased transcription of pro-apoptotic genes in cancer cells treated with TRAIL. Simvastatin triggered apoptosis by transcriptional reduction of BCL-2 due to cytosolic retention of NFκB. Simvastatin also inactivated the PI3k/AKT pathway and reduced the production of the MP-like prostasomes which, respectively, impaired the anti-apoptotic signaling by TF and reduced the procoagulant activity in the vicinity of prostate cancer cells. Intracellular events conducted by the TF/FVIIa complex selectively enhanced PDGF-BB induced chemotaxis which was partly explained by the TF/FVIIa-induced transactivation of the PDGFβ-receptor. This was dependent on Src-family members and engagement of PAR2.

Conclusions: The results presented in this thesis extend the current knowledge of TF-mediated signaling. We report the TF complexes to govern the extrinsic pathway of apoptosis, present data on FVIIa-dependent regulation of apoptosis-related genes, and exclude known surface proteins as transmitters of the anti-apoptotic signals. We moreover describe TF/FVIIa to transactivate the PDGFβ-receptor and play a decisive role in the potentiated chemotaxis toward PDGF-BB in a number of cell types. Finally, we explain the mechanism behind simvastatin-induced apoptosis in cancer cells and how statins interfere with TF-dependent signaling and coagulation.

Place, publisher, year, edition, pages
Uppsala: Universitetsbiblioteket, 2008. 71 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 391
Keyword
Tissue factor, Apoptosis, Migration, Chemotaxis, Simvastatin, Platelet Derived Growth Factor, Cell Signaling, Microparticles, Prostasomes, Trombosis, Coagulation, Prostate Cancer, Breast Cancer, Caspase-3, Caspase-8, NFkappaB, PAR2, Transactivation, Monocytes
National Category
Other Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-9335 (URN)978-91-554-7317-4 (ISBN)
Public defence
2008-11-21, Enghoffsalen, Akademiska sjukhuset, Ingång 50, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-10-30 Created: 2008-10-30Bibliographically approved

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