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First published online September 22, 2005
doi: 10.1242/10.1242/jcs.02587

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TGF-ß-induced apoptosis in endothelial cells mediated by M6P/IGFII-R and mini-plasminogen

Vladimír Leksa^1,2,*,, Samuel Godar^3,*, Herbert B. Schiller¹, Elke Fuertbauer³, Arshad Muhammad³, Katarina Slezakova², Vaclav Horejsi⁴, Peter Steinlein⁵, Ulrich H. Weidle⁶, Bernd R. Binder⁷ and Hannes Stockinger^1,3

¹ BMT, BioMolecular Therapeutics, Brunner Strasse 59, 1235 Vienna, Austria
² Institute of Molecular Biology, Slovak Academy of Sciences, Bratislava, Vlarska 5 83334, Slovak Republic
³ Department of Molecular Immunology, Centre of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Lazarettgasse 19, A1090 Vienna, Austria
⁴ Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, Prague 6, CZ-16637, Czech Republic
⁵ Institute of Molecular Pathology, Dr. Bohr-Gasse 7, 1030 Vienna, Austria
⁶ Roche Applied Science, Nonnenwald 2, 82377 Penzberg, Germany
⁷ Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Lazarettgasse 19, A1090 Vienna, Austria

Author for correspondence (e-mail: vladimir.leksa{at}meduniwien.ac.at)

Transforming growth factor-ß (TGF-ß), a key modulator of endothelial cell apoptosis, must be activated from the latent form (LTGF-ß) to induce biological responses. In the present study, we report activation of TGF-ß by functional and physical co-operation of the mannose-6-phosphate/insulin-like-growth-factor-II receptor (CD222) and the urokinase-type plasminogen activator receptor (CD87). We show that endothelial cells express CD222 and CD87 in a membrane complex and demonstrate that the association of these two receptors is essential for the release of active TGF-ß in the transduced mouse fibroblast used as model cells. By contrast, smooth-muscle cells, which express CD222 and CD87 at similar density to endothelial cells but not in complexed form, do not activate TGF-ß. We also have found that mini-plasminogen is a high-affinity ligand for CD222 and is essential for the activation of TGF-ß by the CD87-CD222 complex to induce apoptosis in endothelial cells. This specific mechanism of TGF-ß-mediated apoptosis in endothelial cells is thus a potential novel target to be considered for treatment of pathological vascular disorders (e.g. tumor angiogenesis).

Key words: Angiogenesis, Apoptosis, Fibrinolysis, TGF-ß, Mini-plasminogen

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