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doi: 10.1242/10.1242/jcs.00081

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Role of ß₃-endonexin in the regulation of NF-B-dependent expression of urokinase-type plasminogen activator receptor

¹ 1. Medizinische Klinik, Klinikum rechts der Isar und Deutsches Herzzentrum, Lazarettstraße 36, 80636 München, Germany
² Institut für Klinische Chemie und Pathobiochemie, Technische Universität München, Ismaningerstraße 22, 81675 München, Germany
³ Institut Albert Bonniot, Joseph Fourier University of Grenoble, Faculty of Medicine, Domaine de la Merci, 38706 La Tronche Cedex, France
⁴ Laboratorium für Molekulare Biologie, Genzentrum der Universität München, Feodor Lynen Strasse 25, 81377 München, Germany
⁵ Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco Comprehensive Cancer Center, San Francisco, CA 94143-0875, USA

^* Author for correspondence (e-mail: gawaz{at}dhm.mhn.de)

Accepted 1 August 2002

Endothelial migration on extracellular matrix is regulated by integrins and proteolysis. Previous studies showed that ß₃-integrins regulate expression of the urokinase-type plasminogen activator receptor (uPAR) through outside-in signalling involving the cytoplasmic domain. Here we show that overexpression of the integrin-binding protein ß₃-endonexin decreased uPAR promoter (-398 base-pair fragment) activity that is constitutively active in endothelial cells. Mutation of the NF-B promoter binding site (-45 bp) impaired the ability of ß₃-endonexin to downregulate uPAR promoter activity. Immunoprecipitation studies showed that ß₃-endonexin interacts directly with the p50/p65 transactivation complex and thereby inhibits binding of B oligonucleotides to the p50/p65 complex. Moreover, binding of ß₃-endonexin to p50 was inhibited in the presence of B but not mutated B oligonucleotides, suggesting a sterical competition between ß₃-endonexin and B DNA for the p50/p65 complex. We therefore propose that ß₃-endonexin acts as regulator of uPAR expression in ß₃-integrin-mediated endothelial cell migration through direct interaction with p50/p65. Since NF-B regulates the expression of matrix degrading enzymes, the present results define a role of ß₃-endonexin in regulating ß₃-integrin-mediated adhesion and pericellular proteolysis.

Key words: ß₃-endonexin, ß₃-integrins, NF-B, uPAR, Angiogenesis

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NF-B: a novel target for ß₃-endonexin

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