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Role of β3-endonexin in the regulation of NF-κB-dependent expression of urokinase-type plasminogen activator receptor

Endothelial migration on extracellular matrix is regulated by integrins and proteolysis. Previous studies showed that β3-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 proteinβ 3-endonexin decreased uPAR promoter (-398 base-pair fragment) activity that is constitutively active in endothelial cells. Mutation of the NF-κB promoter binding site (-45 bp) impaired the ability ofβ 3-endonexin to downregulate uPAR promoter activity. Immunoprecipitation studies showed that β3-endonexin interacts directly with the p50/p65 transactivation complex and thereby inhibits binding of κB oligonucleotides to the p50/p65 complex. Moreover, binding ofβ 3-endonexin to p50 was inhibited in the presence of κB but not mutated κB oligonucleotides, suggesting a sterical competition between β3-endonexin and κB DNA for the p50/p65 complex. We therefore propose that β3-endonexin acts as regulator of uPAR expression in β3-integrin-mediated endothelial cell migration through direct interaction with p50/p65. Since NF-κB regulates the expression of matrix degrading enzymes, the present results define a role of β3-endonexin in regulatingβ 3-integrin-mediated adhesion and pericellular proteolysis.