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

被引:16
作者
Besta, F
Massberg, S
Brand, K
Müller, E
Page, S
Grüner, S
Lorenz, M
Sadoul, K
Kolanus, W
Lengyel, E
Gawaz, M
机构
[1] Klinikum Rechts Der Isar, Med Klin 1, D-80636 Munich, Germany
[2] Deutsch Herzzentrum Munich, D-80636 Munich, Germany
[3] Tech Univ Munich, Inst Klin Chem & Pathobiochem, D-81675 Munich, Germany
[4] Univ Grenoble 1, Inst Albert Bonniot, Fac Med, F-38706 La Tronche, France
[5] Univ Munich, Mol Biol Lab, Genzentrum, D-81377 Munich, Germany
[6] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco Comprehens Canc Ctr, San Francisco, CA 94143 USA
关键词
beta-endonexin; beta(3)-integrins; NF-kappa B; uPAR; angiogenesis;
D O I
10.1242/jcs.00081
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Endothelial migration on extracellular matrix is regulated by integrins and proteolysis. Previous studies showed that beta(3)-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 beta(3)-endonexin decreased uPAR promoter (-398 base-pair fragment) activity that is constitutively active in endothelial cells. Mutation of the NF-kappaB promoter binding site (-45 bp) impaired the ability of beta(3)-endonexin to downregulate uPAR promoter activity. Immunoprecipitation studies showed that beta(3)-endonexin interacts directly with the p50/p65 transactivation complex and thereby inhibits binding of kappaB oligonucleotides to the p50/p65 complex. Moreover, binding of beta(3)-endonexin to p50 was inhibited in the presence of kappaB but not mutated kappaB oligonucleotides, suggesting a sterical competition between beta(3)-endonexin and kappaB DNA for the p50/p65 complex. We therefore propose that beta(3)-endonexin acts as regulator of uPAR expression in beta(3)-integrin-mediated endothelial cell migration through direct interaction with p50/p65. Since NF-kappaB regulates the expression of matrix degrading enzymes, the present results define a role of beta(3)-endonexin in regulating beta(3)-integrin-mediated adhesion and pericellular proteolysis.
引用
收藏
页码:3879 / 3888
页数:10
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