The urokinase receptor. Protein structure and role in plasminogen activation and cancer invasion

Danø, Keld; Behrendt, Niels; Brünner, Nils; Ellis, Vincent; Ploug, Michael; Pyke, Charles

doi:10.1016/0268-9499(94)90717-x

Cited by 253 publications

(137 citation statements)

References 120 publications

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“…Studies on the mechanism responsible for accelerated plasminogen activation on the cell surface are of crucial importance for the understanding of extracellular proteolysis in the context of invasive processes [17]. As evident from the discussion above, important aspects of these studies will be the identification of additional components on the cell with which uPAR and the enzymes of the cascade interact, as well as specific steric features of the plasma membrane allowing the interplay of all of the components involved.…”

Section: Discussionmentioning

confidence: 99%

“…Due to the role of the uPA system in invasive processes the interference with plasminogen activation at the cell surface may have important therapeutic perspectives [17] and in this context, an accelerative effect caused directly by uPAR would be a central potential target. In order to study the functional role of uPAR at the molecular level, we have now investigated the influence of the purified receptor on the activation reactions which proceed in solution with different combinations of the pro-enzymes and active enzymes of the cascade.…”

Section: Introductionmentioning

confidence: 99%

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Effect of purified, soluble urokinase receptor on the plasminogen‐prourokinase activation system

Behrendt

Danø

1996

FEBS Letters

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of purified, soluble urokinase receptor on the plasminogen‐prourokinase activation system

Behrendt

Danø

1996

FEBS Letters

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“…Urokinase-type plasminogen activator (uPA) is often expressed at high levels in malignant brain tumors (Yamamoto et al, 1994), and its activity is enhanced at the invasive edge of these tumors (Pyke et al, 1991). A large body of evidence suggests that uPA plays a key role in tumor progression and invasion by virtue of its ability to activate plasminogen, which degrades many ECM components and activates latent collagenases (Dano et al, 1994). uPA is secreted as a soluble protein by tumor cells and binds to a specific cell-surface receptor, the uPA receptor (uPAR).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells

Chandrasekar

Mohanam

Gujrati³

et al. 2003

Oncogene

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The ability of glioma cells to migrate great distances from a primary tumor mass is the primary cause of tumor recurrence. The urokinase-type plasminogen activator (uPA) is a serine protease that can initiate proteolytic cascades, which result in remodeling of extracellular matrix and basement membrane, allowing cells to move across and through these barriers. The binding between uPA and its receptor uPAR also mediates several signaling events that seem to contribute to the evolution of a migratory phenotype. In this study, we determined how the downregulation of uPA affects the signaling pathways leading to cell migration. Stably transfecting human glioblastoma cells with antisense uPA decreased the amount of cell-bound uPA and disrupted actin cytoskeleton formation and cell migration. The phosphatidylinositol 3-kinase (PI3k) and Akt signaling pathway has been suggested to mediate migration in various cancer cells. The antisense-uPA clones also had less phosphorylated PI3k and Akt than control cells, a finding associated with decreased cell migration, G2/M-phase arrest, and decreased clonogenic survival. Decreased activation of PI3k and the antiapoptotic factor Akt was not sufficient to induce apoptosis in the antisense-uPA clones, but staurosporine sensitized them to apoptosis to a greater extent than control cells. These results indicate that PI3k/ Akt pathway is involved in the signaling cascade required to induce cell migration and that uPA has a direct role in regulating migration.

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“…In addition, uPA is involved also in non-proteolytic signalling events leading to adhesion and chemotaxis (Besser et al, 1996;Blasi, 1997). uPA is also a major component in tumour invasion and metastasis and its high levels in mammary tumours are predictive of poor prognosis (Danù et al, 1994;JaÈ nicke et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

In vivo analysis of the state of the human uPA enhancer following stimulation by TPA

et al. 1999

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We have analysed in vivo the 72.0 kb enhancer of the human urokinase-type plasminogen activator (uPA) gene in HepG2 cells, in which gene expression can be induced by phorbol esters. The results reveal that, within the regulatory region, the enhancer, the silencer and the minimal promoter become hypersensitive to deoxyribonuclease I (DNase I) upon induction of transcription. The hypersensitivity of the enhancer can be reversed after removal of the inducer. In vivo footprinting analysis indicates that all the cis-acting elements of the enhancer, previously identi®ed in vitro, are occupied in vivo upon 12-O-tetradecanoyl-phorbol-13-acetate (TPA) stimulation of HepG2 cells. Micrococcal nuclease (MNase) cleavage of this region fails to reveal discrete nucleosomal boundaries in vivo in close proximity of the enhancer, either before or after stimulation. Furthermore, this region does not lose its nucleosomal con®guration after TPA induction of transcription. An approximately 600 bp long region around the enhancer becomes more, but not fully, accessible to restriction endonucleases upon stimulation. A time-course experiment shows that this accessibility reaches a plateau after a 1 h TPA treatment suggesting the persistent presence of nucleosomes. These results indicate that TPA induces the binding of transcription factors to the uPA enhancer without chromatin remodelling of this region.

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The urokinase receptor. Protein structure and role in plasminogen activation and cancer invasion

Cited by 253 publications

References 120 publications

Effect of purified, soluble urokinase receptor on the plasminogen‐prourokinase activation system

Effect of purified, soluble urokinase receptor on the plasminogen‐prourokinase activation system

Downregulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells

In vivo analysis of the state of the human uPA enhancer following stimulation by TPA

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