Activation of urokinase receptor by a novel interaction between the connecting peptide region of urokinase and αvβ5 integrin

Franco, Paola; Vocca, Immacolata; Carriero, Maria Vincenza; Alfano, Daniela; Cito, Letizia; Longanesi-Cattani, Immacolata; Grieco, Paolo; Ossowski, Liliana; Stoppelli, Maria Patrizia

doi:10.1242/jcs.03067

Cited by 59 publications

(65 citation statements)

References 43 publications

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“…It is also possible that different uPA domains might simultaneously bind to uPAR and one of its co-receptors. 35 Based on this information, a role for uPAR with uPA signaling, however, cannot be excluded. The elevated levels of uPAR in small airway epithelia and alveolar wall cells were also observed in COPD patients with a significant emphysema in our previous study.…”

Section: Discussionmentioning

confidence: 99%

Involvement of urokinase in cigarette smoke extract-induced epithelial–mesenchymal transition in human small airway epithelial cells

Wang

Zhang

et al. 2015

Laboratory Investigation

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Urokinase-type plasminogen activator (uPA) augments inflammation and tissue remodeling during lung injury and repair. The uPA expression in small airway epithelium of chronic obstructive pulmonary disease (COPD) increases. Epithelialmesenchymal transition (EMT) is important in the small airway fibrosis of COPD. This study shows the uPA regulation in cigarette smoke extract (CSE)-induced EMT in human small airway epithelial cell lines (HSAEpiCs). uPA is overexpressed in the small airway epithelium of COPD patients and CSE-treated cell lines. Furthermore, uPA expression correlated with vimentin expression in the small airway epithelium of COPD patients. uPA inhibition blocks CSE-induced EMT by reversing E-cadherin and a-catenin expression and retarding the induction of N-cadherin and vimentin, resulting in reduction in migration. uPA overexpression in HSAEpiC cells also promotes EMT and migration. EMT is partly reversed in uPA-overexpressing HSAEpiC cells through the silencing expression of uPA receptor. In conclusion, this study provides new insights into the contribution of uPA upregulation to EMT associated with small airway remodeling in COPD.

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Section: Discussionmentioning

confidence: 99%

Involvement of urokinase in cigarette smoke extract-induced epithelial–mesenchymal transition in human small airway epithelial cells

Wang

Zhang

et al. 2015

Laboratory Investigation

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“…Cell migration assays were performed in modified Boyden chambers for 4 h or in Dunn chambers for 6 h as previously described [12,17].…”

Section: Motility Assaysmentioning

confidence: 99%

An urokinase receptor antagonist that inhibits cell migration by blocking the formyl peptide receptor

et al. 2008

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Urokinase receptor (uPAR) plays a key role in physiological and pathological processes sustained by an altered cell migration. We have developed peptides carrying amino acid substitutions along the Ser 88 -Arg-Ser-Arg-Tyr 92 (SRSRY) uPAR chemotactic sequence. The peptide pyro glutamic acid (pGlu)-Arg-Glu-Arg-Tyr-NH2 (pERERY-NH 2 ) shares the same binding site with SRSRY and competes with N-formyl-Met-LeuPhe (fMLF) for binding to the G-protein-coupled N-formylpeptide receptor (FPR). pERERY-NH 2 is a dose-dependent inhibitor of both SRSRY-and fMLF-directed cell migration, and prevents agonist-induced FPR internalization and fMLFdependent ERK1/2 phosphorylation. pERERY-NH 2 is a new and potent uPAR inhibitor which may suggest the generation of new pharmacological treatments for pathological conditions involving increased cell migration.

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“…Among these candidate receptors, several are already known as uPAR co-receptors: LRP, gp130, integrins, Endo180, and the IGF-II/M6P receptor. This suggests that different uPA sites might simultaneously bind to uPAR and one of its co-receptors (149). In other words, urokinase may serve as a bridge to cluster and coordinate the functions of uPAR and coreceptors.…”

Section: Other Upa Receptorsmentioning

confidence: 99%

Urokinase and its receptors in chronic kidney disease

Zhang

Eddy

2008

Front Biosci

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Since the recognition that plasminogen activator inhibitor-1 (PAI-1) is a powerful profibrotic molecule, there has been considerable interest in deciphering the extent to which this effect is mediated by its ability to inhibit serine proteases with downstream effects on fibrogenesis. This review will summarize current knowledge about the serine protease urokinase-type plasminogen activator and its high affinity receptor uPAR/CD87 as it pertains to chronic kidney disease (CKD) progression. An emerging theme is that the effects of PAI-1 and uPAR appear to be organ-and site-specific. Normal kidney tubules produce a large quantity of uPA that is secreted into the urinary space. Activity levels increase during CKD presumably due to new sources of production by macrophages and fibroblasts. By activating hepatocyte growth factor and degrading fibrinogen uPA may have anti-fibrotic effects. However CKD severity after experimental ureteral obstruction is not altered by endogenous uPA deficiency. Beneficial effects of exogenous uPA have been reported in experimental models of fibrosis in the lung and liver but CKD awaits exploration.Absent in normal kidneys uPAR is expressed by both renal parenchymal cells and inflammatory cells in a variety of pathological states. Such expression appears beneficial based on studies performed in uPAR-deficient mice. The uPAR promotes bacterial clearance in infectious diseases. In CKD uPAR expression is associated with high uPA activity but its most important effect appears to be due to scavenging activities and effects on cell recruitment and migration. Although uPAR itself is a non-signaling receptor, it interacts with a variety of co-receptors to modify cellular behavior. Best known are interactions with the low-density lipoprotein receptor-related protein (LRP-1) that lead to PAI-1 endocytosis and degradation, and interactions with several integrins to regulate matrix-dependent cell migration. Contacts with the receptor for the complement C5a component and the interleukin −6 receptor gp130 are examples of other recently recognized interactions.In addition to uPA, vitronectin and high molecular weight kininogen are alternate uPAR ligands that could be implicated in CKD progression. uPAR may also be shed from cell membranes. This soluble form (suPAR) has been detected in plasma and urine and is known to be a chemoattractant for leukocytes that express the formyl-peptide-receptor-like receptor

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Activation of urokinase receptor by a novel interaction between the connecting peptide region of urokinase and αvβ5 integrin

Cited by 59 publications

References 43 publications

Involvement of urokinase in cigarette smoke extract-induced epithelial–mesenchymal transition in human small airway epithelial cells

Involvement of urokinase in cigarette smoke extract-induced epithelial–mesenchymal transition in human small airway epithelial cells

An urokinase receptor antagonist that inhibits cell migration by blocking the formyl peptide receptor

Urokinase and its receptors in chronic kidney disease

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