Urokinase/urokinase receptor and vitronectin/αvβ3 integrin induce chemotaxis and cytoskeleton reorganization through different signaling pathways

Degryse, Bernard; Orlando, Simone; Resnati, Massimo; Rabbani, Shafaat A.; Blasi, Francesco

doi:10.1038/sj.onc.1204261

Cited by 94 publications

(81 citation statements)

References 59 publications

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“…The most commonly identified effect is one of "deadhesion", where cells can be released from one matrix footprint (often fibronectin) in order to move forward and attach to another matrix protein such as VN (24). PAI-1 and the locally concentrated active enzyme urokinase are regulators that promote cell detachment and migration by disrupting these VN-uPAR and VN-integrin interactions (70,71,79). In the obstructive uropathy model, uPAR deletion was associated with significantly fewer numbers of interstitial macrophages, perhaps due to the disruption of this pathway (30).…”

Section: Upar Lateral Interactions With Co-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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Section: Upar Lateral Interactions With Co-receptorsmentioning

confidence: 99%

Urokinase and its receptors in chronic kidney disease

Zhang

Eddy

2008

Front Biosci

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“…Independent of proteolysis, u-PA enhances cell invasion through activation of several migration-associated signalling molecules such as extracellular signal-regulated kinases (Nguyen et al, 1998), focal adhesion kinases (Tang et al, 1998) and signal transducers and activators of transcription 1 (STAT1) (Dumler et al, 1998). Such intercellular signal transduction is apparently facilitated by the interaction of u-PAR with integrins (Wei et al, 1996;Degryse et al, 2001) and cytoskeletal components (Xue et al, 1997). In addition, u-PA/u-PAR mediates cellular adhesion to the ECM protein, vitronectin directly through integrin-independent, highaffinity interaction between u-PAR and vitronectin, and indirectly through function modifying lateral associations with integrin family members (Xue et al, 1997;Degryse et al, 2001).…”

mentioning

confidence: 99%

“…Such intercellular signal transduction is apparently facilitated by the interaction of u-PAR with integrins (Wei et al, 1996;Degryse et al, 2001) and cytoskeletal components (Xue et al, 1997). In addition, u-PA/u-PAR mediates cellular adhesion to the ECM protein, vitronectin directly through integrin-independent, highaffinity interaction between u-PAR and vitronectin, and indirectly through function modifying lateral associations with integrin family members (Xue et al, 1997;Degryse et al, 2001).…”

mentioning

confidence: 99%

Bacterial endotoxin enhances colorectal cancer cell adhesion and invasion through TLR-4 and NF-κB-dependent activation of the urokinase plasminogen activator system

et al. 2009

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Perioperative exposure to lipopolysaccharide (LPS) is associated with accelerated metastatic colorectal tumour growth. LPS directly affects cells through Toll-like receptor 4 (TLR-4) and the transcription factor NF-kB. The urokinase plasminogen activator (u-PA) system is intimately implicated in tumour cell extracellular matrix (ECM) interactions fundamental to tumour progression. Thus we sought to determine if LPS directly induces accelerated tumour cell ECM adhesion and invasion through activation of the u-PA system and to elucidate the cellular pathways involved. Human colorectal tumour cell lines were stimulated with LPS. u-PA concentration, u-PA activity, active u-PA, surface urokinase plasminogen activator receptor (u-PAR) and TLR-4 expression were assessed by ELISA, colorimetric assay, western blot analysis and flow cytometry respectively. In vitro tumour cell vitronectin adhesion and ECM invasion were analysed by vitronectin adhesion assay and ECM invasion chambers. u-PA and u-PAR function was inhibited with anti u-PA antibodies or the selective u-PA inhibitors amiloride or WXC-340, TLR-4 by TLR-4-blocking antibodies and NF-kB by the selective NF-kB inhibitor SN-50. LPS upregulates u-PA and u-PAR in a dose-dependent manner, enhancing in vitro tumour cell vitronectin adhesion and ECM invasion by 440% (Po0.01). These effects were ameliorated by u-PA and u-PAR inhibition. LPS activates NF-kB through TLR-4. TLR-4 and NF-kB inhibition ameliorated LPS-enhanced u-PA and u-PAR expression, tumour cell vitronectin adhesion and ECM invasion. LPS promotes tumour cell ECM adhesion and invasion through activation of the u-PA system in a TLR-4-and NF-kB-dependent manner.

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“…17 Second, uPAR, the closest known homologue to C4.4A, induces cell migration either via G protein-coupled receptors 49 or via integrin binding. 50,51 However, C4.4A does not share integrin binding with uPAR. In several carcinoma lines amply expressing a wide range of integrins, integrin precipitates did not contain C4.4A and vice versa.…”

Section: C44a-ln Binding and Cell Migrationmentioning

confidence: 99%

Ly6 family member C4.4A binds laminins 1 and 5, associates with galectin‐3 and supports cell migration

Paret

Bourouba

et al. 2005

Intl Journal of Cancer

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C4.4A is a member of the Ly6 family, with low homology to uPAR. It has been detected mainly on metastasizing carcinoma cells and proposed to be involved in wound healing. So far, C4.4A has been observed as an orphan receptor, and its functional activity has not been explored. Using recombinant rat C4.4A (rrC4.4A) made in a eukaryotic expression system, we demonstrate by immunohistology that C4.4A ligands are strongly expressed in tissues adjacent to squamous epithelia of, e.g., tongue and esophagus, the expression pattern partly overlapping with laminin (LN) and complementing the C4.4A expression that is found predominantly on the basal layers of squamous epithelium. ELISA screening of several components of the extracellular matrix revealed selective binding of rrC4.4A to LN1 and LN5 and that transfection of the BSp73AS tumor line with C4.4A cDNA (BSp73AS-1B1) promoted LN1 and LN5 binding. Binding of BSp73AS-1B1 to LN5 and, less markedly, LN1 induced spreading, lamellipodia formation and migration. C4.4A also associates with galectin-3 in nontransformed tissues and tumor lines. There is evidence that the association of C4.4A with galectin-3 influences LN adhesion. C4.4A was described originally as a metastasis-associated molecule. Our findings that LN1 and LN5 are C4.4A ligands, that galectin-3 associates with C4.4A and that C4.4A ligand binding confers a migratory phenotype are well in line with the supposed metastasis association. ' 2005 Wiley-Liss, Inc.Key words: C4.4A; laminin; galectin; cell migration LNs are adhesive glycoproteins found in the basement membrane. Fifteen LN isoforms have been identified. 1 LN isoforms are tissue-specific and expressed in a developmentally regulated pattern. 2,3 Cell adhesion to LN plays an important role in maintaining normal tissue organization. LNs promote cell adhesion and migration, 4 are involved in the control of cell proliferation and gene expression 5 and stimulate neurite outgrowth, 6 the multitude of functions being brought about by a large array of receptors. 7 The most prominent LN receptors are integrins, but distinct receptors have also been described, e.g., a-dystroglycan, syndecans, the 67 kDa LN receptor and galectins. 7,8 a-Dystroglycan provides a link between the basement membrane and the dystrophin-actin cytoskeleton. 9 Its binding to LN is Ca 2þ -dependent 10 and requires carbohydrate moieties. 11 Binding of syndecans 2 and 4 to LN5 induces expression of MMP-1. 12 Moreover, syndecan 1 interacts with unprocessed LN5 in migrating keratinocytes, and this interaction depends on the presence of the glycosaminoglycan chain. 13 Galectins belong to the family of galactose-specific lectins and bind the lactosamine-type sugars on LN1. 8 However, at high concentrations, galectins 3 and 1 can downregulate adhesion to LN, probably by blocking the cellular attachment sites. 14,15 The 67 kDa LN receptor can act in concert with a6b4 to promote cell adhesion to LN1. 16 It is also involved in the degradation of LN1 and the release of motility fragments. 17 The GPI-ancho...

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Urokinase/urokinase receptor and vitronectin/αvβ3 integrin induce chemotaxis and cytoskeleton reorganization through different signaling pathways

Cited by 94 publications

References 59 publications

Urokinase and its receptors in chronic kidney disease

Urokinase and its receptors in chronic kidney disease

Bacterial endotoxin enhances colorectal cancer cell adhesion and invasion through TLR-4 and NF-κB-dependent activation of the urokinase plasminogen activator system

Ly6 family member C4.4A binds laminins 1 and 5, associates with galectin‐3 and supports cell migration

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