Role of Specific Membrane Receptors in Urokinase-Dependent Migration of Human Keratinocytes

Rosso, Mario Del; Fibbi, Gabriella; Dini, Germana; Grappone, Cecilia; Pucci, Marco; Caldini, Riccardo; Magnelli, Lucia; Fimiani, Michele; Lotti, Torello; Panconesi, E

doi:10.1111/1523-1747.ep12874442

Cited by 68 publications

(28 citation statements)

References 28 publications

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“…25 possible that at low u-PA concentrations, only a few cohorts of u-PARs have the possibility of being stimulated as a result of receptor internalization and u-PA degradation. 27,41 At high u-PA concentrations, the subsequent occupancy of many cohorts of u-PARs, as a result of many cycles of receptor internalization and re-exposure, can stimulate a sustained production of second messengers (namely diacylglycerol 40 ), required to trigger mitosis, as previously reported for PDGF. 44 Studies in other cell systems have shown that u-PA localization on cell membranes enables u-PAR-bearing cells to activate plasmin, membrane-type MMP (MT-MMP), progelatinase A, and perhaps other MMPs 18,45-49 directly on the cell surface, thus providing the cells with a directional proteolytic machinery.…”

Section: Discussionmentioning

confidence: 69%

“…Similar results were obtained in u-PA-dependent mobilization of all the cell types challenged with u-PA under chemotactic conditions. 25,27,[40][41][42] We have previously suggested 41 that clustering of u-PAR at the leading edge of the cell membrane is required to sense the gradient, as in many other ligand-receptor systems. 43 In the presence of high u-PA concentrations, the gradient formation in the lower compartment of the chamber may be too fast, thus increasing the possibility of an overall stimulation of u-PARs that cannot undergo the clustering required to orient the leading edge of the cell in the direction of the gradient.…”

Section: Discussionmentioning

confidence: 99%

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Functions of the fibrinolytic system in human ito cells and its control by basic fibroblast and platelet-derived growth factor

et al. 1999

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Functions of the fibrinolytic system in human ito cells and its control by basic fibroblast and platelet-derived growth factor

et al. 1999

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“…Consideration of any functions for uPA/plasmin in cell migration must also take into account the presence of a specific, high affinity cell surface receptor for uPA which has been characterized on many cell types, including the keratinocyte (Blasi et al, 1987;Vaheri et al, 1990;Dane et al, 1990;Pollanen et al, 1991;Blasi, 1993;Conese and Blasi, 1995;McNeill and Jensen, 1990;Del Rosso et al, 1990;Reinartz et al, 1994;Kramer et al, 1995). The uPA receptor (uPA-R) appears to modulate cell migration in two ways.…”

mentioning

confidence: 99%

“…Many data indicate that the uPA-R, in combination with low aflinity plasminogen binding sites, localizes uPA and plasmin activities to the pericellular space, thereby spatially restricting the generation of proteolytic products (Vaheri et al, 1990;Pollanen et al, 1991). More recent information suggests that the uPA-R may also promote cell migration directly through intracellular signaling events that occur upon ligand-receptor engagement (Del Rosso et al, 1990, 1993Odekon et al, 1992).…”

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confidence: 99%

Protein kinase C mediates up-regulation of urokinase and its receptor in the migrating keratinocytes of wounded cultures, but urokinase is not required for movement across a substratum in vitro

Ando

Jensen

1996

J. Cell. Physiol.

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Both in cell culture and in vivo, keratinocytes that are migrating in response to a wound express enhanced levels of both urokinase-type plasminogen activator (uPA) and the uPA cell surface receptor (uPA-R). To explore the mechanism of this up-regulation, keratinocyte cultures were treated proir to wounding with a variety of metabolic and growth factor inhibitors in order to evaluate their effect on uPA and uPA-R expression. Actinomycin D and cycloheximide inhibited the up-regulation of both uPA and uPA-R, as determined by immunohistochemistry, indicating that RNA and protein syntheses are required for their induction in migrating keratinocytes. Neither removal of protein growth factors from the medium nor addition of inhibitory antibodies to a number of growth factors depressed uPA or uPA-R induction; these findings suggest that a variety of exogenous or endogenous growth factors [i.e., basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), amphiregulin, and tumor necrosis factor-alpha (TNF-alpha) do not have a critical role in the induction of uPA or uPA-R. In contrast, when protein kinase C (PKC) was either down-regulated with bryostatin 5 or inhibited with Ro31-8220 or staurosporine, the expression of both uPA and uPA-R was greatly decreased in migrating keratinocytes. Furthermore, pharmacologic activation of PKC enhanced uPA levels in non-wounded cultures. These data suggest that the enhanced expression of uPA and uPA-R in migrating keratinocytes is mediated by selective activation of PKC in these cells, perhaps secondary to alterations in the cytoskeleton induced by wounding. To test the requirement for uPA during keratinocyte migration in vitro, the extent of migration was quantified in the presence and absence of a variety of inhibitors in the wounded culture model. Migration was not altered by actinomycin D, cycloheximide, any of the above growth factor inhibitors, anti-uPA antibodies, a variety of inhibitors of uPA or plasmin enzymatic activity, or exogenous uPA. The independence of keratinocyte migration in vitro from uPA was further suggested by experiments which combined the phagokinetic assay of migration and the zymographic assay for pericellular uPA activity; no relationship was observed between pericellular uPA activity and the motility of individual cells.

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“…2], In addi tion. receptor bound u-PA may have a role in cell migration [5] and possibly also in cell adhesion [6], Plasminogen activator inhibitors (PAIs) belong to the serine proteinase inhibitor group, serpins [7], PAI-1 is a single-chain 46-54 kD glycoprotein [8. 9] which inhibits sin gle-and two-chain t-PA as well as two-chain u-PA [9.…”

Section: Introductionmentioning

confidence: 99%

Retinal Pigment Epithelial Cells Secrete Urokinase-Type Plasminogen Activator and Its Inhibitor PAI-1

Sirén

Stephens²,

Salonen³

et al. 1992

Ophthalmic Res

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Secretion of plasminogen activators and their inhibitors was examined in cultures of human retinal pigment epithelial (RPE) cells. The methods employed were zymography and reverse zymography, solid-phase immunocapture assay, metabolic labeling followed by immunoprecipitation, and immunofluorescence. The results showed that these cells produce urokinase-type plasminogen activator (u-PA) and a plasminogen activator inhibitor (PAI) which is immunologically and biochemically similar to PAI-1. Tissue-type plasminogen activator activity (t-PA) was not detected, but we detected small amounts of t-PA in an inactive complex with inhibitor in RPE cell-conditioned media. We conclude that RPE cells have the potential to utilize u-PA-catalyzed plasminogen activation which is subject to regulation by PAI-1. These results may have a bearing on the pathogenesis of proliferative retinal diseases.

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Role of Specific Membrane Receptors in Urokinase-Dependent Migration of Human Keratinocytes

Cited by 68 publications

References 28 publications

Functions of the fibrinolytic system in human ito cells and its control by basic fibroblast and platelet-derived growth factor

Functions of the fibrinolytic system in human ito cells and its control by basic fibroblast and platelet-derived growth factor

Protein kinase C mediates up-regulation of urokinase and its receptor in the migrating keratinocytes of wounded cultures, but urokinase is not required for movement across a substratum in vitro

Retinal Pigment Epithelial Cells Secrete Urokinase-Type Plasminogen Activator and Its Inhibitor PAI-1

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