Urokinase-Urokinase Receptor Interaction: Non-Mitogenic Signal Transduction in Human Epidermal Cells

Delrosso, M; Anichini, E; Pedersen, Nina Marie; Blasi, Francesco; Fibbi, Gabriella; Pucci, Marco; Ruggiero, Marco

doi:10.1006/bbrc.1993.1054

Cited by 74 publications

(46 citation statements)

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“…However, our data are not easily explained by events secondary to adhesion, for the reasons stated above; ( 3 ) the receptor appears to either directly or cooperatively transduce signals and influence cellular differentiation/ activation by yet to be elucidated mechanisms. Indeed, uPAR occupancy, per se, independent of catalytic activity stimulates human osteosarcoma cell mitogenesis (28), epidermal cell chemotaxis (29), epithelial cell migration (30), and bovine endothelial cell motility (70). Furthermore, uPAR has been demonstrated to facilitate monocyte chemotaxis independent of uPA (71) and transfection of human kidney 293 cells with the GPIanchored form of uPAR, but not the soluble form of the protein, results in uPA-independent neosynthesis of a gelatin-degrading protease in these transfected cells (Rao, N., unpublished observation).…”

Section: Resultsmentioning

confidence: 99%

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Urokinase receptor is a multifunctional protein: influence of receptor occupancy on macrophage gene expression.

Rao

Shi²,

Chapman³

1995

J. Clin. Invest.

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Binding of urokinase to the glycolipid-anchored urokinase receptor (uPAR) has been implicated in macrophage differentiation. However, no biochemical markers of differentiation have yet been directly linked to uPAR occupancy. As extensive changes in proteolytic profile characterize monocytic differentiation, we have examined the role of uPAR occupancy on protease expression by differentiating phagocytes. Antibodies to either urokinase or to uPAR that prevent receptor binding inhibited induction of cathepsin B in cultured monocytes and both cathepsin B and 92-kD gelatinase mRNA and protein in phorbol diester-stimulated myeloid cells. Mannosamine, an inhibitor of glycolipid anchor assembly, also blocked protease expression. Anti-catalytic urokinase antibodies, excess inactive urokinase, or aprotinin had no effect, indicating that receptor occupancy per se regulated protease expression. Antibodies to the integrins CD11a and CD29 or to the glycolipid-anchored proteins CD14 and CD55 also had no effect. Protease induction was independent of matrix attachment. Antibodies to urokinase or uPAR affected neither the decrease in cathepsin G nor the increase in tumor necrosis factor-a in phorbol esterstimulated cells. These data establish that uPAR is a multifunctional receptor, not only promoting pericellular proteolysis and matrix attachment, but also effecting cysteine-and metallo-protease expression during macrophage differentiation. (J. Clin. Invest. 1995. 96:465-474.)

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Section: Resultsmentioning

confidence: 99%

“…Potentially, uPAR occupancy may directly transduce signals, as has been documented for some GPI-anchored proteins (24,25), and influence the phenotype of macrophages. In fact, uPAR bound uPA has been demonstrated to induce cellular responses both dependent on (26,27) and independent of (28)(29)(30) its catalytic activity.…”

Section: Introductionmentioning

confidence: 99%

Urokinase receptor is a multifunctional protein: influence of receptor occupancy on macrophage gene expression.

Rao

Shi²,

Chapman³

1995

J. Clin. Invest.

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“…For example, it has been shown that the binding of the uPA receptor by the enzymatically inactive amino-terminal fragment of uPA is sufficient to promote human epidermal cell motility (41). In another report, human monocyte chemotaxis was prevented by blocking uPA binding with an anti-uPAR monoclonal antibody but not with an antibody that neutralizes uPA catalytic activity (42).…”

Section: Discussionmentioning

confidence: 99%

Requirement of Receptor-bound Urokinase-type Plasminogen Activator for Integrin αvβ5-directed Cell Migration

Yebra

Parry

Strömblad

et al. 1996

Journal of Biological Chemistry

239

147

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The urokinase plasminogen activator (uPA) interacts with its cell surface receptor (uPAR), providing an inducible, localized cell surface proteolytic activity, thereby promoting cellular invasion. Evidence is provided for a novel function of cell surface-associated uPA⅐uPAR. Specifically, induction of cell surface expression of uPA⅐uPAR by growth factors or phorbol ester was necessary for vitronectin-dependent carcinoma cell migration, an event mediated by integrin ␣v␤5. Cell migration on vitronectin was blocked with either a soluble form of uPAR, an antibody that disrupts uPA binding to uPAR, or a monoclonal antibody to ␣v␤5. Moreover, plasminogen activator inhibitor type 2 blocked this migration event but did not affect adhesion, suggesting a direct role for uPA enzyme activity in this process and that migration but not adhesion of these cells is regulated by uPA⅐uPAR. Growth factor-mediated induction of uPA⅐uPAR on the carcinoma cell surface promotes a specific motility event mediated by integrin ␣v␤5, since cells transfected with the ␤3 integrin subunit expressed ␣v␤3 and migrated on vitronectin independently of growth factors or uPA⅐uPAR expression. This relationship between ␣v␤5 and the uPA⅐uPAR system has significant implications for regulation of motility events associated with development, angiogenesis, and tumor metastasis.

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“…In addition to binding urokinase, uPAR is a multifunctional protein implicated in cellular adhesion (12,13), migration (14,15), and signaling (16). We have previously documented a nonproteolytic role for uPAR as a cellular adhesion receptor for the matrixlike form of vitronectin (17,18).…”

Section: Introductionmentioning

confidence: 99%

Plasmin and plasminogen activator inhibitor type 1 promote cellular motility by regulating the interaction between the urokinase receptor and vitronectin.

Waltz

Natkin²,

Fujita³

et al. 1997

J. Clin. Invest.

258

205

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The urokinase receptor (uPAR) coordinates plasmin-mediated cell-surface proteolysis and promotes cellular adhesion via a binding site for vitronectin on uPAR. Because vitronectin also binds plasminogen activator inhibitor type 1 (PAI-1), and plasmin cleavage of vitronectin reduces PAI-1 binding, we explored the effects of plasmin and PAI-1 on the interaction between uPAR and vitronectin. PAI-1 blocked cellular binding of and adhesion to vitronectin by over 80% (IC 50 ‫ف‬ 5

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Urokinase-Urokinase Receptor Interaction: Non-Mitogenic Signal Transduction in Human Epidermal Cells

Cited by 74 publications

References 0 publications

Urokinase receptor is a multifunctional protein: influence of receptor occupancy on macrophage gene expression.

Urokinase receptor is a multifunctional protein: influence of receptor occupancy on macrophage gene expression.

Requirement of Receptor-bound Urokinase-type Plasminogen Activator for Integrin αvβ5-directed Cell Migration

Plasmin and plasminogen activator inhibitor type 1 promote cellular motility by regulating the interaction between the urokinase receptor and vitronectin.

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