Protein Kinase C-dependent in VivoPhosphorylation of Prourokinase Leads to the Formation of a Receptor Competitive Antagonist

Franco, Paola; Massa, Ornella; Garcı́a-Rocha, Mar; Chiaradonna, Ferdinando; Iaccarino, Ciro; Correas, Isabel; Méndez, Enrique; Ávila, Jesús; Blasi, Francesco; Mp, Stoppelli

doi:10.1074/jbc.273.42.27734

Cited by 22 publications

(17 citation statements)

References 46 publications

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“…This observation has led to the suggestion that naturally occurring phosphorylated uPA and the di-substituted form may be competitive antagonists of uPAR signaling (Franco et al, 1998). This observation has led to the suggestion that naturally occurring phosphorylated uPA and the di-substituted form may be competitive antagonists of uPAR signaling (Franco et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Receptor-Dependent Urokinase Signaling by Specific Ser to Glu Substitutions

Carriero¹,

Franco²,

Gargiulo³

et al. 2002

Biological Chemistry

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We have previously reported that phosphorylation of human urokinase on Ser138/303 abolishes its catalytic-independent motogen and proadhesive abilities, whereas receptor binding is not affected. Here we show that substitution of the two relevant serines with glutamic acid residues impairs the ability of urokinase to mobilize a variety of human and mouse cell lines as well as human primary T lymphocytes. Accordingly, urokinase receptor-dependent signaling, leading to cytoskeletal rearrangements and paxillin re-distribution, does not occur in MCF-7 breast carcinoma cells exposed to 'phosphorylation-like' urokinase. Unlike the wild-type form, di-substituted urokinase is unable to induce the physical association of urokinase receptor with alphavbeta5 vitronectin receptor, which is required for MCF-7 urokinase-dependent cell migration. Finally, the di-substituted variant fails to activate p55fgr, a member of the Src tyrosine kinase family, which mediates cell migration and adhesion of U937 myelomonocytic cells. In conclusion, the finding that specific amino acid substitutions strongly interfere with the ability of urokinase to stimulate cell migration, and the associated intracellular events uncover a novel way to regulate urokinase receptor-dependent signaling.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Receptor-Dependent Urokinase Signaling by Specific Ser to Glu Substitutions

Carriero¹,

Franco²,

Gargiulo³

et al. 2002

Biological Chemistry

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“…We previously demonstrated that a phosphomimetic form of uPA, in which Ser138 was substituted with glutamic acid, exhibited an impaired ability to induce migration, suggesting the chemotactic relevance of the region surrounding Ser138 Franco et al, 1998). We have now focused on the role of the CP region (residues 132-158) in the uPAdependent signaling.…”

Section: Resultsmentioning

confidence: 99%

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

Franco

Vocca

Carriero

et al. 2006

Journal of Cell Science

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The serine protease urokinase (uPA) binds to the urokinase receptor (uPAR) through its growth-factor domain (GFD, residues 1-49), affecting cell migration, adhesion and growth. Here, we show that uPA can promote cytoskeletal rearrangements and directional cell migration in a GFD-independent manner, through a new and specific interaction between an internal uPA domain coined `connecting peptide' (residues 132-158) and cell-surface integrin αvβ5. Remarkably, a peptide corresponding to this region (CPp, residues 135-158) retains the ability to bind to αvβ5, eliciting cytoskeletal rearrangements and directing cell migration at a concentration as low as 1-10 pM. These effects are lost in cells not expressing uPAR, indicating that the uPAR is required for CPp-dependent signaling. Furthermore, the CPp-αvβ5-integrin interaction enhances F-actin-enriched protrusions and cell migration induced by the well-established interaction between the uPAR-binding peptide (GFDp, residues 12-32) of uPA and uPAR. These results provide new insight into the function of uPA, which - through individual domains - can engage two different surface receptors (uPAR and αvβ5 integrin), thus initiating and potentiating intracellular signaling and migration.

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“…This prevents the catalytic-independent ability of pro-uPA to promote myelomonocytic cell adhesion and motility [127]. The phosphorylation is induced by PKC activation [128]. The effects on cell adhesion and motility, however, do not occur through modulation of the interaction between pro-uPA and uPAR or uPAR and vitronectin [128].…”

Section: Cell Invasion Adhesion and Migrationmentioning

confidence: 99%

“…The phosphorylation is induced by PKC activation [128]. The effects on cell adhesion and motility, however, do not occur through modulation of the interaction between pro-uPA and uPAR or uPAR and vitronectin [128]. A step subsequent to pro-uPA binding to uPAR must be affected by pro-uPA phosphorylation.…”

Section: Cell Invasion Adhesion and Migrationmentioning

confidence: 99%

The plasminogen activator system: biology and regulation

Irigoyen

Muñoz‐Cánoves²,

Montero

et al. 1999

CMLS, Cell. Mol. Life Sci.

348

271

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The regulation of plasminogen activation involves genes for two plasminogen activators (tissue type and urokinase type), two specific inhibitors (type 1 and type 2), and a membrane-anchored urokinase-type plasminogen-activator-specific receptor. This system plays an important role in various biological processes involving extracellular proteolysis. Recent studies have revealed that the system, through interplay with integrins and the extracellular matrix protein vitronectin, is also involved in the regulation of cell migration and proliferation in a manner independent of proteolytic activity. The genes are expressed in many different cell types and their expression is under the control of diverse extracellular signals. Gene expression reflects the levels of the corresponding mRNA, which should be the net result of synthesis and degradation. Thus, modulation of mRNA stability is an important factor in overall regulation. This review summarizes current understanding of the biology and regulation of genes involved in plasminogen activation at different levels.

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Protein Kinase C-dependent in VivoPhosphorylation of Prourokinase Leads to the Formation of a Receptor Competitive Antagonist

Cited by 22 publications

References 46 publications

Inhibition of Receptor-Dependent Urokinase Signaling by Specific Ser to Glu Substitutions

Inhibition of Receptor-Dependent Urokinase Signaling by Specific Ser to Glu Substitutions

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

The plasminogen activator system: biology and regulation

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