An uncleavable uPAR mutant allows dissection of signaling pathways in uPA-dependent cell migration

Roberta Mazzieri, Silvia D'Alessio, Richard Kamgang Kenmoe, Liliana Ossowski, Francesco Blasi

Research output: Contribution to journalArticle

Abstract

Urokinase-type plasminogen activator (uPA) binding to uPAR induces migration, adhesion, and proliferation through multiple interactions with G proteins-coupled receptor FPRL1, integrins, or the epidermal growth factor (EGF) receptor (EGFR). At least two forms of uPAR are present on the cell surface: full-length and cleaved uPAR, each specifically interacting with one or more transmembrane proteins. The connection between these interactions and the effects on the signaling pathways activation is not clear. We have exploited an uPAR mutant (hcr, human cleavage resistant) to dissect the pathways involved in uPA-induced cell migration. This mutant is not cleaved by proteases, is glycosylphosphatidylinositol anchored, and binds uPA with a normal K d. Both wild-type (wt) and hcr-uPAR are able to mediate uPA-induced migration, are constitutively associated with the EGFR, and associate with α3β1 integrin upon uPA binding. However, they engage different pathways in response to uPA. wt-uPAR requires both integrins and FPRL1 to mediate uPA-induced migration, and association of wt-uPAR to α3β1 results in uPAR cleavage and extracellular signal-regulated kinase (ERK) activation. On the contrary, hcr-uPAR does not activate ERK and does not engage FPRL1 or any other G protein-coupled receptor, but it activates an alternative pathway initiated by the formation of a triple complex (uPAR-α3β1- EGFR) and resulting in the autotyrosine phosphorylation of EGFR.

Original languageEnglish
Pages (from-to)367-378
Number of pages12
JournalMolecular Biology of the Cell
Volume17
Issue number1
DOIs
Publication statusPublished - Jan 2006

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Urokinase-Type Plasminogen Activator
Cell Movement
Dissection
Epidermal Growth Factor Receptor
Integrins
Extracellular Signal-Regulated MAP Kinases
G-Protein-Coupled Receptors
Glycosylphosphatidylinositols
Peptide Hydrolases
Phosphorylation
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

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An uncleavable uPAR mutant allows dissection of signaling pathways in uPA-dependent cell migration. / Mazzieri, Roberta; D'Alessio, Silvia; Kenmoe, Richard Kamgang; Ossowski, Liliana; Blasi, Francesco.

In: Molecular Biology of the Cell, Vol. 17, No. 1, 01.2006, p. 367-378.

Research output: Contribution to journalArticle

Mazzieri, Roberta ; D'Alessio, Silvia ; Kenmoe, Richard Kamgang ; Ossowski, Liliana ; Blasi, Francesco. / An uncleavable uPAR mutant allows dissection of signaling pathways in uPA-dependent cell migration. In: Molecular Biology of the Cell. 2006 ; Vol. 17, No. 1. pp. 367-378.
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