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

Mazzieri, Roberta, D'Alessio, Silvia, Kenmoe, Richard Kamgang, Ossowski, Liliana and Blasi, Francesco (2006) An uncleavable uPAR mutant allows dissection of signaling pathways in uPA-dependent cell migration. Molecular Biology of the Cell, 17 1: 367-378. doi:10.1091/mbc.E05-07-0635

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Author Mazzieri, Roberta
D'Alessio, Silvia
Kenmoe, Richard Kamgang
Ossowski, Liliana
Blasi, Francesco
Title An uncleavable uPAR mutant allows dissection of signaling pathways in uPA-dependent cell migration
Journal name Molecular Biology of the Cell   Check publisher's open access policy
ISSN 1059-1524
Publication date 2006-01
Sub-type Article (original research)
DOI 10.1091/mbc.E05-07-0635
Open Access Status File (Publisher version)
Volume 17
Issue 1
Start page 367
End page 378
Total pages 12
Place of publication Bethesda, MD, United States
Publisher American Society for Cell Biology
Language eng
Formatted 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 Kd. 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.
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Q-Index Status Provisional Code
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Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
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