QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 17, Issue 1, 367-378, January 2006

This Article Full Text Full Text (PDF) All Versions of this Article: E05-07-0635v1 17/1/367    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mazzieri, R. Articles by Blasi, F. Search for Related Content PubMed PubMed Citation Articles by Mazzieri, R. Articles by Blasi, F.

An Uncleavable uPAR Mutant Allows Dissection of Signaling Pathways in uPA-dependent Cell Migration

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

^* Department of Molecular Biology and Functional Genomics, Università Vita Salute San Raffaele and S. Raffaele Scientific Institute, 20132 Milan, Italy; FIRC Institute of Molecular Oncology, 20116 Milan, Italy; and Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 11029

Submitted July 15, 2005; Revised September 26, 2005; Accepted October 21, 2005
Monitoring Editor: Richard Assoian

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 31 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 31 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-31-EGFR) and resulting in the autotyrosine phosphorylation of EGFR.

Abbreviations used: EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; hcr, human cleavage-resistant uPAR; ATF, amino-terminal fragment; GPI, glycosylphosphatidylinositol; fMLP, formyl-methyonyl-leucyl-proline; FPR, formyl-methyonyl-leucyl-proline receptor; IP, immunoprecipitation; JNK, c-Jun NH₂-terminal kinase; uPA, urokinase-type plasminogen activator; uPAR, urokinase-type plasminogen activator receptor.

These authors contributed equally to this work.

Address correspondence to: Francesco Blasi (blasi.francesco{at}hsr.it).

This article has been cited by other articles:

				S. D'Alessio, L. Gerasi, and F. Blasi uPAR-deficient mouse keratinocytes fail to produce EGFR-dependent laminin-5, affecting migration in vivo and in vitro J. Cell Sci., December 1, 2008; 121(23): 3922 - 3932. [Abstract] [Full Text] [PDF]

				C.-H. Tang, M. L. Hill, A. N. Brumwell, H. A. Chapman, and Y. Wei Signaling through urokinase and urokinase receptor in lung cancer cells requires interactions with {beta}1 integrins J. Cell Sci., November 15, 2008; 121(22): 3747 - 3756. [Abstract] [Full Text] [PDF]

				A. M. Bernstein, S. S. Twining, D. J. Warejcka, E. Tall, and S. K. Masur Urokinase Receptor Cleavage: A Crucial Step in Fibroblast-to-Myofibroblast Differentiation Mol. Biol. Cell, July 1, 2007; 18(7): 2716 - 2727. [Abstract] [Full Text] [PDF]

				C. D. Madsen, G. M. S. Ferraris, A. Andolfo, O. Cunningham, and N. Sidenius uPAR-induced cell adhesion and migration: vitronectin provides the key J. Cell Biol., June 21, 2007; 177(5): 927 - 939. [Abstract] [Full Text] [PDF]

				Y. Wei, C.-H. Tang, Y. Kim, L. Robillard, F. Zhang, M. C. Kugler, and H. A. Chapman Urokinase Receptors Are Required for {alpha}5beta1 Integrin-mediated Signaling in Tumor Cells J. Biol. Chem., February 9, 2007; 282(6): 3929 - 3939. [Abstract] [Full Text] [PDF]