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First published online 1 August 2006
doi: 10.1242/jcs.03067

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Activation of urokinase receptor by a novel interaction between the connecting peptide region of urokinase and vß5 integrin

Paola Franco^1,*, Immacolata Vocca^1,*, Maria V. Carriero², Daniela Alfano¹, Letizia Cito¹, Immacolata Longanesi-Cattani², Paolo Grieco³, Liliana Ossowski⁴ and Maria P. Stoppelli^1,

¹ Institute of Genetics and Biophysics `Adriano Buzzati-Traverso', National Research Council, Via P. Castellino 111, 80131 Naples, Italy
² Department of Experimental Oncology, National Cancer Institute of Naples, Via M. Semmola, Naples, Italy
³ Department of Pharmaceutical and Toxicological Chemistry, University Federico II, Naples, Italy
⁴ Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA

Author for correspondence (e-mail: stoppell{at}igb.cnr.it)

Accepted 25 May 2006

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 vß5. Remarkably, a peptide corresponding to this region (CPp, residues 135-158) retains the ability to bind to vß5, 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-vß5-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 vß5 integrin), thus initiating and potentiating intracellular signaling and migration.

Key words: uPA, uPAR signaling, Cytoskeleton

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