Activation of urokinase receptor by a novel interaction between the connecting peptide region of urokinase and alpha v beta 5 integrin

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 GFDindependent manner, through a new and specific interaction between an internal uPA domain coined 'connecting peptide' (residues 132-158) and cell-surface integrin "v!5. Remarkably, a peptide corresponding to this region (CPp, residues 135-158) retains the ability to bind to "v!5, 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-"v!5-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 "v!5 integrin), thus initiating and potentiating intracellular signaling and migration.