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 GFD-independent manner, through a new and specific interaction between an internal uPA domain coined ;connecting peptide' (residues 132-158) and cell-surface integrin alpha v beta 5. Remarkably, a peptide corresponding to this region (CPp, residues 135-158) retains the ability to bind to alpha v beta 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-alpha v beta 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 alpha v beta 5 integrin), thus initiating and potentiating intracellular signaling and migration.
Franco
Paola
P
Institute of Genetics and Biophysics Adriano Buzzati-Traverso, National Research Council, Via P. Castellino 111, 80131 Naples, Italy.
Vocca
Immacolata
I
Carriero
Maria V
MV
Alfano
Daniela
D
Cito
Letizia
L
Longanesi-Cattani
Immacolata
I
Grieco
Paolo
P
Ossowski
Liliana
L
Stoppelli
Maria P
MP
D000199:Actins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D002633:Chemotaxis; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D019030:Receptors, Vitronectin / Q000378:metabolism*; D015398:Signal Transduction; D020298:U937 Cells; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D000199:Actins; D016023:Integrins; C524898:PLAUR protein, human; D010446:Peptide Fragments; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; D014568:Urokinase-Type Plasminogen Activator