A urokinase-sensitive region of the human urokinase receptor is responsible for its chemotactic activity.
The role of urokinase-type plasminogen activator (uPA) and its receptor (uPAR/CD87) in cell migration and invasion is well substantiated. Recently, uPA has been shown to be essential in cell migration, since uPA-/- mice are greatly impaired in inflammatory cell recruitment. We have shown previously that the uPA-induced chemotaxis requires interaction with and modification of uPAR/CD87, which is the true chemoattracting molecule acting through an unidentified cell surface component which mediates this cell surface chemokine activity. By expressing and testing several uPAR/CD87 variants, we have located and functionally characterized a potent uPAR/CD87 epitope that mimics the effects of the uPA-uPAR interaction. The chemotactic activity lies in the region linking domains 1 and 2, the only protease-sensitive region of uPAR/CD87, efficiently cleaved by uPA at physiological concentrations. Synthetic peptides carrying this epitope promote chemotaxis and activate p56/p59(hck) tyrosine kinase. Both chemotaxis and kinase activation are pertussis toxin sensitive, involving a Gi/o protein in the pathway.
Fazioli
F
F
Department of Biology and Biotechnology (DIBIT), San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy.
Resnati
M
M
Sidenius
N
N
Higashimoto
Y
Y
Appella
E
E
Blasi
F
F
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D018925:Chemokines / Q000502:physiology; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D017931:DNA Primers; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D037342:Pertussis Toxin; D016133:Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000737:chemistry* / Q000502:physiology*; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D018925:Chemokines; D017931:DNA Primers; C524898:PLAUR protein, human; D010446:Peptide Fragments; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin; D014568:Urokinase-Type Plasminogen Activator; D019204:GTP-Binding Proteins