Urokinase/urokinase receptor and vitronectin/alpha(v)beta(3) integrin induce chemotaxis and cytoskeleton reorganization through different signaling pathways.
Vitronectin (VN) and pro-urokinase (pro-uPA) stimulated migration of rat smooth muscle cells in a dose-dependent and additive way, and induced motile-type changes in cell morphology together with a complete reorganization of the actin filaments and of the microtubules. All these effects were inhibited by pertussis toxin, or by antibodies directed against the urokinase receptor (uPAR) or against the VN receptor alpha(v)beta(3) suggesting that an association between the two receptors is required to mediate both signals. Investigation of the signaling pathways showed that increasing the intracellular cAMP resulted in a selective inhibition of VN-induced cell migration. On the other hand, PD 98059, an inhibitor of MEK, differentially inhibited the pro-uPA- but not the VN-induced cell migration. Phosphorylation and nuclear translocation of Erk by pro-uPA was directly observed. We conclude that the signaling pathways of pro-uPA and VN must be at least in part different.
Degryse
B
B
Department of Molecular Pathology and Medicine, Università Vita-Salute San Raffaele, Via Olgettina 58, 20132 Milano, Italy.
Orlando
S
S
Resnati
M
M
Rabbani
S A
SA
Blasi
F
F
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D003599:Cytoskeleton / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation; D020935:MAP Kinase Signaling System / Q000502:physiology; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D037342:Pertussis Toxin; D051381:Rats; D020239:Receptor Cross-Talk / Q000502:physiology; D011956:Receptors, Cell Surface / Q000276:immunology / Q000502:physiology*; D055293:Receptors, Urokinase Plasminogen Activator; D019030:Receptors, Vitronectin / Q000276:immunology / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology / Q000502:physiology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D019096:Vitronectin / Q000494:pharmacology / Q000502:physiology*
D000906:Antibodies; C524900:Plaur protein, rat; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D019030:Receptors, Vitronectin; D011994:Recombinant Proteins; D010566:Virulence Factors, Bordetella; D019096:Vitronectin; D037342:Pertussis Toxin; D020928:Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator; C067551:saruplase