Urokinase signal transduction and its role in cell migration.
Urokinase and its receptor uPAR play a role in cell migration that is being actively characterized. We previously reported that urokinase potentiates cell migration in human airway smooth muscle cells only where there is some primary migratory stimulus such as PDGF or recent exposure to growth medium. In this study, we examined the signaling of urokinase through its receptor, which lacks an intracellular domain and is presumed to act through associations with other membrane proteins. Whereas PDGF (30 min) and PDGF with urokinase increased the amount of the tyrosine dephosphorylase SHP2 in the membrane fraction, urokinase alone (30 min) decreased membrane SHP2. Analysis of the time course of urokinase stimulation showed that SHP2 was brought into association with the urokinase receptor uPAR between 2.5 and 20 min of urokinase, and later dissociated from it. Focal adhesion kinase was steadily lost from association with uPAR during urokinase stimulation, but its phosphorylation state increased and it became cleaved to smaller molecules. Association of uPAR with caveolin also decreased during urokinase stimulation. In contrast, the tyrosine kinase Src increased in the membrane fraction in response to urokinase stimulation. Disruption of raft structures by cyclodextrin treatment led to potentiation of PDGF chemotaxis, similar to urokinase action. Blocking of dephosphorylase activity with vanadate reduced basal cell migration and blocked the action of urokinase on PDGF chemotaxis. These observations support a role for urokinase in altering the phosphorylation state of focal adhesions, leading to breakdown of their structure and facilitation of cell motility.-Carlin, S. M., Resink, T. J., Tamm, M., Roth, M. Urokinase signal transduction and its role in cell migration.
Carlin
Stephen M
SM
Pulmonary Cell Research, Department of Research, University Hospital Basel, Basel, Switzerland.
Resink
Therese J
TJ
Tamm
Michael
M
Roth
Michael
M
D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D003505:Cyclodextrins / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007820:Laryngeal Mucosa / Q000166:cytology; D021962:Membrane Microdomains / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011956:Receptors, Cell Surface / Q000502:physiology; D055293:Receptors, Urokinase Plasminogen Activator; D015398:Signal Transduction / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*; D014638:Vanadates / Q000494:pharmacology
D003505:Cyclodextrins; D047908:Intracellular Signaling Peptides and Proteins; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D014638:Vanadates; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; D014568:Urokinase-Type Plasminogen Activator