Functional Relevance of Urinary-type Plasminogen Activator Receptor-α3β1 Integrin Association in Proteinase Regulatory Pathways

摘要: Abstract Squamous cell carcinoma of the oral cavity is characterized by persistent, disorganized expression integrin α3β1 and enhanced production urinary-type plasminogen activator (uPA) its receptor (uPAR) relative to normal mucosa. Because multivalent aggregation up-regulates uPA induces a dramatic co-clustering uPAR, we explored hypothesis that lateral ligation uPAR contributes regulation in mucosal cells. To investigate mechanisms which uPAR/α3β1 binding enhances expression, integrin-dependent signal activation was assessed. Both Src ERK1/2 were phosphorylated response aggregation, blocking kinase activity completely abrogated induction, whereas inhibition epidermal growth factor tyrosine did not alter expression. Proteinase up-regulation occurred at transcriptional level mutation AP1 (–1967) site promoter blocked uPAR/integrin-mediated activation. redistributed clustered integrins, requirement for interaction Clustering presence peptide (α325) disrupts prevented induction. Depletion surface using small interfering RNA also induction following clustering. These results confirmed genetic strategy α3 null epithelial cells reconstituted with wild type integrin, but mutant unable bind induced upon clustering, confirming critical role integrin-regulated proteinase Disruption α325 or filopodia formation matrix invasion, indicating this stimulates invasive behavior. Together these data support model wherein matrix-induced clustering ofα3β1 promotes interaction, thereby potentiating cellular transduction pathways culminating uPA-dependent