Involvement of the [uPAR : uPA : PAI-1 : LRP] complex in human myogenic cell motility

The urokinase-type plasminogen activator system is a proteolytic system inv olved in tissue remodeling and cell migration. At the cell surface, recepto r (uPAR)-bound urokinase (uPA) binds its inhibitor PAI-1, localized in the matrix, and the complex is internalized by endocytic receptors, such as the low-density lipoprotein receptor-related protein (LRP), We previously prop osed a nonproteolytic role for the uPA system in human myogenic cell differ entiation in vitro, i.e., cell fusion, and showed that myogenic cells can u se PAI-1 as an adhesion matrix molecule. The aim of this study was to defin e the role of the uPA system in myogenic cell migration that is necessary f or fusion, Using a two-dimensional motility assay and microcinematography, we showed that any interference with the [uPAR:uPA:PAI-1] complex formation , and interference with LRP binding to this complex, markedly decreased myo genic cell motility. This phenomenon was reversible and independent of plas min activity. Inhibition of cell motility was associated with suppression o f both filopodia and membrane ruffling activity. [uPAR:uPA:PAI-1:LRP] compl ex formation involves high-affinity molecular interactions and results in q uick internalization of the complex. It is likely that this complex support s the membrane ruffling activity involved in the guidance of the migrating cell toward appropriate sites for attachment. (C) 2000 Academic Press.