Cellular migration, over simple surfaces or through complex stromal barriers, requires coordination between detachment/re-adhesion cycles, involving structural components of the extracellular matrix and their surface-binding elements (integrins), and the precise regulation of the pericellular proteolytic microenvironment. It is now apparent that several proteases and protease inhibitors, most notably urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1), also interact with several cell surface receptors transducing intracellular signals that significantly affect both motile and proliferative programs. These events appear distinct from the original function of uPA/PAI-1 as modulators of the plasmin-based proteolytic cascade. The multifaceted interactions of PAI-1 with specific matrix components (i.e., vitronectin), the low-density lipoprotein receptor-related protein-1 (LRP1), and the uPA/uPA receptor complex have dramatic consequences on the migratory phenotype and may underlie the pathophysiologic sequalae of PAI-1 deficiency and overexpression. This paper focuses on the increasingly intricate role of PAI-1 as a major mechanistic determinant of the cellular migratory phenotype. 1. Introduction The switch between a sessile and migratory cellular phenotype is triggered, in part, by the activation of signaling pathways that regulate the expression of the involved genes, (e.g., [1, 2]). While the actual genomic response varies as a consequence of cell type, the acquisition of a core “plasticity” signature (at both the mRNA and proteomic levels) represents the transition to a motile phenotype whether over simple planar surfaces or through complex matrix barriers in normal as well as transformed keratinocytes, (e.g., [2–7]). Global transcriptome profiling of both wounded keratinocyte cultures and epithelial tumor cells has highlighted the requirement for precise spatial/temporal control of pericellular proteolysis and matrix remodeling in the integration of the cellular motile/tissue repair responses [2, 5]. Indeed, among the transcriptional outputs (i.e., genes with altered expression) that typify the migratory or invasive phenotype, urokinase plasminogen activator (uPA) and its major negative regulator plasminogen activator inhibitor type-1 (PAI-1) are among the most highly induced transcripts, (e.g., [4, 5, 8]) (Figure 1). PAI-1 belongs to the serine protease inhibitor (SERPIN) protein family that also includes PAI-2 and PAI-3 (protein C inhibitor), protease nexin-1, and neuroserpin (reviewed in [9]). uPA and PAI-1 (also
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