PAI-1: An Integrator of Cell Signaling and Migration

Ralf-Peter Czekay,Stephen P Higgins,R Matthew Klein,Paul J Higgins,Rohan Samarakoon,Cynthia E Wilkins-Port,Jessica M Overstreet,Jennifer Freytag,Craig E Higgins

doi:10.1155/2011/562481

Abstract

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.

Highlights

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])
plasminogen activator inhibitor type-1 (PAI-1) belongs to the serine protease inhibitor (SERPIN) protein family that includes PAI-2 and PAI3, protease nexin-1, and neuroserpin. urokinase plasminogen activator (uPA) and PAI-1 are both the targets and modifiers of pathways that impact proliferative/migratory events (Figure 2) and coordinately titrate the overall pericellular proteolytic balance directly as well as indirectly by activating several members of the matrix metalloproteinase (MMP) family
Motile epithelial cells focalize both uPA, following interaction with its cell surface receptor uPAR, and PAI-1, upon binding of this SERPIN to uPA/uPAR or vitronectin (VN), to the leading edge where they modulate the interrelated events of matrix remodeling and migration, (e.g., [10,11,12])

Summary

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]). High stromal PAI1 levels, correlate with a poor prognosis in various cancers [14,15,16] and typify diseases in which fibrosis and/or cellular infiltration are common pathologic features (e.g., scarring anomalies, renal fibrosis, atherosclerosis) [17,18,19,20,21]. These findings suggest that PAI-1-dependent preservation of the surrounding matrix may facilitate cell locomotion in vivo, perhaps by fine-tuning the proteolytic activity to optimize tissue penetration. This paper focuses on the most recent developments in this field and on the complex proteolytic as well as nonproteolytic functions of PAI-1 in the cellular motile program

PAI-1-Regulated Cell Migration

Cytoplasm

Summary