DMCA
Is Plasminogen Activator Inhibitor-1 the Molecular Switch That Governs Urokinase Receptor-mediated Cell Adhesion and Release?
| Citations: | 40 - 4 self |
BibTeX
@MISC{Deng_isplasminogen,
author = {Gang Deng and Scott A. Curriden and Soujuan Wang and Steven Rosenberg and David J. Loskutoff},
title = {Is Plasminogen Activator Inhibitor-1 the Molecular Switch That Governs Urokinase Receptor-mediated Cell Adhesion and Release?},
year = {}
}
Share
 |
 |
 |
 |
||
OpenURL
Abstract
Abstract. Induction of the urokinase type plasminogen activator receptor (uPAR) promotes cell adhesion through its interaction with vitronectin (VN) in the extracellular matrix, and facilitates cell migration and invasion by localizing uPA to the cell surface. We provide evidence that this balance between cell adhesion and cell detachment is governed by PA inhibitor-1 (PAl-l). First, we demonstrate that uPAR and PAL1 bind to the same site in VN (i.e., the amino-terminal somatomedin B domain; SMB), and that PAI-1 competes with uPAR for binding to SMB. Domain swapping and mutagenesis studies indicate that the uPAR-binding sequence is located within the central region of the SMB domain, a region previously shown to contain the PAl-l-binding motif. Second, we show that PAI-1 dissociates bound VN from uPAR and detaches U937 cells from their VN substratum. This PAL1 mediated release of cells from VN appears to occur independently of its ability to function as a protease inhibitor, and may help to explain why high PAI-1 levels indicate a poor prognosis for many cancers. Finally, we show that uPA can rapidly reverse this effect of PAI-1. Taken together, these results suggest a dynamic regulatory role for PAI-1 and uPA in uPAR-mediated cell adhesion and release. T UMOR invasion and metastasis depend upon the coordinated expression and temporal regulation of a series of proteolytic (Chen, 1992; Dano et al., 1985; Mignatti and Rifkin, 1993) and adhesive (Nesbit and Herlyn, 1994) events. Urokinase-type plasminogen activator (uPA) 1 is one of the proteases frequently implicated in these processes (Dano et al., 1985; Mignatti and Rifkin, 1993; Cohen et al., 1991; Vassalli et al., 1991). It is a serine protease that catalyzes the conversion of plasminogen into plasmin. Plasmin itself is a broadly acting trypsin-like enzyme that not only degrades fibrin and a variety of extracellular matrix (ECM) proteins, but also may activate metalloproteinases
Keyphrases
plasminogen activator inhibitor-1 governs urokinase receptor-mediated cell adhesion molecular switch extracellular matrix cell adhesion poor prognosis high pai-1 level temporal regulation cell detachment pal-l-binding motif cell surface umor invasion coordinated expression urokinase type plasminogen activator receptor protease inhibitor dynamic regulatory role vn substratum smb domain domain swapping detaches u937 cell urokinase-type plasminogen activator pal1 bind amino-terminal somatomedin domain central region pai-1 competes upar-binding sequence serine protease many cancer mutagenesis study upar-mediated cell adhesion trypsin-like enzyme
