The plasminogen activator/plasmin system.

Abstract

Over the last 10 years, our knowledge ofextracellular proteolysis has progressed dramatically. Different enzymatic cascades cooperate to achieve extracellular matrix (ECM)I degradation, and a number of participant proteins have been characterized and cloned. Physiological inhibitors have been identified for most of these enzymes. Also, the concept of focused proteolysis, through binding of enzymes and inhibitors to specific regions ofthe extracellular milieu, has received broad experimental support. Finally, the biosynthesis of many of the relevant proteases and inhibitors has been shown to be under the control of hormones and growth factors. Plasminogen activators (PAs) and their inhibitors (PAIs) are thought to be key participants in the balance ofproteolytic and antiproteolytic activities that regulates matrix turnover. This article summarizes the evidence that supports this contention, discusses the role of PAspecific cell surface binding sites, and also draws attention to a number of instances in which the presence of PAs cannot be reconciled with an exclusive function in ECM degradation.The plasminogen activator/plasmin system ENZYMES PAs are serine proteases of tryptic specificity. Two enzymes, differing mostly in the domain organization and function of their noncatalytic regions, have been identified in mammals: urokinase-type PA (uPA) and tissue-type PA (tPA) (1). They are the products of distinct genes, and are secreted as singlechain (sc) proteins; whereas sc tPA is active, sc uPA is essentially inactive (pro-uPA) (2). Cleavage of pro-uPA by plasmin, kallikrein, Factor XIIa or cathepsin B (3) yields the disulfidelinked two-chain active enzyme. The two PAs have distinct targeting determinants in their noncatalytic regions: the "growth factor domain" of uPA directs the binding of the enzyme (and that ofpro-uPA) to a plasma membrane receptor (4,5), whereas other structural domains in tPA (the "finger" region and the "kringles") allow its binding to fibrin and other It is impossible to select a small set of references that would provide appropriate coverage of the entire field discussed. We have thus included references to reviews and to recent papers that can be used to trace back earlier work. We apologize to all our colleagues whose contributions are not adequately referenced, as well as to our readers.Receivedfor components of the ECM (6). These and perhaps additional interactions, for instance with heparinlike molecules, could have a dramatic effect on the focusing of PA-controlled proteolysis (7). The different extracellular addressing ofthe two PAs suggests that they play different biological roles.Plasminogen is the prefered substrate for PAs, but other molecules may also be cleaved by one or the other PA; for instance, avian uPA exerts a plasmin-independent effect on the morphology of chick fibroblasts (8). Plasminogen is present in plasma and extracellular fluids at a 1-2 AM concentration, in the range of the Km of the activation reaction. It can associate with fibrin and other proteins via lysi...

Angiostatin's molecular mechanism: Aspects of specificity and regulation elucidated

“…Angiostatin and endostatin are endogenously produced in the tumor stroma through the action of proteinases that are induced as part of the angiogenic cascade [Vassalli et al, 1991]. These internal cleavage fragments of plasminogen and collagen XVIII, respectively, therefore exemplify a theme in vascular biology that a given signal initiates a cascade that generates both positive and negative regulators of angiogenesis.…”

Alterations in plasminogen activation correlate with epithelial cell dysplasia grading in colorectal adenomas

“…The grade of epithelial cell dysplasia is a hallmark of malignant potential in the process known as the adenoma-carcinoma sequence (Muto et al, 1975;O'Brien et al, 1990;Hamilton, 1992). While the morphological changes taking place during the development and progression of colorectal dysplasia can readily be detected by histopathology, the proteolytic alterations underlying these multiple events remain unclear.It has been shown that components of the plasminogen activation system are key participants in the regulation of extracellular matrix turnover during cell migration, tissue modelling and malignant invasion (Konishi et al, 1982;Vassalli et al, 1991;Blasi, 1993). Previous studies have shown that tissue extracts from colorectal carcinomas have increased levels of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitors (PAI) and decreased levels of tissue-type plasminogen activator (tPA) compared with morphologically normal adjacent mucosa (Gelister et al, 1986;Sier et al, 1991a).…”

“…It has been shown that components of the plasminogen activation system are key participants in the regulation of extracellular matrix turnover during cell migration, tissue modelling and malignant invasion (Konishi et al, 1982;Vassalli et al, 1991;Blasi, 1993). Previous studies have shown that tissue extracts from colorectal carcinomas have increased levels of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitors (PAI) and decreased levels of tissue-type plasminogen activator (tPA) compared with morphologically normal adjacent mucosa (Gelister et al, 1986;Sier et al, 1991a).…”

Epidermal growth factor‐binding protein activates soluble and receptor‐bound single chain urokinase‐type plasminogen activator

“…Urokinase type plasminogen activator (u-PA) is the primary enzyme responsible for plasminogen activation at the cell surface (reviewed in [1]). u-PA, while bound to its cellular receptor, urokinase type plasminogen activator receptor (uPAR), activates cell-associated plasminogen, generating plasmin.…”

“…Cell-associated plasmin directly degrades glycoproteins of the extracellular matrix and activates metalloproteinases that digest extracellular matrix collagen. This u-PA-dependent cell-surface proteinase cascade promotes cellular migration and extracellular matrix remodeling during several biological processes including chemotaxis, angiogenesis, neurite outgrowth, and wound repair [1]. *Corresponding author.…”