A Model of the Reactive Form of Plasminogen Activator Inhibitor-1

Aertgeerts, K.; Bondt, H.L. De; Ranter, Camiel De; Declerck, Paul

doi:10.1006/jsbi.1994.1058

Cited by 25 publications

(22 citation statements)

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“…While the N-terminal somatomedin B region of vitronectin is necessary and sufficient for inhibitor binding [37,381, the secondary site within the heparin-binding region [13,14,171 appears to be required for matrix association, indicating that both sites in intact multimeric vitronectin are required [14]. Recent studies using mutational [39] and structure prediction analysis [40] also suggested a large complementary surface area in plasminogen-activator inhibitor-1 for interaction with vitronectin.…”

Section: Discussionmentioning

confidence: 99%

Limited Plasmin Proteolysis of Vitronectin

Kost

Benner

Stockmann

et al. 1996

European Journal of Biochemistry

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The adhesion protein vitronectin is associated with extracellular matrices and serves as cofactor for plasminogen-activator inhibitor-1 . Limited proteolysis by plasmin converts vitronectin into defined fragments which are detectable at sites of intlammation and angiogenesis. The loss and gain of binding functions of vitronectin fragments for macromolecular ligands was characterized in the present study. The initially generated 61 -63-kDa vitronectin-( 1 -348)-fragment serves as typical binding component for plasminogen and binding function was lost upon carboxypeptidase B treatment indicating the importance of a C-terminal lysine. Complementary binding sites reside in isolated plasminogen kringles 1-3 (designated angiostatin) as deduced from direct binding and ligand blotting experiments. A synthetic vitronectin-(331 -348)-peptide from the C-terminus of the 61 -63-kDa fragment could mimic plasminogen and angiostatin binding. Also, the immobilized peptide bound tissue plasminogen-activator and mediated plasmin formation, comparable to fibrinogen-derived peptides. The 61 -63-kDa vitronectin fragment was indistinguishable in its adhesive properties to intact vitronectin and bound active but not latent plasminogen-activator inhibitor-1 . Late plasminolysis of vitronectin resulted in the processing of the N-terminal region of the protein with the generation of 42 kDd3S-kDa fragments that had GIy89 as new N-terminus and that were ineffective in promoting cell adhesion. Thus, at sites of cell-matrix interactions which become proteolytically modified by plasmin during inflammatory and angiogenic processes, vitronectin serves as plasminogedangiostatin-binding factor. Due to this differential change in functions particularly at sites of deposition in the vascular system or at wound sites vitronectin is considered to be an important morpho-regulatory factor.Keywords: angiostatin ; plasmin ; vitronectin; adhesion ; proteolysis.The molecular dynamics in stabilization and destabilization of cellular contacts is under strict control in many biological systems as diverse as embryo implantation, histogenesis, angiogenesis, cellular extravasation or tumor metastasis [ 11. Cell-specific hydrolytic enzymes and the plasminogen-activation system have been implicated in many instances as modulators of the cell-matrix micro-environment. Thus, cell migration, invasion and cell proliferation rely on a proteolytic/anti-proteolytic balance based on cell-surface-restricted reactions. In particular, cell surface receptors for urokinase [2], tissue plasminogen activator 131 or cellular binding sites for plasminogen [4] are positioned for localized generation of plasmin. The early phase of plasminogen activation is controlled by several serine protease inhibitors of which extracellular matrix-associated plasminogen-activator inhibitor-1 appears to be the predominant one [S]. The multifunctional adhesive protein vitronectin serves as binding and stabilization factor for plasminogen-activator inhibitor-1 [6 -XI, and colocalization of both compo...

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Section: Discussionmentioning

confidence: 99%

Limited Plasmin Proteolysis of Vitronectin

Kost

Benner

Stockmann

et al. 1996

European Journal of Biochemistry

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“…The black spheres indicate basic residues, which were implicated in binding of anthranilic acid derivatives to PAI-1 [191]. The figure is a Molscript display of the model of Aertgeerts et al [197].…”

Section: Serpin Inhibitors In the Plasminogen Activation Systemmentioning

confidence: 99%

The plasminogen activation system in tumor growth, invasion, and metastasis

Andreasen

Egelund

Petersen

2000

Cellular and Molecular Life Sciences (CMLS)

866

783

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Generation of the serine proteinase plasmin from the extracellular zymogen plasminogen can be catalyzed by either of two other serine proteinases, the urokinase- and tissue-type plasminogen activators (uPA and tPA). The plasminogen activation system also includes the serpins PAI-1 and PAI-2, and the uPA receptor (uPAR). Many findings, gathered over several decades, strongly suggest an important and causal role for uPA-catalyzed plasmin generation in cancer cell invasion through the extracellular matrix. Recent evidence suggests that the uPA system is also involved in cancer cell-directed tissue remodeling. Moreover, the system also supports cell migration and invasion by plasmin-independent mechanisms, including multiple interactions between uPA, uPAR, PAI-1, extracellular matrix proteins, integrins, endocytosis receptors, and growth factors. These interactions seem to allow temporal and spatial reorganizations of the system during cell migration and a selective degradation of extracellular matrix proteins during invasion. The increased knowledge about the plasminogen activation system may allow utilization of its components as targets for anti-invasive therapy.

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“…Bacterial lysates (in 50 mM sodium phosphate (pH 6.0) buffer with 0.15 M NaCl) containing the mutants were incubated with or without 50 mM DTT for 30 minutes at room temperature. Subsequently, a twofold molar excess of uPA was added and the samples were analyzed by SDS/10% PAGE, followed by Western blot 55 and detection by the enhanced chemiluminescence (ECL) method (Amersham Pharmacia Biotech AB., Uppsala, Sweden). Detection of the amount of complex before and after reduction was performed by using a phosphoimager (GS-250 Molecular Imagere; Bio-Rad).…”

Section: Time-resolved Fluorescence Experimentsmentioning

confidence: 99%