Plasminogen activator inhibitor 1 (PAI) is bound to vitronectin in plasma

Wiman, Björn; Almquist, Å.; Sigurðardóttir, Ólöf; Lindahl, Tomas

doi:10.1016/0014-5793(88)80999-2

Cited by 170 publications

(82 citation statements)

References 14 publications

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“…3). Results from mass spectroscopic analyses of all peptide fragments generated were consistent with enzyme specificities and the disulfide connectivity, Cys 5 (Table 1). Second, sSMB-2 and sSMB-4 were functionally indistinguishable with respect to PAI-1 binding.…”

Section: Resultssupporting

confidence: 55%

“…Many regulatory functions of vitronectin result from its ability to interact with plasminogen activator inhibitor 1 (PAI-1), 2 a member of the serine protease inhibitor superfamily that inhibits both tissue-and urinary-type plasminogen activators (3)(4)(5)(6). PAI-1 plays important roles in thrombosis and fibrinolysis and has been implicated in hemostasis, angiogenesis, and tumor metastasis (7)(8)(9)(10)(11).…”

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confidence: 99%

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Defining the Native Disulfide Topology in the Somatomedin B Domain of Human Vitronectin

Zou

Yuan

et al. 2007

Journal of Biological Chemistry

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The N-terminal 44 amino acid residues of the human plasma glycoprotein vitronectin, known as the somatomedin B (SMB) domain, mediates the interaction between vitronectin and plasminogen activator inhibitor 1 (PAI-1) in a variety of important biological processes. Despite the functional importance of the Cys-rich SMB domain, how its four disulfide bridges are arranged in the molecule remains highly controversial, as evidenced by three different disulfide connectivities reported by several laboratories. Using native chemical ligation and orthogonal protection of selected Cys residues, we chemically synthesized all three topological analogs of SMB with predefined disulfide connectivities corresponding to those previously published. In addition, we oxidatively folded a fully reduced SMB in aqueous solution, and prepared, by CNBr cleavage, the N-terminal segment of 51 amino acid residues of intact vitronectin purified from human blood. Proteolysis coupled with mass spectrometric analysis and functional characterization using a surface plasmon resonance based vitronectin-PAI-1-SMB competition assay allowed us to conclude that 1) only the Vitronectin is a multidomain plasma glycoprotein involved in a variety of biological processes such as cell adhesion, cell migration, modulation of the immune system, and regulation of blood coagulation and fibrinolysis (1, 2). Many regulatory functions of vitronectin result from its ability to interact with plasminogen activator inhibitor 1 (PAI-1), 2 a member of the serine protease inhibitor superfamily that inhibits both tissue-and urinary-type plasminogen activators (3-6). PAI-1 plays important roles in thrombosis and fibrinolysis and has been implicated in hemostasis, angiogenesis, and tumor metastasis (7-11). Low abundant PAI-1 circulates in blood complexed with vitronectin (12); unliganded PAI-1 undergoes rapid "selfinactivation" into an inactive "latent" form in which the inhibitory reactive-site loop inserts as a new strand into the main ␤-sheet of the molecule (13-15). Ample evidence suggests that vitronectin regulates the activity of PAI-1 and PAI-1-mediated cellular events by stabilizing the active form of the inhibitor and delaying its conformational transition to the latent state (16 -18). Conversely, PAI-1 mediates, via binding, vitronectin-dependent cell adhesion and migration (19 -23). Thus, molecular recognition between vitronectin and PAI-1 is of great importance in biology.Loskutoff and colleagues (24 -27) first pinpointed a high affinity PAI-1-binding site in vitronectin to the N-terminal somatomedin B (SMB) domain of the adhesive glycoprotein. The SMB domain consists of 44 amino acid residues (28 -31), including eight conserved cysteines that form four functionally indispensable intramolecular disulfide bridges (24). Kamikubo et al. (32) reported that an N-terminal fragment of VN of 97 amino acid residues, expressed in the cytoplasm of Escherichia coli and purified by immuno-affinity chromatography, showed activity in PAI-1 binding and antibody recognition simi...

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Section: Resultssupporting

confidence: 55%

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confidence: 99%

Defining the Native Disulfide Topology in the Somatomedin B Domain of Human Vitronectin

Zou

Yuan

et al. 2007

Journal of Biological Chemistry

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“…Free active PAI-1 spontaneously decays into an inactive 'latent' form when in solution in the test tube, or following its secretion in cell culture medium [45]. However, its inhibitory activity is stabilized and prolonged by binding to vitronectin present in plasma, platelets, and ECM [46][47][48]. The high affinity between vitronectin and PAI-1 raises the possibility that vitronectin may concentrate and localize PAI-1 inhibitory activity to specific tissue areas.…”

Section: Physiological Inhibitors Of the Plasminogen Systemmentioning

confidence: 99%

Role of plasminogen activator-plasmin system in tumor angiogenesis

Rakic¹,

Maillard²,

Jost³

et al. 2003

Cellular and Molecular Life Sciences (CMLS)

119

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New blood formation or angiogenesis has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization. Angiogenesis is associated with important extracellular remodeling involving different proteolytic systems among which the plasminogen system plays an essential role. It belongs to the large serine proteinase family and can act directly or indirectly by activating matrix metalloproteinases or by liberating growth factors and cytokines sequestered within the extracellular matrix. Migration of endothelial cells is associated with significant upregulation of proteolysis and conversely, immunoneutralization or chemical inhibition of the system reduces angiogenesis in vitro. On the other hand genetically altered mice developed normally without overt vascular anomalies indicating the possibility of compensation by other proteases in vivo. Nevertheless, they have in some experimental settings revealed unanticipated roles for previously characterized proteinases or their inhibitors. In this review, the complex mechanisms of action of the serine proteases in pathological angiogenesis are summarized alongside possible therapeutic applications.

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“…Levels of the oligomeric forms of vitronectin in serum relative to plasma also increase; indicating the process of coagulation alters vitronectin structure and function (10 -12, 14). The altered, oligomeric form of vitronectin is generated, at least in part, by interactions with other plasma proteins such as thrombin-antithrombin complexes (11, 12, 14, 15, and complement C5b-9 complexes (11, 12, 16).A portion of vitronectin in plasma (17,18), and in platelets is complexed with type 1 plasminogen activator inhibitor (PAI-1) 1 (8,9,19), an interaction that induces the formation of higher order complexes (4,5,20,21) and influences the structure and function of both PAI-1 and vitronectin. Thus, when bound to vitronectin, PAI-1 is stabilized in its active conformation (22, 23), and thrombin is more readily inactivated by PAI-1 (24).…”

mentioning

confidence: 99%

“…A portion of vitronectin in plasma (17,18), and in platelets is complexed with type 1 plasminogen activator inhibitor (PAI-1) 1 (8,9,19), an interaction that induces the formation of higher order complexes (4,5,20,21) and influences the structure and function of both PAI-1 and vitronectin. Thus, when bound to vitronectin, PAI-1 is stabilized in its active conformation (22,23), and thrombin is more readily inactivated by PAI-1 (24).…”

mentioning

confidence: 99%

Incorporation of Vitronectin into Fibrin Clots

Podor¹,

Campbell²,

Chindemi³

et al. 2002

Journal of Biological Chemistry

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19788 -19794). The current studies were undertaken to further examine the interactions between vitronectin and fibrin(ogen). Comparison of vitronectin levels in plasma with those in serum indicates that ϳ20% of plasma vitronectin is incorporated into the clot. When the time course of biotinylated-vitronectin incorporation into clots formed from 125 I-fibrinogen is monitored, vitronectin incorporation into the clot parallels that of fibrinogen in the absence or presence of activated factor XIII. Vitronectin binds specifically to fibrin matrices with an estimated K d of ϳ0.6 M. Additional vitronectin subunits are assembled on fibrin-bound vitronectin multimers through self-association. Confocal microscopy of fibrin clots reveals the globular vitronectin aggregates anchored at intervals along the fibrin fibrils. This periodicity raised the possibility that vitronectin interacts with the ␥A/␥ variant of fibrin(ogen) that represents about 10% of total fibrinogen. In support of this concept, the vitronectin which contaminates fibrinogen preparations co-purifies with the ␥A/␥ fibrinogen fraction, and clots formed from ␥A/␥ fibrinogen preferentially bind vitronectin. These studies reveal that vitronectin associates with fibrin during coagulation, and may thereby modulate hemostasis and inflammation.Vitronectin is a multifunctional plasma glycoprotein that participates in the regulation of coagulation, fibrinolysis, and the complement cascade (reviewed in Refs. 1 and 2). Vitronectin also regulates cell adhesion and pericellular proteolysis on surfaces of cells and extracellular matrices (1-5). Like fibrinogen, vitronectin is found in plasma at micromolar concentrations (6), and is stored in megakaryocyte and platelet ␣-granules (7-9). In plasma, vitronectin circulates as a native, monomeric form that is a mixture of 72-kDa single-chain and two-chain disulfide-linked species (10 -12). Under normal conditions, less than 3% of plasma vitronectin is comprised of more reactive oligomeric forms that display enhanced affinity for heparin or heparin-like molecules, and for the conformationsensitive monoclonal antibody 8E6 (10 -12).During acute phase response, plasma vitronectin levels increase (6), with a relative increase in the percentage of oligomeric vitronectin (13). Levels of the oligomeric forms of vitronectin in serum relative to plasma also increase; indicating the process of coagulation alters vitronectin structure and function (10 -12, 14). The altered, oligomeric form of vitronectin is generated, at least in part, by interactions with other plasma proteins such as thrombin-antithrombin complexes (11, 12, 14, 15, and complement C5b-9 complexes (11, 12, 16).A portion of vitronectin in plasma (17,18), and in platelets is complexed with type 1 plasminogen activator inhibitor (PAI-1) 1 (8,9,19), an interaction that induces the formation of higher order complexes (4,5,20,21) and influences the structure and function of both PAI-1 and vitronectin. Thus, when bound to vitronectin, PAI-1 is stabilized in its active conforma...

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Plasminogen activator inhibitor 1 (PAI) is bound to vitronectin in plasma

Cited by 170 publications

References 14 publications

Defining the Native Disulfide Topology in the Somatomedin B Domain of Human Vitronectin

Defining the Native Disulfide Topology in the Somatomedin B Domain of Human Vitronectin

Role of plasminogen activator-plasmin system in tumor angiogenesis

Incorporation of Vitronectin into Fibrin Clots

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