scholarly journals Tissue plasminogen activator is a ligand of cation-independent mannose 6-phosphate receptor and consists of glycoforms that contain mannose 6-phosphate

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
James J. Miller ◽  
Richard N. Bohnsack ◽  
Linda J. Olson ◽  
Mayumi Ishihara ◽  
Kazuhiro Aoki ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Dependent Manner ◽  
Plasminogen Activation ◽  
Urokinase Plasminogen Activator Receptor ◽  
Plasminogen Activation System ◽  
Extracellular Region ◽  
Glycosylation Sites ◽  
Tissue Plasminogen ◽  
Mannose 6 Phosphate

AbstractPlasmin is the key enzyme in fibrinolysis. Upon interaction with plasminogen activators, the zymogen plasminogen is converted to active plasmin. Some studies indicate plasminogen activation is regulated by cation-independent mannose 6-phosphate receptor (CI-MPR), a protein that facilitates lysosomal enzyme trafficking and insulin-like growth factor 2 downregulation. Plasminogen regulation may be accomplished by CI-MPR binding to plasminogen or urokinase plasminogen activator receptor. We asked whether other members of the plasminogen activation system, such as tissue plasminogen activator (tPA), also interact with CI-MPR. Because tPA is a glycoprotein with three N-linked glycosylation sites, we hypothesized that tPA contains mannose 6-phosphate (M6P) and binds CI-MPR in a M6P-dependent manner. Using surface plasmon resonance, we found that two sources of tPA bound the extracellular region of human and bovine CI-MPR with low-mid nanomolar affinities. Binding was partially inhibited with phosphatase treatment or M6P. Subsequent studies revealed that the five N-terminal domains of CI-MPR were sufficient for tPA binding, and this interaction was also partially mediated by M6P. The three glycosylation sites of tPA were analyzed by mass spectrometry, and glycoforms containing M6P and M6P-N-acetylglucosamine were identified at position N448 of tPA. In summary, we found that tPA contains M6P and is a CI-MPR ligand.

Enhancement of Tissue Plasminogen Activator-Catalyzed Plasminogen Activation by Escherichia coii S Fimbriae Associated with Neonatal Septicaemia and Meningitis

1991 ◽  
Vol 65 (05) ◽  
pp. 483-486 ◽  
Author(s):  
Jaakko Parkkinen ◽  
Jörg Hacker ◽  
Timo K Korhonen
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Surface Protein ◽  
Protein S ◽  
Aminocaproic Acid ◽  
Bacterial Invasion ◽  
Dependent Manner ◽  
Plasminogen Activation ◽  
Plasmin Activity ◽  
Tissue Plasminogen

SummaryThe effect of Escherichia coli strains isolated from blood and cerebrospinal fluid of septic infants on plasminogen activation was studied. These strains typically carry a filamentous surface protein, S fimbria, that has formerly been shown to bind to endothelial cells and interact with plasminogen. The bacteria effectively promoted plasminogen activation by tissue plasminogen activator (t-PA) which was inhibited by s-aminocaproic acid. A recombinant strain expressing S fimbriae accelerated t-PA-catalyzed plasminogen activation to a similar extent as did the wild-type strains whereas the nonfimbriate recipient strain had no effect. After incubation with t-PA and plasminogen, the S-fimbriate strain displayed bacterium-bound plasmin activity whereas the nonfimbriate strain did not. Bacterium-associated plasmin generation was also observed with a strain expressing mutagenized S fimbriae that lack the cell-binding subunit SfaS but not with a strain lacking the major subunit SfaA. Both t-PA and plasminogen bound to purified S fimbriae in a lysine-dependent manner and purified S fimbriae accelerated t-PA-catalyzed plasminogen activation. The results indicate that E. coli S fimbriae form a complex with t-PA and plasminogen which enhances the rate of plasminogen activation and generates bacterium-bound plasmin. This may promote bacterial invasion and persistence in tissues and contribute to the systemic activation of fibrinolysis in septicaemia.

Cellular mechanisms regulating non-haemostatic plasmin generation

2002 ◽  
Vol 30 (2) ◽  
pp. 189-194 ◽  
Author(s):  
R. Bass ◽  
V. Ellis
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Serine Proteases ◽  
Transmembrane Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Plasminogen Activation ◽  
Cellular Mechanisms ◽  
Spongiform Encephalopathies ◽  
Plasminogen Activation System ◽  
Tissue Plasminogen

A variety of proteases have the potential to degrade the extracellular matrix (ECM), thereby influencing the behaviour of cells by removing physical barriers to cell migration, altering cell-ECM interactions or releasing ECM-associated growth factors. The plasminogen activation system of serine proteases is particularly implicated in this pericellular proteolysis and is involved in pathologies ranging from cancer invasion and metastasis to fibroproliferative vascular disorders and neurodegeneration. A central mechanism for regulating plasmin generation is through the binding of the two plasminogen activators to specific cellular receptors: urokinase-type plasminogen activator to the glycolipid-anchored membrane protein uPAR, and tissue plasminogen activator to a type-II transmembrane protein recently identified on vascular smooth muscle cells. These binary complexes interact with membrane-associated plasminogen to form higher order activation complexes that greatly reduce the Km for plasminogen activation and, in some cases, protect the proteases from their cognate serpin inhibitors. Various other proteins that are involved in cell adhesion and migration also interact with these complexes, modulating the activity of this efficient and spatially restricted proteolytic system. Recent observations demonstrate that certain forms of the prion protein can stimulate tissue plasminogen activator-catalysed plasminogen activation, which raises the possibility that these proteases may also have a role in the pathogenesis of the transmissible spongiform encephalopathies.

The potentiating effect of platelet on plasminogen activation by tissue plasminogen activator

1985 ◽  
Vol 40 (6) ◽  
pp. 853-861 ◽  
Author(s):  
K. Deguchi ◽  
S. Murashima ◽  
S. Shirakawa ◽  
C. Soria ◽  
J. Soria ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Plasminogen Activation ◽  
Tissue Plasminogen

scholarly journals β2-glycoprotein i is a cofactor for tissue plasminogen activator-mediated plasminogen activation

2009 ◽  
Vol 60 (2) ◽  
pp. 559-568 ◽  
Author(s):  
Chunya Bu ◽  
Lei Gao ◽  
Weidong Xie ◽  
Jainwei Zhang ◽  
Yuhong He ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Plasminogen Activation ◽  
Glycoprotein I ◽  
Tissue Plasminogen

scholarly journals The cartilage-specific lectin C-type lectin domain family 3 member A (CLEC3A) enhances tissue plasminogen activator–mediated plasminogen activation

2017 ◽  
Vol 293 (1) ◽  
pp. 203-214 ◽  
Author(s):  
Daniela Lau ◽  
Dzemal Elezagic ◽  
Gabriele Hermes ◽  
Matthias Mörgelin ◽  
Alexander P. Wohl ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Plasminogen Activation ◽  
Domain Family ◽  
Lectin Domain ◽  
Tissue Plasminogen

Kinetics Of Plasminogen Activation By Tissue Plasminogen Activator. Role Of Fibrin

1981 ◽  
Author(s):  
M Hoylaerts ◽  
D C Rijken ◽  
H R Lijnen ◽  
D Collen
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Catalytic Efficiency ◽  
Reaction Scheme ◽  
Plasminogen Activation ◽  
Catalytic Rate Constant ◽  
Activation Rate ◽  
Tissue Plasminogen ◽  
Human Plasminogen ◽  
Straight Lines

The activation of human plasminogen (P) by two-chain tissue plasminogen activator (A) was studied in the presence of fibrin films (F) of increasing size and surface density. Initial rates of plasminogen activation (v) were determined as a function both of the plasminogen and fibrin concentration. The activation rate was strongly dependent on the presence of fibrin and plots of 1/v versus 1/ [p] or 1 /[F] yielded straight lines. The kinetic data were in agreement with the following reaction scheme.According to this model tissue plasminogen activator would bind to fibrin with a dissociation constant (KF of 0.2 µM and this complex fixes plasminogen with a Michaelis constant (Kp’) of 0.15 µM (Glu-plasminogen) or 0.02 µM (Lys-plasminogen) to form a ternary complex, converted to plasmin with a catalytic rate constant kcat = 0.05 s-1. This mechanism implies that both plasminogen and tissue plasminogen activator are concentrated on the fibrin surface through formation of a fibrin bridge. Activation of plasminogen in the absence of fibrin occurs with Km = 65 µM (Glu-plasminogen) or Km= 19 µM (Lys-plasminogen) and kcat = 0.05 s-1. Our data suggest that fibrin enhances the activation rate of plasminogen by tissue plasminogen activator by increasing the affinity of plasminogen for fibrin-bound tissue plasminogen activator and not by influencing the catalytic efficiency of the enzµMe. These data also support the hypothesis that fibrinolysis is both triggered by and directed towards fibrin.Generated plasmin was quantitated by measuring the rate of solubilization of 125I-labeled fibrin.

Absence of specific cell-surface binding of tissue plasminogen activator in uterine cells

1990 ◽  
Vol 5 (1) ◽  
pp. 7-14 ◽  
Author(s):  
M. Ayub ◽  
N. Jenkins ◽  
J. O. White
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Carcinoma Cells ◽  
Scatchard Analysis ◽  
Specific Cell ◽  
Dependent Manner ◽  
Surface Binding ◽  
Tissue Plasminogen ◽  
Liver Membranes ◽  
Fold Excess

ABSTRACT Tissue plasminogen activator (tPA), an arginine-specific serine protease, is an oestrogen-regulated protein in uterine and breast cancer tissue. It contains a domain which shares homology with epidermal growth factor (EGF). The aim of the present study was to determine whether specific tPA receptors or EGF receptors mediate the binding of tPA to cells and whether tPA possesses intrinsic mitogenic activity. The binding of 125I-labelled tPA to rat uterine and liver membranes was shown to be non-specific and could not be displaced by unlabelled tPA or EGF. Furthermore, acid washing of cell membranes did not unmask specific tPA-binding sites. In contrast, 125I-labelled EGF binding to both rat uterine and liver membranes was displaced in a dose-dependent manner by unlabelled EGF, and Scatchard analysis of the binding data revealed dissociation constant (Kd) values of 2·4 and 0·71 nm respectively. Unlabelled tPA (up to 20 000-fold excess) did not displace 125I-labelled EGF binding to these membranes. A study of the binding of 125I-labelled tPA and 125I-labelled EGF to endometrial carcinoma cells (Ishikawa), cervical carcinoma cells (HOG-1) and vulval carcinoma cells (A431) showed that up to a 100-fold excess of EGF or a 1000-fold excess of tPA did not displace 125I-labelled tPA binding to these cells. In contrast, 125I-labelled EGF binding was displaced by unlabelled EGF (Kd values for Ishikawa and HOG-1 cells were 2·72 and 1·92 nm respectively) but not by unlabelled tPA (1000-fold excess). Treatment of Ishikawa and HOG-1 cells with EGF (20 ng/ml) for up to 6 days stimulated [3H]thymidine incorporation 1·3- to 2-fold and 3·5- to 4·7-fold respectively. Human recombinant tPA (10 IU/ml) was without effect on both cell lines over 6 days of treatment. It was concluded that although tPA contains an EGF-like domain it does not bind specifically to membrane preparations from rat uterine or liver cells or to cultured uterine cancer cells, and does not displace bound 125I-labelled EGF. Furthermore, tPA does not have mitogenic properties similar to those of EGF.

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