Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P00750 (PLA)
16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over the past decade, the existence of cell-surface receptors for components of the plasminogen system, t-PA, u-PA, plasminogen and plasmin, has been demonstrated. Plasminogen receptors have been detected on virtually all cell types tested, and occupancy has also been demonstrated in biological settings. Characteristic features of plasminogen receptors include their relatively low affinity and their extraordinarily high density on many cells. These receptors recognize the lysine binding sites associated with the kringles of plasminogen. Plasminogen receptors include proteins with carboxyl-terminal lysine residues (enolase and annexin II are representatives) and nonproteins, such as gangliosides. Plasminogen binding to cells enhances plasmin activity by augmenting plasminogen activation, increasing the enzymatic activity of plasmin, and protecting plasmin for inactivation by inhibitors. t-PA receptors serve two major functions, clearance and cell-surface localization. The liver is the main organ for t-PA clearance; parenchymal, endothelial and Kupffer cells are all capable of t-PA uptake. Clearance receptors on these cells are heterogeneous and include ones which recognize the carbohydrate side chains of t-PA and ones which take up t-PA: PAI-1 complexes. Receptors which recognize free t-PA also mediate liver clearance, and alpha 2-MR/LRP is a representative of this latter category. Receptors that localize t-PA on cell surfaces serve a profibrinolytic function. Vascular endothelial cells are rich in such receptors, and annexin II is a representative of these t-PA binding sites. Circulating blood cells also bind t-PA, and some of the sites on these cells are shared with plasminogen. Cells of neuronal origin are capable of binding t-PA with high affinity; and amphoterin, a protein involved in neurite outgrowth, may be a neuronal t-PA receptor. Overall, the plasminogen system is one of the most widely distributed and versatile of the cell surface-proteinase systems. By activating bound plasminogen by cell-bound plasminogen activators, the cell harnesses the broad proteolytic activity of plasmin. Cells can then utilize this activity to perform functions such as assisting in cell migration.
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PMID:Receptors for plasminogen and t-PA: an update. 754 65

Sequencing of two internal peptides from the putative human endothelial cell tissue plasminogen activator (t-PA) receptor identified an analog of the calcium- and phospholipid-binding protein, annexin II (Ann-II). The polymerase chain reaction-derived, full-length cDNA revealed complete sequence identity with the heavy chain of Ann-II, and ligand-precipitated receptor protein immunoreacted specifically with a monoclonal antibody to Ann-II. Transfected 293 cells bound plasminogen (Kd = 114 nM; Bmax = 347,000) as well as t-PA (Kd = 48 nM; Bmax = 380,000). Antisense oligonucleotides directed against endothelial cell Ann-II mRNA inhibited binding of both t-PA and plasminogen by 49% and 38%, respectively. The K307T mutant of Ann-II expressed on 293 cells failed to bind plasminogen, while the K328I mutant bound this ligand in a manner equivalent to the wild-type. Binding of plasminogen to both the wild-type and the K328I mutant was blocked by pretreatment of 293 cells with carboxypeptidase B. These data suggest a novel mechanism whereby a plasmin-like serine protease may cleave Ann-II at Lys307-Arg308, exposing a new carboxyl-terminal lysine residue (Lys307) for binding and efficient activation of plasminogen.
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PMID:An endothelial cell receptor for plasminogen/tissue plasminogen activator. I. Identity with annexin II. 806 40

In the preceding paper (Hajjar, K. A., Jacovina, A. T., and Chacko, J. (1994) J. Biol. Chem. 269, 21191-21197), we identified a M(r) = 40,000 endothelial cell receptor for tissue plasminogen activator (t-PA) and plasminogen (PLG) as the calcium- and phospholipid-binding protein, annexin II (Ann-II). Here, we examined the effect of Ann-II on t-PA-dependent plasminogen activation in a purified system. Purified native Ann-II bound t-PA, plasminogen, and plasmin with high affinity (Kd = 25 nM, 161 nM, and 75 nM, respectively). At fixed plasminogen concentrations, preincubation with purified native Ann-II was associated with an approximately 21-fold increase in the rate of Glu-PLG activation and an approximately 14-fold increase in activation of Lys-PLG. Three irrelevant proteins had no effect on plasmin formation, while fibrinogen increased the rate of Glu-PLG activation by approximately 4-fold. Annexin-II-mediated enhancement of t-PA-dependent plasminogen activation was 90-95% inhibited by epsilon-aminocaproic acid or by pretreatment of Ann-II with carboxypeptidase B, indicating a carboxyl-terminal lysine-dependent interaction. Kinetic analyses revealed that Ann-II conferred an approximately 60-fold increase in catalytic efficiency upon t-PA-dependent activation of either Glu-PLG or Lys-PLG. Thus, Ann-II-mediated assembly of plasminogen and t-PA may promote and localize constitutive plasmin generation on the surface of the blood vessel wall.
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PMID:An endothelial cell receptor for plasminogen/tissue plasminogen activator (t-PA). II. Annexin II-mediated enhancement of t-PA-dependent plasminogen activation. 806 41

Endothelial cells express a cell surface co-receptor for plasminogen and tissue plasminogen activator (t-PA) which we recently identified as annexin II (Hajjar, K. A., Jacovina, A. T., and Chacko, J. (1994) J. Biol. Chem. 269, 21191-21197). This protein enhances the catalytic efficiency of t-PA-dependent plasmin generation by 60-fold (Cesarman, G. M., Guevara, C. A., and Hajjar, K. A. (1994) J. Biol. Chem. 269, 21198-21203). Here, we demonstrate that annexin II is constitutively translocated to the endothelial cell surface within 16 h of biosynthesis, and that cell surface annexin II comprises 4.3 +/- 1.0% of the total cellular pool. Exogenous 125I-annexin II bound to EGTA-washed endothelial cells with high affinity (Kd 49 nM) and in a calcium-dependent (I50 = 3 microM), phospholipid-sensitive manner. Peptides KASMKGLGTDED and YDSMKGKGTRDK, mimicking the calcium-binding "endonexin" motif (KGXGT) of annexin II, blocked its interaction with endothelial cells. Recombinant annexin II, bearing the calcium-binding site substitution D161A of core repeat 2, failed to compete with binding of the wild type protein to the cell surface, while E246A and D321A mutants, corresponding to core repeats 3 and 4, behaved as effective competitors. These data suggest that translocated annexin II interacts with cell surface phospholipid via a high affinity calcium-dependent binding site that includes residues 118-122 (KGLGT) and the coordinating Asp161 of core repeat 2. Thus, calcium-regulated expression of annexin II on the endothelial cell surface may play a central role in control of plasmin-mediated processes.
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PMID:Interaction of the fibrinolytic receptor, annexin II, with the endothelial cell surface. Essential role of endonexin repeat 2. 870 54

We demonstrated previously that tissue-type plasminogen activator (t-PA) bound to its specific receptor (t-PAR) on human umbilical vein endothelial cells (HUVEC) in suspension and that t-PAR of mol wt. 20 kDa interacted only with t-PA to form 90 kDa complex (Fukao, H., Hagiya, Y., Nonaka, T., Okada, K., and Matsuo, O. (1992) Biochem. Biophys. Res. Commun. 187, 956-962). In the present study, 20 kDa t-PAR was purified from HUVEC and the function of the t-PAR was investigated by analyzing its effect on plasminogen activation by t-PA. About 2.2 microg t-PAR protein was purified from cell lysate of 1.0 X 10(9) HUVEC as a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) by gel filtration with TSK-3000SW and reversed phase separation with high performance liquid chromatography (HPLC). 125I-t-PA but not 125I-plasminogen specifically bound to the purified t-PAR in ligand blot assay. Plasminogen activation by t-PA in the presence of purified t-PAR in solution was increased. Furthermore, t-PA bound to immobilized t-PAR efficiently expressed its plasminogen activation activity. Kinetic analysis revealed that t-PA in the presence of soluble t-PAR and t-PA bound to immobilized t-PAR exhibited 34- and 90-fold increase in plasminogen activation, respectively. The t-PAR did not interact with anti-annexin II antibody. These findings indicate that the 20 kDa t-PAR is a novel molecule which immobilizes t-PA and enhances its proteolytic activity on the cell surface of endothelial cells.
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PMID:Enhancement of tissue-type plasminogen activator (t-PA) activity by purified t-PA receptor expressed in human endothelial cells. 909 97

In this paper, we have characterized the regulation of plasmin activity by annexin II tetramer (AIIt). Plasmin activity was measured by a fibrin lysis assay in which a fibrin polymer was produced from purified components and the extent of polymer lysis was determined by following changes in turbidity. Extrinsic lysis of the fibrin polymer, initiated by addition of tissue plasminogen activator (t-PA), was totally blocked if AIIt was present during fibrin polymer formation. Furthermore, fibrin polymer formed in the presence of AIIt was resistant to extrinsic lysis initiated by addition of plasmin. AIIt bound to fibrin polymer under conditions in which polymer lysis was inhibited. Plasmin-dependent extrinsic lysis of the fibrin polymer was also blocked if AIIt was present in the incubation medium, and under these conditions the amidolytic activity of plasmin, measured with an artificial substrate, was inhibited about 5-fold. In contrast, in the absence of fibrin, and at an AIIt/plasmin molar ratio of 526, the amidolytic activity of plasmin was inhibited by only 22.3% +/- 7.4% (mean +/- SD, n = 5) by AIIt. Plasmin-dependent fibrinolysis was only slightly inhibited if fibrin polymer was formed in the presence of annexins I, II, V, or VI. These results identify AIIt as an in vitro regulator of plasmin activity.
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PMID:Annexin II tetramer inhibits plasmin-dependent fibrinolysis. 942 87

Annexin II tetramer (AIIt) is a major Ca2+-binding protein of endothelial cells which has been shown to exist on both the intracellular and extracellular surfaces of the plasma membrane. In this report, we demonstrate that AIIt stimulates the activation of plasminogen by facilitating the tissue plasminogen activator (t-PA)-dependent conversion of plasminogen to plasmin. Fluid-phase AIIt stimulated the rate of activation of [Glu]plasminogen about 341-fold compared with an approximate 6-fold stimulation by annexin II. AIIt bound to [Glu]plasminogen(S741C-fluorescein) with a Kd of 1. 26 +/- 0.04 microM (mean +/- S.D., n = 3) and this interaction resulted in a large conformational change in [Glu]plasminogen. Kinetic analysis established that AIIt produces a large increase of about 190-fold in the kcat, app and a small increase in the Km,app which resulted in a 90-fold increase in the catalytic efficiency (kcat/Km) of t-PA for [Glu]plasminogen. AIIt also stimulated the t-PA-dependent activation of [Lys]plasminogen about 28-fold. Furthermore, other annexins such as annexin I, V, or VI did not produce comparable activation of t-PA-dependent conversion of [Glu]plasminogen to plasmin. The stimulation of the activation of [Glu]plasminogen by AIIt was Ca2+-independent and inhibited by epsilon-aminocaproic acid. AIIt bound to human 293 cells potentiated t-PA-dependent plasminogen activation. AIIt that was bound to phospholipid vesicles or heparin also stimulated the activation of [Glu]plasminogen 5- or 11-fold, respectively. Furthermore, immunofluorescence labeling of nonpermeabilized HUVEC revealed a punctated distribution of AIIt subunits on the cell surface. These results therefore identify AIIt as a potent in vitro activator of plasminogen.
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PMID:The role of annexin II tetramer in the activation of plasminogen. 946 44

Recent evidence indicates a potential role for the plasmin/plasminogen activator system in the prevention of atherosclerotic vascular disease. Fibrin deposition is a common histologic feature of the tissues of mice that are genetically deficient in one or more key components of the fibrinolytic system. Cell surface receptors may support fibrinolytic surveillance in both intravascular and extravascular locations by stimulating the efficiency plasmin generation and by protecting plasmin from its inhibitors. In vitro studies suggest that the endothelial cell receptor, annexin II, which independently binds both plasminogen and t-PA, could play a key role in the process. Binding of plasminogen to annexin II is specifically inhibited in the presence of excess concentrations of the atherogenic LDL-like particle Lp(a). Similarly, t-PA binding to annexin II is blocked by homocysteine, a sulfhydryl-containing amino acid that is associated with atherogenesis and that directly derivatizes the t-PA binding domain of annexin II. Elucidation of the precise role of annexin II in fibrinolytic surveillance, however, will await in vivo study.
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PMID:Modulation of annexin II by homocysteine: implications for atherothrombosis. 980 20

Annexin II tetramer (AIIt) is an important endothelial cell surface protein receptor for plasminogen and t-PA. AIIt, a heterotetramer, is composed of two p36 subunits (called annexin II) and two p11 subunits. In this report, we have compared the ability of the isolated p36 and p11 subunits to stimulate t-PA-dependent [Glu]plasminogen activation. The fluid-phase recombinant p11 subunit stimulated the rate of t-PA-dependent activation of [Glu]plasminogen about 46-fold compared to an approximate stimulation of 2-fold by the recombinant p36 subunit and 77-fold by recombinant AIIt. The stimulation of t-PA-dependent activation of [Glu]plasminogen by the p11 subunit was Ca2+-independent and inhibited by epsilon-aminocaproic acid. [Glu]Plasminogen bound to a p11 subunit affinity column and could be eluted with epsilon-aminocaproic acid. Both AIIt and the p11 subunit protected t-PA and plasmin from inactivation by PAI-1 and alpha2-antiplasmin, respectively. A peptide to the C terminus of the p11 subunit (85-Y-F-V-V-H-M-K-Q-K-G-K-K-96) inhibited the p11-dependent stimulation of t-PA-dependent plasminogen activation. In addition, a deletion mutant of the p11 subunit, missing the last two C-terminal lysine residues, retained only about 15% of the activity of the wild-type p11 subunit. Similarly, a mutant AIIt composed of the wild-type p36 subunit and the p11 subunit deletion mutant possessed about 12% of the wild-type activity. These results, therefore, suggest that the C-terminal lysine residues of the p11 subunit bind plasminogen and participate in the stimulation of t-PA-dependent activation of plasminogen by AIIt.
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PMID:The p11 subunit of the annexin II tetramer plays a key role in the stimulation of t-PA-dependent plasminogen activation. 983 89

The plasminogen activator system consists of two proteins: tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), which act upon their specific receptors to generate plasmin from plasminogen located on the cell surface. Plasmin then acts directly and indirectly to degrade the components of the extracellular matrix (ECM). This process is likely to be important in the normal turnover of the ECM of fetal membranes and in its premature weakening in preterm premature rupture of the fetal membranes. Quantitative Northern analysis and in situ hybridization have shown that the decidua expresses mRNA for tPA. However, the immunolocalized tPA protein was most strongly associated with the amnion and chorion, as was its receptor annexin II, suggesting that the amnion and chorion are the targets for decidual tPA. At term, decidual tPA expression was unaffected by labor, and the tPA receptor was elevated both before and after labor. At preterm, the converse was found: decidual tPA expression was significantly (p < 0. 05) up-regulated by labor, but the tPA receptor was not. The results suggest that the generation of plasmin at term would be controlled by an increased concentration of the tPA receptor in the amnion and chorion, whereas at preterm a pathological increase in plasmin would be generated by an overexpression of tPA, initiated by labor.
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PMID:Tissue plasminogen activator and its receptor in the human amnion, chorion, and decidua at preterm and term. 1008 78


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