Tissue Plasminogen Activator is Endocytosed by Mannose and Galactose Receptors of Rat Liver Cells

Smedsrød, Bård; Einarsson, Monica; Pertoft, Håkan

doi:10.1055/s-0038-1647519

Cited by 78 publications

(59 citation statements)

References 11 publications

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“…Furthermore, mannose residues also seem to play an important role in endocytosis since we observed a significant reduction in hepatic distribution and uptake after deglycosylation. Mannose recognition was probably mediated by specific receptors in hepatic and kidney cells as shown previously by other investigators who observed that the endocytosis of plasminogen-activating factor was mediated by mannose receptors on liver endothelium and by galactose receptors on parenchymal cells (23). Plasminogen-activating factor endocytosis was shown to be greater in endothelial cells (43), but it was practically absent in Kupffer cells.…”

Section: Discussionsupporting

confidence: 70%

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The renal and hepatic distribution of Bence Jones proteins depends on glycosylation: a scintigraphic study in rats

Prado¹,

Nicastri²,

Costa³

et al. 1997

Braz J Med Biol Res

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The aim of the present study was to evaluate renal and liver distribution of two monoclonal immunoglobulin light chains. The chains were purified individually from the urine of patients with multiple myeloma and characterized as lambda light chains with a molecular mass of 28 kDa. They were named BJg (high amount of galactose residues exposed) and BJs (sialic acid residues exposed) on the basis of carbohydrate content. A scintigraphic study was performed on male Wistar rats weighing 250 g for 60 min after iv administration of 1 mg of each protein (7.4 MBq), as the intact proteins and also after carbohydrate oxidation. Images were obtained with a Siemens gamma camera with a high-resolution collimator and processed with a MicroDelta system. Hepatic and renal distribution were established and are reported as percent of injected dose. Liver uptake of BJg was significantly higher than liver uptake of BJs (94.3 vs 81.4%) (P<0.05). This contributed to its greater removal from the intravascular compartment, and consequently lower kidney accumulation of BJg in comparison to BJs (5.7 vs 18.6%) (P<0.05). After carbohydrate oxidation, there was a decrease in hepatic accumulation of both proteins and consequently a higher renal overload. The tissue distribution of periodate-treated BJg was similar to that of native BJs: 82.7 vs 81.4% in the liver and 17.3 vs 18.6% in the kidneys. These observations indicate the important role of sugar residues of Bence Jones proteins for their recognition by specific membrane receptors, which leads to differential tissue accumulation and possible toxicity.

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Section: Discussionsupporting

confidence: 70%

“…Many investigators have shown that sugar residues interfere with the pattern of tubular reabsorption (19) (22). Endocytosis of plasminogenactivating factor is mediated by mannose receptors on endothelial cells rather than galactose receptors on parenchymal cells (23).…”

Section: Introductionmentioning

confidence: 99%

The renal and hepatic distribution of Bence Jones proteins depends on glycosylation: a scintigraphic study in rats

Prado¹,

Nicastri²,

Costa³

et al. 1997

Braz J Med Biol Res

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“…1 (45)(46)(47). To evaluate the potential role for a carbohydrate receptor in HepG2 clearance oft-PA, binding of 125I-t-PA was studied in the presence ofthree forms ofglycosylated albumin (Fig.…”

Section: Introductionmentioning

confidence: 99%

alpha-Fucose-mediated binding and degradation of tissue-type plasminogen activator by HepG2 cells.

Hajjar

Reynolds²

1994

J. Clin. Invest.

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The glycoprotein tissue-type plasminogen activator (t-PA) is subject to hepatic clearance in humans. Here, the interaction of t-PA with a well-differentiated hepatoma cell line (HepG2) was examined. Suspended HepG2 cells bound '25I-t-PA in a specific, saturable, and reversible fashion through a Ca2'-dependent, active site-independent mechanism. Binding isotherms indicated a high affinity system with a single class of saturable binding sites (Kd 39 nM; maximum binding capacity 493,000 sites per cell). Bound t-PA was rapidly degraded at 37°C in a manner inhibited by lysosomotropic agents or metabolic inhibitors. Pretreatment of t-PA with monoclonal antibodies against the EGF/fibronectin finger domain, but not kringle 2 or kringle 1, reduced total binding by 86%. Binding of 125i-t-PA to HepG2 cells was inhibited by monosaccharides fucose and galactose and by the neoglycoprotein fucosyl-albumin. Enzymatic removal of a-fucose residues, but not a-galactose, high mannose, or complex oligosaccharide from '25I-t-PA, reduced specific binding by 60±5%. Binding was also inhibited by high, but not low, molecular weight urokinase, which contains an EGF-based threonine-linked a-fucose homologous to that of t-PA. These data suggest that EGF-associated 0-linked a-fucose may mediate t-PA binding and degradation by HepG2 cells. This mechanism may be relevant to other proteins with analogous structures. (J. Clin. Invest. 1994. 93:703-710.)

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“…Although most studies have been made on the role of the sugar chain in the plasma clearance of t-PA, [22][23][24][25] little is known about the influence of the sugar chains on the fibrin affinity. In this study, we determined the influence of the sugar chain on the fibrin affinity using 4 kinds of t-PAs, which have differing sugar chain structures.…”

Section: )mentioning

confidence: 99%

“…21) This partial glycosylation results in t-PA being expressed as two major glycoforms, termed Type I and Type II, which are defined by the presence and absence of the complex type oligosaccharide at Asn184, respectively. Although most studies have been made on the role of the sugar chain in the plasma clearance of t-PA, [22][23][24][25] little is known about the influence of the sugar chains on the fibrin affinity. In this study, we determined the influence of the sugar chain on the fibrin affinity using 4 kinds of t-PAs, which have differing sugar chain structures.…”

mentioning

confidence: 99%

Influence of Sugar Chain on Fibrin Affinity of Recombinant t-PA.

Aoki¹,

Shimizu

Shimonishi

et al. 2001

Biological & Pharmaceutical Bulletin

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Tissue plasminogen activator (t-PA) is a serine protease that cleaves plasminogen into its active form, plasmin. The plasmin then subsequently degrades fibrin.1,2) The activity of t-PA is markedly stimulated in the presence of fibrin. 2)Human t-PA produced by recombinant DNA technology is presently available for clinical use in patients with acute myocardial infarction. [3][4][5] Although t-PA is thought to be clinically superior to streptokinase and urokinase because of its specific affinity for fibrin, the rapid clearance of t-PA from circulating blood sometimes requires the administration of high doses to obtain therapeutic blood levels, which can lead to bleeding incidents due to a decrease in plasma fibrinogen levels.6,7) To solve this problem, several types of mutant type t-PAs (mt-PAs) have been developed. [8][9][10][11][12][13][14] Although most of them are superior to wild type t-PA (WT t-PA) in terms of plasma half life, they are inferior to WT t-PA in terms of activity. They are generally produced by modification of the peptide chain, therefore, these modifications cause the loss of activity and fibrin affinity. [15][16][17] t-PA is composed of 5 domains: finger, epidermal growth factor (EGF)-like, kringle 1 and 2, and serine protease domain. All of them are assumed to be necessary for t-PA to exhibit physiological activity, especially the finger (F) and kringle 2 (K2) domains are indispensable for fibrin affinity. 18,19) In contrast, modification of the sugar chain is not expected to affect the function of each domain. t-PA is glycosylated at three sites, Asn117, Asn184, and Asn448. The sugar moiety at Asn117 carries a high mannose structure, whereas those at Asn184 and Asn448 carry complex type oligosaccharides.20) The Asn184 glycosylation site has been shown to be variably glycosylated by steric hindrance between the kringle 1 and 2 domains.21) This partial glycosylation results in t-PA being expressed as two major glycoforms, termed Type I and Type II, which are defined by the presence and absence of the complex type oligosaccharide at Asn184, respectively. Although most studies have been made on the role of the sugar chain in the plasma clearance of t-PA, [22][23][24][25] little is known about the influence of the sugar chains on the fibrin affinity. In this study, we determined the influence of the sugar chain on the fibrin affinity using 4 kinds of t-PAs, which have differing sugar chain structures.It has been reported that the binding of t-PA to fibrin is mediated by two discrete domains, the F and K2 domains. 26,27) Binding mediated through these domains can be distinguished on the basis of competition for fibrin binding by lysine analogues such as e-amino caproic acid (EACA), which eliminates K2 dependent binding, but does not eliminate F dependent binding. We also demonstrated the role of sugar chains in the fibrin affinity mediated via these domains one by one, using EACA in this study. MATERIALS AND METHODSChemicals Recombinant WT t-PA (lot R8803, 1.3 mg/ ml) and Gln117 t-PA (lot GYL013, ...

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Tissue Plasminogen Activator is Endocytosed by Mannose and Galactose Receptors of Rat Liver Cells

Cited by 78 publications

References 11 publications

The renal and hepatic distribution of Bence Jones proteins depends on glycosylation: a scintigraphic study in rats

The renal and hepatic distribution of Bence Jones proteins depends on glycosylation: a scintigraphic study in rats

alpha-Fucose-mediated binding and degradation of tissue-type plasminogen activator by HepG2 cells.

Influence of Sugar Chain on Fibrin Affinity of Recombinant t-PA.

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