| Regulation of the urokinase-type plasminogen activator receptor on vascular smooth muscle cells is under the control of thrombin and other mitogens. | |
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MedLine Citation:
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PMID: 1327097 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The urokinase-type plasminogen activator receptor (u-PAR) was demonstrated on cultured smooth muscle cells (SMCs) of bovine aorta. Binding of 125I-urokinase-type plasminogen activator (u-PA) was concentration dependent and saturable within 45-60 minutes. A similar concentration and time dependence was found in functional plasminogen activation studies. Human two-chain high-molecular-weight u-PA and its proenzyme (pro-u-PA) bound specifically with identical affinity (Kd). Activation of pro-u-PA was strongly accelerated on binding to SMCs and occurred only in the presence of plasminogen on the cell surface. A 100-fold molar excess of unlabeled high-molecular-weight u-PA effectively blocked binding of the radiolabeled ligands; tissue-type plasminogen activator, plasminogen, low-molecular-weight u-PA, and unrelated proteins did not. 125I-u-PA binding was abolished by a monoclonal antibody against the specific u-PA sequence responsible for u-PAR binding. Binding of u-PA sharply decreased on SMC exposure to phosphatidylinositol-specific phospholipase C, confirming the glycan phospholipid cell anchorage of u-PAR. Bovine and human alpha-thrombin (240 nM) increased the binding of 125I-u-PA fivefold, translating into an increase in the number of sites per cell from about 10(5) to 5 x 10(5) without significant change in the Kd (1.29 +/- 0.39 nM). Active site blockade of thrombin by D-Phe-Pro-Arg-chloromethyl ketone resulted in the total loss of stimulatory activity, as did the use of the inactive active site thrombin mutant, S205A. Hirugen (100 microM), which blocks the anion-binding exosite of thrombin, blocked u-PAR stimulating activity. Thus, both the catalytic activity and integrity of the exosite are important for thrombin's stimulatory activity. Other SMC mitogens (epidermal growth factor, transforming growth factor-beta 1, basic fibroblast growth factor, platelet-derived growth factor, and phorbol 12-myristate 13-acetate) increased u-PAR expression on SMCs six- to 20-fold while concomitantly increasing Kd four- to 10-fold. In all cases the induction of u-PAR was dependent on de novo protein synthesis. These observations assign a possible role for thrombin and other mitogens in u-PAR regulation, thereby influencing the pericellular proteolysis that is important in SMC migration and atheromatous plaque development. |
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Authors:
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U Reuning; N U Bang |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Arteriosclerosis and thrombosis : a journal of vascular biology / American Heart Association Volume: 12 ISSN: 1049-8834 ISO Abbreviation: Arterioscler. Thromb. Publication Date: 1992 Oct |
Date Detail:
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Created Date: 1992-11-25 Completed Date: 1992-11-25 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 9101388 Medline TA: Arterioscler Thromb Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 1161-70 Citation Subset: IM |
Affiliation:
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Lilly Laboratories for Clinical Research, Eli Lilly & Company, Indianapolis, IN 46285. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Aorta / metabolism Arteriosclerosis / metabolism Binding Sites / drug effects Cattle Cell Movement Epidermal Growth Factor / pharmacology Fibroblast Growth Factor 2 / pharmacology Glycosylphosphatidylinositols Hirudins / analogs & derivatives, pharmacology Muscle, Smooth, Vascular / metabolism* Peptide Fragments / pharmacology Plasminogen Activators / metabolism* Platelet-Derived Growth Factor / pharmacology Receptors, Cell Surface / drug effects, metabolism* Receptors, Urokinase Plasminogen Activator Thrombin / metabolism*, pharmacology Transforming Growth Factor beta / pharmacology Urokinase-Type Plasminogen Activator / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Glycosylphosphatidylinositols; 0/Hirudins; 0/PLAUR protein, human; 0/Peptide Fragments; 0/Platelet-Derived Growth Factor; 0/Receptors, Cell Surface; 0/Receptors, Urokinase Plasminogen Activator; 0/Transforming Growth Factor beta; 103107-01-3/Fibroblast Growth Factor 2; 121822-23-9/hirugen; 62229-50-9/Epidermal Growth Factor; EC 3.4.21.-/Plasminogen Activators; EC 3.4.21.5/Thrombin; EC 3.4.21.73/Urokinase-Type Plasminogen Activator |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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