Cellular degradation of free and inhibitor-bound tissue-type plasminogen activator--requirement for a co-receptor?
The low density lipoprotein receptor-related protein (LRP) is a multiligand clearance receptor that removes free tissue-type plasminogen activator (t-PA) or complexes of t-PA with plasminogen activator inhibitor type 1 (PAI-1) from the blood circulation or the pericellular space. Co-receptors are essential for LRP-mediated clearance of several ligands (e.g. glycosaminoglycans for thrombin/protease nexin and lipoprotein lipase, and the urokinase receptor for urokinase/PAI-1 complexes). The present study was undertaken to investigate whether LRP-mediated t-PA clearance requires a co-receptor as well. In five cell lines from different organs and species degradation of t-PA and t-PA/PAI-1 was mediated by LRP (or LRP-like receptors). No degradation of t-PA and t-PA/PAI-1 occurred in THP-1 or U-937 human monocyte-like cells, despite the presence of functional LRP. As glycosaminoglycans can bind t-PA and PAI-1 we investigated whether they are involved in t-PA/PAI-1 degradation. Pre-treatment of COS cells or HT1080 cells with chlorate, an inhibitor of glycosaminoglycan sulfation, did not decrease t-PA/PAI-1 degradation. Furthermore, CHO cells genetically deficient in glycosaminoglycans efficiently degraded t-PA/PAI-1. Thus it is unlikely that glycosaminoglycans are co-receptors for degradation of t-PA or t-PA/PAI-1. This study indicates that THP-1 and U-937 cells lack a critical component (co-receptor?) for the LRP-mediated degradation of t-PA.
Camani
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Division of Angiology and Hemostasis, University Hospital Geneva, Switzerland.
Gavin
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Kruithof
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EK
D000818:Animals; D019556:COS Cells; D002704:Chlorates / Q000494:pharmacology; D005434:Flow Cytometry; D006025:Glycosaminoglycans / Q000037:antagonists & inhibitors / Q000502:physiology; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D018832:Molecular Chaperones / Q000494:pharmacology; D009928:Organ Specificity; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D051381:Rats; D011971:Receptors, Immunologic / Q000502:physiology; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D013045:Species Specificity; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000187:drug effects* / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D002704:Chlorates; D006025:Glycosaminoglycans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D018832:Molecular Chaperones; D017395:Plasminogen Activator Inhibitor 1; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D006493:Heparin; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator