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-I I) from the blood circulation or the pericellular space. Co-receptors are e ssential for LRP-mediated clearance of several ligands (e.g. glycosaminogly cans for thrombin/protease nexin and lipoprotein lipase. and the urokinase receptor for urokinase/PAI-1 complexes). The present study was undertaken t o 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 an d 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 degradat ion. Pre-treatment of COS cells or HT1080 cells with chlorate, an inhibitor of glycosaminoglycan sulfation, did not decrease t-PA/PAI-1 degradation. F urthermore. CHO cells genetically deficient in glycosaminoglycans efficient ly 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.