Low density lipoprotein receptor-related protein is necessary for the internalization of both tissue-type plasminogen activator-inhibitor complexes and free tissue-type plasminogen activator.
Tissue-type plasminogen activator (t-PA) is used as a thrombolytic agent in treatment of myocardial infarction. However, large doses of this agent must be administered in treatment to maintain a thrombolytic state because t-PA is cleared rapidly from circulation. We designed specific ligands to distinguish between two major mechanisms by which t-PA is taken into cells and degraded. One of these mechanisms involves internalization of complexes between t-PA and its cognate inhibitor plasminogen activator inhibitor type-1 (PAI-1); the other mechanism is independent of PAI-1. Using specific inhibitors for low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP), we show that the degradation by hepatocytes of both free t-PA and t-PA.PAI-1 complexes involve the receptor LRP. We demonstrate that fibroblasts degrade both free t-PA (PAI-1-independent) and t-PA complexed with its specific inhibitor PAI-1 (PAI-1-dependent), whereas genetically altered fibroblasts that do not express LRP neither internalize nor degrade these ligands. We also show that a PAI-1-independent, t-PA ligand can inhibit the degradation of both free t-PA and t-PA.PAI-1 complexes. We propose LRP is the receptor for both PAI-1-independent and PAI-1-dependent t-PA ligands.
Orth
K
K
Department of Biochemistry, University of Texas Southwestern Medical School, Dallas 75235.
Willnow
T
T
Herz
J
J
Gething
M J
MJ
Sambrook
J
J
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D000882:Haplorhini; D007074:Immunoglobulin G / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000166:cytology / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D008969:Molecular Sequence Data; D015849:Plasminogen Inactivators / Q000378:metabolism*; D051381:Rats; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D007074:Immunoglobulin G; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D015849:Plasminogen Inactivators; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D011993:Recombinant Fusion Proteins; D004815:Epidermal Growth Factor; D005982:Glutathione Transferase; D010959:Tissue Plasminogen Activator