Complexes of tissue-type plasminogen activator and its serpin inhibitor plasminogen-activator inhibitor type 1 are internalized by means of the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor.
Tissue-type plasminogen activator and urokinase are serine proteases secreted by many cell types that participate in biological processes, such as tissue restructuring, cell migration, and tumor metastasis. Clinically, these proteases are used to dissolve coronary fibrin clots that are the proximal causes of acute myocardial infarction. In vivo, the activity of these enzymes is controlled by plasminogen-activator inhibitors, members of the serpin family of protease inhibitors. This study shows that tissue-type plasminogen activator-inhibitor complexes bind in solution to low density lipoprotein receptor-related protein (LRP), a large heterodimeric ubiquitous membrane receptor. In cultured cells, endocytosis and degradation of these complexes is reduced by polyclonal antibodies directed against LRP and inhibited by a M(r) 39,000 protein that binds to LRP and inhibits its interaction with previously known ligands, including apolipoprotein E and alpha 2-macroglobulin. We propose a role for LRP in the clearance of plasminogen activator-inhibitor complexes that is analogous to its function in the endocytosis of alpha 2-macroglobulin-protease complexes.
Orth
K
K
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas 75235.
Madison
E L
EL
Gething
M J
MJ
Sambrook
J F
JF
Herz
J
J
D000818:Animals; D000911:Antibodies, Monoclonal; D002460:Cell Line; D004705:Endocytosis; D015151:Immunoblotting; D007700:Kinetics; D008114:Liver Neoplasms, Experimental; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D015849:Plasminogen Inactivators / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D011971:Receptors, Immunologic / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D015849:Plasminogen Inactivators; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator