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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

Authors

  • K. Orth
  • T.E. Willnow
  • J. Herz
  • M.J. Gething
  • J. Sambrook

Journal

  • Journal of Biological Chemistry

Citation

  • J Biol Chem 269 (33): 21117-21122

Abstract

  • 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.


DOI

doi:cgi/content/abstract/269/33/21117