Low density lipoprotein receptor-related protein/α2-macroglobulin receptor mediates cellular uptake of pro-urokinase

Maria Z. Kounnas, Jack Henkin, W. Scott Argraves, Dudley K. Strickland*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

161 Scopus citations


The low density lipoprotein receptor-related protein/ α2-macroglobulin receptor (LRP) is a large cell surface receptor consisting of a 515-kDa heavy chain and an 85-kDa light chain proteolytically derived from a 600-kDa precursor. Previous work has shown that LRP is responsible for mediating the internalization of urinary-type plasminogen activator (uPA) complexed to plasminogen activator inhibitor type I (PAI-1) (Nykjær et al., 1992; Herz et al., 1992). The current study indicates that pro-urokinase (pro-uPA) and two chain urokinase (tc-uPA) bind directly to purified LRP, and that LRP mediates their internalization and degradation in Hep G2 cells. In vitro binding assays demonstrated that pro-uPA and tc-uPAbind to purified LRP with affinities (Kd = 45 and 60 nM, respectively) that are approximately 15 to 20-fold weaker than the affinity of uPA-PAI-1 complex for LRP (Kd = 3 nM). Competitive binding experiments revealed that pro-uPA and tc-uPA completely inhibit binding of uPA·PAI-1 complexes to purified LRP. The binding of 125I-pro-uPA to LRP is blocked by the 39-kDa receptor-associated protein, but not by an amino-terminal fragment of uPA, which is known to block binding of uPA to the urokinase receptor. 125I-Pro-uPA can be internalized and degraded by Hep G2 cells independent of PAI-1. Both the internalization and degradation are completely blocked by receptor-associated protein or affinity-purified LRP antibodies, indicating that LRP is mediating this process. These processes are also blocked by the amino-terminal fragment, which suggests that the favored pathway for uPA metabolism is initial binding to the urokinase receptor, followed by ligand transfer to LRP, then internalization leading to degradation.

Original languageEnglish (US)
Pages (from-to)21862-21867
Number of pages6
JournalJournal of Biological Chemistry
Issue number29
StatePublished - Oct 15 1993

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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