Dissecting mannose 6-phosphate-insulin-like growth factor 2 receptor complexes that control activation and uptake of plasminogen in cells

V. Leksa, K. Pfisterer, G. Ondrovičová, B. Binder, S. Lakatošová, C. Donner, H.B. Schiller, A. Zwirzitz, K. Mrvová, V. Pevala, E. Kutejová, H. Stockinger

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

The plasminogen (Plg) activation cascade on the cell surface plays a central role in cell migration and is involved in a plethora of physiological and pathological processes. Its regulation is coordinated by many receptors, in particular the urokinase-type plasminogen activator receptor (uPAR, CD87), receptors that physically interact and functionally cooperate with uPAR, and Plg binding molecules. Here we studied the impact of one of the Plg binding molecules, the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P-IGF2R, CD222), on cellular Plg activation. By developing both in vitro and in vivo Plg activation assays on size-fractionated lysates of M6P-IGF2R-silenced cells, we identified Plg-associated complexes with M6P-IGF2R as the regulatory factor. Using lipid raft preserving versus dissolving detergents, we found lipid dependence of the Plg regulatory function of these complexes. Furthermore, M6P-IGF2R-silencing in uPAR-positive human cell lines reduced internalization of Plg, resulting in elevated Plg activation. In contrast, the expression of human M6P-IGF2R in mouse embryonic fibroblasts derived from M6P-IGF2R knock-out mice enhanced Plg internalization. Finally, peptide 18-36 derived from the Plg-binding site within M6P-IGF2R enhanced Plg uptake. Thus, by targeting Plg to endocytic pathways, M6P-IGF2R appears to control Plg activation within cells that might be important to restrict plasmin activity to specific sites and substrates.

Original languageEnglish
Pages (from-to)22450-22462
Number of pages13
JournalJournal of Biological Chemistry
Volume287
Issue number27
DOIs
Publication statusPublished - 29 Jun 2012

Keywords

  • Animals
  • Cell Compartmentation/physiology
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cell Movement/physiology
  • Endocytosis/physiology
  • Fibrinolysin/metabolism
  • Fibrinolysis/physiology
  • Fibroblasts/cytology
  • Humans
  • Kidney Neoplasms
  • Membrane Microdomains/physiology
  • Mice
  • Monocytes/cytology
  • Mutagenesis, Site-Directed
  • Plasminogen/metabolism
  • RNA, Small Interfering/genetics
  • Receptor, IGF Type 2/genetics

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