Lactoferrin is a natural inhibitor of plasminogen activation

A. Zwirzitz, M. Reiter, R. Skrabana, A. Ohradanova-Repic, O. Majdic, M. Gutekova, O. Cehlar, E. Petrovčíková, E. Kutejova, G. Stanek, H. Stockinger, V. Leksa

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

The plasminogen system is essential for dissolution of fibrin clots, and in addition, it is involved in a wide variety of other physiological processes, including proteolytic activation of growth factors, cell migration, and removal of protein aggregates. On the other hand, uncontrolled plasminogen activation contributes to many pathological processes (e.g. tumor cells’ invasion in cancer progression). Moreover, some virulent bacterial species (e.g. Streptococci or Borrelia) bind human plasminogen and hijack the host’s plasminogen system to penetrate tissue barriers. Thus, the conversion of plasminogen to the active serine protease plasmin must be tightly regulated. Here, we show that human lactoferrin, an iron-binding milk glycoprotein, blocks plasminogen activation on the cell surface by direct binding to human plasminogen. We mapped the mutual binding sites to the N-terminal region of lactoferrin, encompassed also in the bioactive peptide lactoferricin, and kringle 5 of plasminogen. Finally, lactoferrin blocked tumor cell invasion in vitro and also plasminogen activation driven by Borrelia. Our results explain many diverse biological properties of lactoferrin and also suggest that lactoferrin may be useful as a potential tool for therapeutic interventions to prevent both invasive malignant cells and virulent bacteria from penetrating host tissues.

Original languageEnglish
Pages (from-to)8600-8613
Number of pages14
JournalJournal of Biological Chemistry
Volume293
Issue number22
DOIs
Publication statusPublished - 1 Jun 2018

Keywords

  • Borrelia/metabolism
  • Cell Movement
  • Cells, Cultured
  • Crystallography, X-Ray
  • Fibrinolysin/metabolism
  • Fibrinolysis
  • Humans
  • Lactoferrin/chemistry
  • Plasminogen/antagonists & inhibitors
  • Protein Conformation
  • Streptococcus/metabolism

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