TY - JOUR
T1 - Lactoferrin is a natural inhibitor of plasminogen activation
AU - Zwirzitz, A.
AU - Reiter, M.
AU - Skrabana, R.
AU - Ohradanova-Repic, A.
AU - Majdic, O.
AU - Gutekova, M.
AU - Cehlar, O.
AU - Petrovčíková, E.
AU - Kutejova, E.
AU - Stanek, G.
AU - Stockinger, H.
AU - Leksa, V.
N1 - Funding Information:
This work was supported by Austrian Science Fund Grants P19014-B13, P22908, and I00300; Science and Technology Assistance Agency of the Slovak Republic Grant APVV-16-0452; Slovak Grant Agency VEGA Grant 2/0020/17; the European Union Seventh Framework Program (FP7/2007– 2013) under grant agreement NMP4-LA-2009-228827 NANOFOL; and the EU structural funds ITMS 26240220008. The research was also supported by the European Union’s Horizon 2020 Research and Innovation Program under Grant Agreement 683356 (FOLSMART). The authors declare that they have no conflicts of interest with the contents of this article.
Publisher Copyright:
© 2018 Zwirzitz et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2018/6/1
Y1 - 2018/6/1
N2 - 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.
AB - 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.
KW - Borrelia/metabolism
KW - Cell Movement
KW - Cells, Cultured
KW - Crystallography, X-Ray
KW - Fibrinolysin/metabolism
KW - Fibrinolysis
KW - Humans
KW - Lactoferrin/chemistry
KW - Plasminogen/antagonists & inhibitors
KW - Protein Conformation
KW - Streptococcus/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85048053489&partnerID=8YFLogxK
U2 - 10.1074/jbc.RA118.003145
DO - 10.1074/jbc.RA118.003145
M3 - Article
C2 - 29669808
VL - 293
SP - 8600
EP - 8613
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 22
ER -