Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 293, Issue 22, Pages 8600-8613Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.003145
Keywords
protease; protease inhibitor; mannose 6-phosphate (M6P); tumor; bacteria; lactoferricin; Lyme disease; M6P; IGF2R; plasmin; transferrin; fibrinolysis; plasminogen; lactoferrin; insulin-like growth factor 2 receptor; cell invasion; Borrelia
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Funding
- Austrian Science Fund [P19014-B13, P22908, I00300]
- Science and Technology Assistance Agency of the Slovak Republic [APVV-16-0452]
- Slovak Grant Agency VEGA Grant [2/0020/17]
- European Union Seventh Framework Program (FP7) [NMP4-LA-2009-228827 NANOFOL]
- EU structural funds [ITMS 26240220008]
- European Union's Horizon 2020 Research and Innovation Program [683356]
- Austrian Science Fund (FWF) [P19014, P22908] Funding Source: Austrian Science Fund (FWF)
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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.
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