LfR [Lf (lactoferrin) receptor] is expressed in most mammalian tissues, including placental trophoblasts, and is presumed to mediate the internalization of Lf. However, the physiological significance of trophoblast LfR is not understood. Using the CT (cytotrophoblast) cell model BeWo, we demonstrated that transfection with LfR siRNA (small interfering RNA) significantly decreased apo- but not holo-Lf uptake compared with mock-transfected controls and that apo- but not holo-Lf significantly increased MMP (matrix metalloproteinase)-2 activity. As Lf functionality is related to the presence (holo-Lf) or absence (apo-Lf) of iron within the Lf molecule, our results suggest that apo-Lf may play a role in cellular invasion. Moreover, we detected LfR (∼105 kDa) in association with the plasma membrane, and ligand blotting confirmed that Lf binds to a LfR of ∼105 kDa. Apo-Lf treatment significantly increased LfR abundance at the plasma membrane and internalization probably occurs via clathrin-mediated endocytosis through early and recycling endosomes, as LfR was co-localized with EEA1 (early endosome antigen 1) and TfR (transferrin receptor) using confocal microscopy, and hypertonic medium (0.4 M sucrose) significantly inhibited apo-Lf internalization. In summary, our data demonstrate that apo- but not holo-Lf is internalized by LfR and suggest that, following internalization via LfR, apo-Lf plays a role in CT invasiveness by inducing MMP-2 activity. Moreover, LfR facilitates apo-Lf uptake specifically through clathrin-mediated endocytosis into early endosomes and potentially into a recycling pathway. Taken together, our data provide a new dimension in understanding ligand-dependant function that may be directly related to the ability of LfR to selectively internalize apo- but not holo-Lf.
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Research Article|
March 27 2008
Lactoferrin receptor mediates apo- but not holo-lactoferrin internalization via clathrin-mediated endocytosis in trophoblasts
Veronica Lopez;
Veronica Lopez
*Department of Nutrition, University of California, One Shields Ave., Davis, CA 95616, U.S.A.
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Shannon L. Kelleher;
Shannon L. Kelleher
†Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802, U.S.A.
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Bo Lönnerdal
Bo Lönnerdal
1
*Department of Nutrition, University of California, One Shields Ave., Davis, CA 95616, U.S.A.
1To whom correspondence should be addressed (email bllonnerdal@ucdavis.edu).
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Publisher: Portland Press Ltd
Received:
March 20 2007
Revision Received:
December 18 2007
Accepted:
January 02 2008
Accepted Manuscript online:
January 02 2008
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 411 (2): 271–278.
Article history
Received:
March 20 2007
Revision Received:
December 18 2007
Accepted:
January 02 2008
Accepted Manuscript online:
January 02 2008
Citation
Veronica Lopez, Shannon L. Kelleher, Bo Lönnerdal; Lactoferrin receptor mediates apo- but not holo-lactoferrin internalization via clathrin-mediated endocytosis in trophoblasts. Biochem J 15 April 2008; 411 (2): 271–278. doi: https://doi.org/10.1042/BJ20070393
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