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J. Biol. Chem., Vol. 281, Issue 34, 24472-24478, August 25, 2006

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Interaction of Human Lactoferrin with Cell Adhesion Molecules through RGD Motif Elucidated by Lactoferrin-binding Epitopes^*

Kotaro Sakamoto, Yuji Ito¹, Toshiyuki Mori², and Kazuhisa Sugimura

From the Faculty of Engineering, Kagoshima University, Korimoto, Kagoshima 890-0065, Japan and the Molecular Targets Development Program, Center for Cancer Research, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702

Lactoferrin (LF) is an iron-binding secretory protein, which is distributed in the secondary granules of polynuclear lymphocytes as well as in the milk produced by female mammals. Although it has multiple functions, for example antimicrobial, immunomodulatory, antiviral, and anti-tumor metastasis activities, the receptors responsible for these activities are not fully understood. In this study, the binding epitopes for human LF were first isolated from a hexameric random peptide library displayed on T7 phage. Interestingly, two of the four isolated peptides had a representative cell adhesion motif, Arg-Gly-Asp (RGD), implying that human LF interacts with proteins with the RGD motif. We found that human LF bound to the RGD-containing human extracellular matrix proteins, fibronectin and vitronectin. Furthermore, human LF inhibited cell adhesion to these matrix proteins in a concentration-dependent manner but not to the RGD-independent cell adhesion molecule like laminin or collagen. These results indicate that a function of human LF is to block the various interactions between the cell surface and adhesion molecules. This may explain the multifunctionality of LF.

Received for publication, May 24, 2006

^* This work was supported in part by the Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Present address: Biomedical Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.

¹ To whom correspondence should be addressed. Tel.: 81-99-285-8346; Fax: 81-99-258-4706; E-mail: yito{at}be.kagoshima-u.ac.jp.

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