title: Role of CXC chemokine receptor type 4 as a lactoferrin receptor.
abstract: Lactoferrin exerts its biological activities by interacting with receptors on target cells, including LDL receptor-related protein-1 (LRP-1/CD91), intelectin-1 (omentin-1), and Toll-like receptor 4 (TLR4). However, the effects mediated by these receptors are not sufficient to fully explain the many functions of lactoferrin. C-X-C-motif cytokine receptor 4 (CXCR4) is a ubiquitously expressed G-protein coupled receptor for stromal cell-derived factor-1 (SDF-1/CXCL12). Lactoferrin was found to be as capable as SDF-1 in blocking infection by an HIV variant that uses CXCR4 as a co-receptor (X4-tropic HIV), suggesting that lactoferrin interacts with CXCR4. We addressed whether CXCR4 acts as a lactoferrin receptor using HaCaT human keratinocytes and Caco-2 human intestinal cells. We found that bovine lactoferrin interacted with CXCR4-containing lipoparticles, and that this interaction was not antagonized by SDF-1. In addition, activation of Akt in response to lactoferrin was abrogated by AMD3100, a small molecule inhibitor of CXCR4, or by a CXCR4-neutralizing antibody, suggesting that CXCR4 functions as a lactoferrin receptor able to mediate activation of the PI3K-Akt signaling pathway. Lactoferrin stimulation mimicked many aspects of SDF-1-induced CXCR4 activity, including receptor dimerization, tyrosine phosphorylation, and ubiquitination. Cycloheximide chase assays indicated that turnover of CXCR4 was accelerated in response to lactoferrin. These results indicate that CXCR4 is a potent lactoferrin receptor that mediates lactoferrin-induced activation of Akt signaling.
authors.affiliation: a Functional Biomolecules Research Group, National Institute of Livestock and Grassland Science, National Agriculture and Food Research Organization (NARO), 2 Ikenodai, Tsukuba, Ibaraki 305-0901, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Takayama
authors.affiliation: a Functional Biomolecules Research Group, National Institute of Livestock and Grassland Science, National Agriculture and Food Research Organization (NARO), 2 Ikenodai, Tsukuba, Ibaraki 305-0901, Japan.
authors.forename: Reiji
authors.initials: R
authors.lastname: Aoki
authors.affiliation: a Functional Biomolecules Research Group, National Institute of Livestock and Grassland Science, National Agriculture and Food Research Organization (NARO), 2 Ikenodai, Tsukuba, Ibaraki 305-0901, Japan.|b Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Uchida
authors.affiliation: b Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tajima
authors.affiliation: a Functional Biomolecules Research Group, National Institute of Livestock and Grassland Science, National Agriculture and Food Research Organization (NARO), 2 Ikenodai, Tsukuba, Ibaraki 305-0901, Japan.|c Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Aoki-Yoshida
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002417:Cattle; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D007781:Lactoferrin / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D011956:Receptors, Cell Surface; C038340:lactoferrin receptors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D007781:Lactoferrin
keywords: Akt; CXCR4; SDF-1/CXCL12; dimerization; dimérisation; ubiquitination