title: Identification of mannose receptor as receptor for hepatocyte growth factor β-chain: novel ligand-receptor pathway for enhancing macrophage phagocytosis.
abstract: Hepatocyte growth factor (HGF), a heterodimer composed of the α-chain and β-chain, exerts multifunctional actions for tissue repair and homeostasis via its receptor, MET. HGF is cleaved by proteases secreted from inflammatory cells, and NK4 and β-chain remnant (HGF-β) are generated. Here, we provide evidence that HGF-β binds to a new receptor other than MET for promoting a host cell clearance system. By an affinity cross-linking, radiolabeled HGF-β was bound to liver non-parenchymal cells, particularly to Kupffer cells and sinusoidal endothelial cells, but not to parenchymal hepatocytes. The cross-linked complex was immunoprecipitated by anti-HGF antibody, but not anti-MET antibody, implying that HGF-β binds to non-parenchymal cells at a site distinct from MET. Mass spectrometric detection of the ligand receptor complex revealed that the binding site of HGF-β was the mannose receptor (MR). Actually, an ectopic expression of MR in COS-7 cells, which express no endogenous MR or MET, enabled HGF-β to bind these cells at a K(D) of 89 nM, demonstrating that MR is the new receptor for HGF-β. Interaction of HGF-β and MR was diminished by EGTA, and by an enzymatic digestion of HGF-β sugar chains, suggesting that MR may recognize the glycosylation site(s) of HGF-β in a Ca(2+)-dependent fashion. Notably, HGF-β, but not other MR ligands, enhanced the ingestion of latex beads, or of apoptotic neutrophils, by Kupffer cells, possibly via an F-actin-dependent pathway. Thus, the HGF-β·MR complex may provide a new pathway for the enhancement of cell clearance systems, which is associated with resolution of inflammation.
authors.affiliation: Kringle Pharma Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ohnishi
authors.forename: Kiyomasa
authors.initials: K
authors.lastname: Oka
authors.forename: Shinya
authors.initials: S
authors.lastname: Mizuno
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D016466:CHO Cells; D019556:COS Cells; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002522:Chlorocebus aethiops; D006224:Cricetinae; D022781:Hepatocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007728:Kupffer Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000235:genetics / Q000378:metabolism*; D010587:Phagocytosis / Q000276:immunology*; D011485:Protein Binding / Q000502:physiology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*
chemical_list: D037181:Lectins, C-Type; D008024:Ligands; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met