title: Mannan-binding protein blocks the activation of metalloproteases meprin alpha and beta.
abstract: Mannan-binding protein (MBP) is a C-type serum lectin that is known to be a host defense factor involved in innate immunity, and recognizes mannose, fucose, and N-acetylglucosamine residues. Although some exogenous MBP ligands have been reported, little is known about its endogenous ligands. In the present study, we found that endogenous MBP ligands are highly expressed in the brush border epithelial cells of kidney-proximal tubules by immunohistochemistry, and both meprin alpha and beta (meprins), as novel endogenous MBP ligands, have been identified through affinity chromatography and mass spectrometry. Meprins are membrane-bound and secreted zinc metalloproteases extensively glycosylated and highly expressed in kidney and small intestinal epithelial cells, leukocytes, and certain cancer cells. Meprins are capable of cleaving growth factors, extracellular matrix proteins, and biologically active peptides. Deglycosylation experiments indicated that the MBP ligands on meprins are high mannose- or complex-type N-glycans. The interaction of MBP with meprins resulted in significant decreases in the proteolytic activity and matrix-degrading ability of meprins. Our results suggest that core N-linked oligosaccharides on meprins are associated with the optimal enzymatic activity and that MBP is an important regulator for modulation of the localized meprin proteolytic activity via N-glycan binding. Because meprins are known to be some of the major matrix-degrading metalloproteases in the kidney and intestine, MBP, which functions as a natural and effective inhibitor of meprins, may contribute, as a potential therapeutic target, to tumor progression by facilitating the migration, intravasation, and metastasis of carcinoma cells, and to acute renal failure and inflammatory bowel diseases.
authors.affiliation: Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hirano
authors.forename: Bruce Yong
authors.initials: BY
authors.lastname: Ma
authors.forename: Nana
authors.initials: N
authors.lastname: Kawasaki
authors.forename: Kazumichi
authors.initials: K
authors.lastname: Okimura
authors.forename: Makoto
authors.initials: M
authors.lastname: Baba
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Keiko
authors.initials: K
authors.lastname: Miwa
authors.forename: Nobuko
authors.initials: N
authors.lastname: Kawasaki
authors.forename: Shogo
authors.initials: S
authors.lastname: Oka
authors.forename: Toshisuke
authors.initials: T
authors.lastname: Kawasaki
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004789:Enzyme Activation; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism; D037102:Lectins / Q000378:metabolism; D008024:Ligands; D037601:Mannose-Binding Lectin / Q000502:physiology*; D008666:Metalloendopeptidases / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data
chemical_list: D016326:Extracellular Matrix Proteins; D037102:Lectins; D008024:Ligands; D037601:Mannose-Binding Lectin; D008666:Metalloendopeptidases; C053833:meprin A