Prometastatic effect of N-acetylglucosaminyltransferase V is due to modification and stabilization of active matriptase by adding beta 1-6 GlcNAc branching.
Oligosaccharide moieties of glycoproteins are structurally altered during development, carcinogenesis, and malignant transformations. It is well known that beta1-6 GlcNAc branching, a product of UDP-GlcNAc alpha-mannoside beta1-6-N-acetylglucosaminyltransferase (GnT-V), is associated with malignant transformation as the results of such alterations. However, the mechanism by which beta1-6 GlcNAc branching is linked to metastasis remains unclear, because the identification of specific glycoprotein(s) that are glycosylated by GnT-V and its biological function have not been examined. We herein report that matriptase, which activates both urokinase-type plasminogen activator and hepatocyte growth factor, is a target protein for GnT-V. The overexpression of GnT-V in gastric cancer cells leads to severe peritoneal dissemination in athymic mice, which can be attributed to the increased expression of matriptase. This increase was due to the acquired resistance of matriptase to degradation, since it is glycosylated by GnT-V and a corresponding increase in the active form. These results indicate that this process is a key element in malignant transformation, as the direct result of oligosaccharide modification.
Ihara
Shinji
S
Department of Biochemistry, Osaka University Medical School/Graduate School of Medicine, B1, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Miyoshi
Eiji
E
Ko
Jeong Heon
JH
Murata
Kohei
K
Nakahara
Susumu
S
Honke
Koichi
K
Dickson
Robert B
RB
Lin
Chen-Yong
CY
Taniguchi
Naoyuki
N
D000117:Acetylglucosamine / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004848:Epithelium / Q000201:enzymology; D005434:Flow Cytometry; D005647:Fucosyltransferases / Q000378:metabolism; D006801:Humans; D037102:Lectins / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism / Q000494:pharmacology*; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D017830:Octoxynol / Q000494:pharmacology; D009844:Oligosaccharides / Q000737:chemistry; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014357:Trypsin / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D017077:Culture Media, Conditioned; D037102:Lectins; D008565:Membrane Proteins; D009844:Oligosaccharides; D017830:Octoxynol; D005647:Fucosyltransferases; D017351:N-Acetylglucosaminyltransferases; C054599:beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase; C052254:alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase; C020559:Glycoprotein 6-alpha-L-fucosyltransferase; D012697:Serine Endopeptidases; C485595:matriptase; C485596:ST14 protein, human; C118992:St14 protein, mouse; D014357:Trypsin; D000117:Acetylglucosamine