Functional glycomics and evidence for gain- and loss-of-functions of target proteins for glycosyltransferases involved in N-glycan biosynthesis: their pivotal roles in growth and development, cancer metastasis and antibody therapy against cancer

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概要

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• N-Acetylglucosaminyltransferase V (GnT-V), N-acetylglucosaminyltransferase III (GnT-III) and α1-6 fucosyltransferase (Fut8) catalyze reactions that form biologically important branching N-linked sugar chains in glycoproteins. The above three branching N-glycan sugar chains, β1-6 GlcNAc branching, bisecting GlcNAc and core fucose (α1-6 fucose), play major roles in cancer invasion and metastasis, the inhibition of cancer metastasis, and antibody-dependent cellular cytotoxicity (ADCC), growth and development, respectively. A functional glycomic approach identified the gain- and loss-of-functions of glycoproteins as the result of the aberrant glycosylation. A membrane-type metal dependent serine proteinase designated matriptase which contains β1-6 GlcNAc branching became resistant to auto-digestion and proteolysis by trypsin, and resulted in a constitutively active form which might be implicated in cancer invasion and metastasis. GnT-V also acts as an angiogenic factor without the mediation of functions as a glycosyltransferase. Recently, a GnT-V homologue, GnT-IX has been identified. This gene is expressed at relatively high levels in the brain and acts on N-glycans to form a unique branched structure, as well as O-mannosyl glycans. The addition of bisecting GlcNAc to various signaling molecules or adhesion molecules suppresses cancer metastasis. Fut8 knock-out mice, due to the lack of a core fucose (α1-6 fucose) in target glycoproteins, show disorders in growth and development. The presence of a bisecting GlcNAc or the absence of a core fucose in IgG molecules enhances ADCC activity for killing tumor cells by up to 10 to 100 fold and therefore is thought to have considerable use in antibody therapy against cancer. These data clearly indicate that gain- and loss-of-functions of target proteins for these glycosyltransferases are biologically important. (Communicated by Tamio YAMAKAWA, M.J.A., Feb. 12, 2004)

• 日本学士院の論文

著者

• Gu Jianguo

  Division Of Regulatory Glycobiology Institute Of Molecular Biomembrane And Glycobiology Tohoku Pharm

• TAKAHASHI Motoko

  Department of Biochemistry Osaka University Medical School

• TANIGUCHI Naoyuki

  Department of Biochemistry Osaka University Medical School

• Takahashi Motoko

  大阪大学 医学系研究科生化学

• Takahashi M

  Department Of Biochemistry Sapporo Medical University School Of Medicine

• Taniguchi Naoyuki

  大阪大学 医学系研究科生化学

• Taniguchi N

  Department Of Biochemistry Osaka University Graduate School Of Medicine

• MIYOSHI Eiji

  Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of

• Taniguchi Naoyuki

  Department Of Biochemistry Room B-1 Osaka University Medical School

• Taniguchi Naoyuki

  Department Of Biochemistry Osaka University Graduate School Of Medicine

• Miyoshi Eiji

  Department Of Biochemistry School Of Allied Health Science Osaka University Faculty Of Medicine

• GU Jianguo

  Department of Biochemistry, Osaka University Graduate School of Medicine

• Taniguchi N

  Department Of Disease Glycomics Research Institute For Microbial Diseases Osaka University

• Taniguchi Naoyuki

  Department Of Disease Glycomics (seikagaku Corporation) The Institute Of Scientific And Industrial R

• TANIGUCHI Naoyuki

  Department of Biochemistry, Osaka University Graduate School of Medicine

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