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

Abstract

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)