Glycoprotein
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Biological Functions of a Soluble Form of N-acetylglucosaminyltransferase V (GnT-V)

 It is a well-known fact that oligosaccharide structures of glycoproteins and expression of glycosyltransferases change in malignant transformation. In approximately 300 kinds of these enzymes, N-acetylglucosaminyltransferase V (GnT-V) is one of the most important glycosyltransferases which are involved in tumor metastasis. Recent studies of GnT-V-deficient mice have demonstrated that GnT-V is essential for tumor metastasis as well as tumor growth (1). Mammary tumor growth and metastases induced by the polyomavirus middle T oncogene were considerably less in GnT-V- deficient mice than in transgenic littermates expressing GnT-V. On the other hand, since expression of GnT-V was elevated at the stage of chronic hepatitis as well as in the metastatic lesion of a rodent model of hepatocarcinogenesis (2), GnT-V is assumed to be involved in the early event of carcinogenesis. The most important biological phenomenon in the early phase of carcinogenesis is expected to be immortalization and tumor angiogenesis. In 1993, Pierces and Taniguchis groups performed protein purification and cDNA cloning of GnT-V. After 10 years, a unique function of GnT-V as an angiogenesis inducer was found (3). The mechanisms for GnT-V-induced tumor angiogenesis were due to completely different functions from those of glycosyltransferases. In general, glycosyltransferases are located in the Golgi apparatus and involved in the oligosaccharide modification of glycoproteins/glycolipids. However, a glycosyltransferase also exists in the serum of patients and it is reported to be a biomarker for certain diseases. Certain proteases digest a glycosyltransferase and secrete into the condition medium of cells. This type of glycosyltransferase is the soluble form. In the case of GnT-V, the soluble form of the enzyme has the biological function of angiogenesis. The basic domain of GnT-V, KRKRKK, which is located in the 264-269 amino acid sequence, promotes a release of bFGF from the extra cellular matrix, resulting in tumor angiogenesis (see Fig.1). Many kinds of cytokines/growth factors attach to proteoglycans such as heparansulfates in the extra cellular matrix. If the basic domain of GnT-V is associated with the release or activation of these factors, the soluble form of GnT-V could have a variety of biological functions. Furthermore, the identification of a protease which is responsible for cleavage and secretion of GnT-V may provide new insights in glycobiology.
Fig.1. Biological functions of a soluble from of glycosyl transferase.
 
 
Eiji Miyoshi (Osaka University, Graduate School of Medicine, Department of Molecular Biochemistry & Clinical Investigation)
References (1) Dennis JW, Pawling J, Cheung P, Partridge E, Demetriou M. UDP-N-acetylglucosamine: alpha-6-D-mannoside beta1,6 N-acetylglucosaminyltransferase V (Mgat5) deficient mice. Biochim Biophys Acta 2002 Dec 19;1573(3):414-422
(2) Miyoshi E, Nishikawa A, Ihara Y, Gu J, Sugiyama T, Hayashi N, Fusamoto H, Kamada T, Taniguchi N. N-acetylglucosaminyltransferase III and V messenger RNA levels in LEC rats during hepatocarcinogenesis Cancer Res 1993 Sep 1;53(17):3899-3902
(3) Saito T, Miyoshi E, Sasai K, Nakano N, Eguchi H, Honke K, Taniguchi N. A secreted type of beta 1,6-N-acetylglucosaminyltransferase V (GnT-V) induces tumor angiogenesis without mediation of glycosylation: a novel function of GnT-V distinct from the original glycosyltransferase activity. J Biol Chem 2002 May 10;277(19):17002-17008

Links
Regulation of High Branching in N-linked Oligosaccharides (Eiji Miyoshi and Naoyuki Taniguchi)
Nov. 20, 2003

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