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Human Tumor Suppressor EXT Gene Family Members EXTL1 And Human tumor suppressor EXT gene family members EXTL1 and EXTL3 encode ␣1,4- N-acetylglucosaminyltransferases that likely are involved in heparan sulfate͞ heparin biosynthesis Byung-Taek Kim*, Hiroshi Kitagawa*, Jun-ichi Tamura†, Toshiyuki Saito‡, Marion Kusche-Gullberg§, Ulf Lindahl§, and Kazuyuki Sugahara*¶ *Department of Biochemistry, Kobe Pharmaceutical University, Higashinada-ku, Kobe 658-8558, Japan; †Department of Environmental Sciences, Faculty of Education and Regional Sciences, Tottori University, Tottori 680-8551, Japan; ‡Genome Research Group, National Institute of Radiological Sciences, Anagawa 4-9-1, Inage-ku, Chiba 263-8555, Japan; and §Department of Medical Biochemistry and Microbiology, University of Uppsala, The Biomedical Center, S-751 23 Uppsala, Sweden Communicated by Sen-itiroh Hakomori, Pacific Northwest Research Institute, Seattle, WA, April 17, 2001 (received for review February 22, 2001) The tumor suppressors EXT1 and EXT2 are associated with hered- xylose to specific Ser residues, followed by the addition of two itary multiple exostoses and encode bifunctional glycosyltrans- Gals and GlcA, each reaction being catalyzed by the respective, ferases essential for chain polymerization of heparan sulfate (HS) specific glycosyltransferase:xylosyltransferase, Gal transferases I and its analog, heparin (Hep). Three highly homologous EXT-like and II, and GlcA transferase I (GlcAT-I) (1, 8). Chain polymer- genes, EXTL1–EXTL3, have been cloned, and EXTL2 is an ␣1,4- ization for HS͞Hep is initiated once an ␣-GlcNAc is transferred GlcNAc transferase I, the key enzyme that initiates the HS͞Hep to this linkage-region tetrasaccharide core by the action of synthesis. In the present study, truncated forms of EXTL1 and ␣-GlcNAc transferase I (GlcNAcT-I) (9), whereas ␤-GalNAc EXTL3, lacking the putative NH2-terminal transmembrane transfer triggers CS͞DS synthesis (10, 11). The first hexosamine and cytoplasmic domains, were transiently expressed in COS-1 cells transfer, therefore, is considered to be the critical determining and found to harbor ␣-GlcNAc transferase activity. EXTL3 used not step in which the HS͞Hep and CS͞DS chains are selected. After only N-acetylheparosan oligosaccharides that represent growing attachment of the first ␣-GlcNAc residue, the resultant nascent ␤ ␤ HS chains but also GlcA 1–3Gal 1-O-C2H4NH-benzyloxycarbonyl pentasaccharide is elongated further by alternate additions of (Cbz), a synthetic substrate for ␣-GlcNAc transferase I that deter- GlcA and GlcNAc to form HS͞Hep backbones by the actions of mines and initiates HS͞Hep synthesis. In contrast, EXTL1 used only copolymerases, which exhibit dual catalytic activities of GlcA the former acceptor. Neither EXTL1 nor EXTL3 showed any glucu- transferase II (HS-GlcAT-II) and ␣-GlcNAc transferase II ronyltransferase activity as examined with N-acetylheparosan oli- (GlcNAcT-II) (8). Such HS͞Hep precursor chains subsequently gosaccharides. Heparitinase I digestion of each transferase-reac- are modified through a series of reactions of N-deacetylation͞ tion product showed that GlcNAc had been transferred exclusively N-sulfation of GlcNAc, epimerization of GlcA, and O-sulfation through an ␣1,4-configuration. Hence, EXTL3 most likely is in- at various positions of both residues (2), which confers the volved in both chain initiation and elongation, whereas EXTL1 structural diversity on HS͞Hep. possibly is involved only in the chain elongation of HS and, maybe, Recently, two independent studies revealed the connection Hep as well. Thus, their acceptor specificities of the five family between HS-synthesizing glycosyltransferases and an EXT gene members are overlapping but distinct from each other, except for family of tumor suppressors: (i) identification of EXT1 as the EXT1 and EXT2 with the same specificity. It now has been clarified gene that is capable of restoring HS synthesis in HS-deficient that all of the five cloned human EXT gene family proteins harbor mutant cells (12) and (ii) identification of EXT2 by direct peptide glycosyltransferase activities, which probably contribute to the sequencing of HS copolymerase purified from bovine serum synthesis of HS and Hep. (13). EXT1 and EXT2 are associated with the development of hereditary multiple exostoses (HME), an autosomal dominant eparan sulfate (HS) is a glycosaminoglycan (GAG) found disorder characterized by aberrant bone formation most com- Habundantly on the surfaces of most cells and in the extra- monly originating from the juxtaepiphyseal regions of the long cellular space as proteoglycans (1). HS proteoglycans are known bones (14–16). More recent studies have established firmly that to function as cofactors in a variety of biological processes such recombinant forms of EXT1 and EXT2 indeed have both as cell adhesion, blood coagulation, angiogenesis, morphogen- GlcNAc and GlcA transferase activities (17) and form an esis, and regulation of growth factors and cytokine effects (2). EXT1͞EXT2 heterooligomeric complex in the Golgi apparatus Most, if not all, of their biological activities are assumed to be attributable to the HS side chains that interact with diverse protein ligands through specific saccharide sequences (3). Re- Abbreviations: GlcNAcT-I and GlcNAcT-II, ␣-GlcNAc transferases I and II; Cbz, benzyloxy- carbonyl; CHO, Chinese hamster ovary; CS, chondroitin sulfate; DS, dermatan sulfate; EXT, cent evidence indicates that HS chains are critically involved in hereditary multiple exostoses gene; GAG, glycosaminoglycan; GlcAT-I, glucuronyltrans- the development of Drosophila melanogaster by interacting with ferase I; Hep, heparin; HS-GlcAT-II, heparan sulfate glucuronyltransferase II; CS-GlcAT-II, signaling molecules, including Hedgehog, Wingless, and fibro- chondroitin sulfate glucuronyltransferase II; HME, hereditary multiple exostoses; HS, hepa- blast growth factor, and HS deficiency causes severe malforma- ran sulfate. tion in developing fly (4, 5) and mouse (6) embryos. ¶To whom reprint requests should be addressed at: Department of Biochemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, In addition to HS and its analog, heparin (Hep), chondroitin Japan. E-mail: [email protected]. sulfate (CS) and dermatan sulfate (DS) also are synthesized on ␤ ␤ The publication costs of this article were defrayed in part by page charge payment. This the common GAG–protein linkage region, GlcA 1–3Gal 1– article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. 3Gal␤1–4Xyl␤1-O-Ser (7), which is formed by the addition of §1734 solely to indicate this fact. 7176–7181 ͉ PNAS ͉ June 19, 2001 ͉ vol. 98 ͉ no. 13 www.pnas.org͞cgi͞doi͞10.1073͞pnas.131188498 Downloaded by guest on September 27, 2021 (17–19) to yield a more active, biologically relevant enzyme form in the fusion protein that had the cleavable insulin signal (17, 18). It should be noted that deficiency of either EXT1 or sequence for secretion and protein A for purification. EXT2 causes HME (15, 16). These findings indicate that both The cDNA fragment encoding a truncated form of EXTL3 EXT1 and EXT2 are essential glycosyltransferases for HS bio- lacking the NH2-terminal first 90 aa was amplified with the synthesis. previously cloned EXTL3 cDNA (23) as a template by PCR by However, three EXT-like genes homologous to EXT genes using a 5Ј primer (5Ј-CGAGATCTGAAGAGCTCCTG- have been isolated: EXTL1, EXTL2͞EXTR2, and EXTL3͞ CAGCTGGA-3Ј) containing an in-frame BglII site and 3Ј EXTR1 (20–23). Their chromosomal locations imply that they primer (5Ј-CGAGATCTTCTGCTCATCCTCTTCCCCAG-3Ј) also might be tumor suppressors (20, 21, 24, 25), although they containing a BglII site located 37 bp downstream of the stop are not linked with HME. EXTL2 protein is an N-acetyl- codon. PCR was carried out by using Pfu polymerase with 30 hexoaminyltransferase that transfers not only GalNAc but also cycles of 95°C for 30 sec, 56°C for 30 sec, and 72°C for 300 sec. GlcNAc to the common linkage-region core tetrasaccharide The amplified fragments were digested with BglII and cloned through ␣1,4-linkage and is a strong candidate for the key into the BamHI site of pEF-BOS͞IP. enzyme leading to HS͞Hep biosynthesis, segregating it from CS͞DS biosynthesis (26). Identification of EXTL2 as GlcNAcT-I Expression of the Soluble Forms of EXTL1 and EXTL3 in COS-1 Cells. for HS͞Hep synthesis suggested that other EXT-like genes also Each expression plasmid (6.7 ␮g) was transfected into COS-1 have some roles in HS formation. In the present study, soluble cells on 100-mm plates by using FuGENE6 (Roche Molecular forms of EXTL1 and EXTL3 were transiently expressed in Biochemicals, Tokyo) according to the instructions supplied by COS-1 cells and their glycosyltransferase activities were the manufacturer. Two days after transfection, 1 ml of the revealed. medium was collected and the secreted fusion protein was purified by incubation with 10 ␮l of IgG-Sepharose (Amersham Materials and Methods Pharmacia) for2hat4°C. The beads recovered by centrifugation Materials. UDP-[3H]GlcNAc (60 Ci͞mmol), UDP-[U-14C]GlcA were washed with each assay buffer described below, resus- (285.2 mCi͞mmol), and UDP-[3H]GalNAc (10 Ci͞mmol) were pended in the same buffer, and then tested for glycosyltrans- purchased from NEN. Unlabeled UDP-GlcNAc, UDP-GlcA, ferase activities. For GlcNAc transferase assays, the reaction and UDP-GalNAc were supplied by Sigma. Flavobacterium mixture of a total volume of 20 ␮l contained 10 ␮lofthe heparinum heparitinase
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