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Heparan-Sulfate 6-O-Sulfotransferase 1-3 (HS6ST1-3)

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Handbook of Glycosyltransferases and Related Genes

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Abstract

The functions of heparan sulfate (HS) are involved in various cellular processes such as proliferation, differentiation, adhesion, migration, morphology, and maintenance of stem cells (Habuchi et al. 2004; Bishop et al. 2007; Lindahl and Li 2009; Buresh et al. 2010; Shah et al. 2011; Buresh-Stiemke et al. 2012). It has been shown that HS plays some roles in various physiological phenomena such as inflammation, blood coagulation, tumor cell invasion, and malignancy. Moreover, infections of host cells with pathogens such as viruses, bacteria, and parasites have been shown to occur through the interactions with cell surface HS on host cells (Mettenleiter et al. 1990; Trybala et al. 1996; Liu and Thorp 2002). 6-O-Sulfate residues in HS are greatly involved in the above various biological and pathological processes primarily by modulating various signal transduction pathways such as fibroblast growth factors (FGFs), vascular endothelial growth factors (VEGFs), Wnts, and hedgehog. HS 6-O-sulfotransferases (HS6STs) transfer sulfate to position 6 of the N-sulfoglucosamine/N-acetylglucosamine residue in heparin/HS. Three isoforms are identified in mouse and human. All HS6STs are type II transmembrane proteins with short cytoplasmic domain at the N-terminus, followed by transmembrane and luminal domain which have 3′-phosphoadenosine 5′- phosphosulfate (PAPS) binding site and sulfotransferase activity localized at the Golgi apparatus.

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References

  • Backen AC, Cole CL, Lau SC, Clamp AR, McVey R, Gallagher JT, Jayson GC (2007) Heparan sulphate synthetic and editing enzymes in ovarian cancer. Br J Cancer 96:1544–1548. doi:10.1038/sj.bjc.6603747

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Baronchelli S, Villa N, Redaelli S, Lissoni S, Saccheri F, Panzeri E, Conconi D, Bentivegna A, Crosti F, Sala E, Bertola F, Marozzi A, Pedicini A, Ventruto M, Police MA, Dalpra L (2012) Investigating the role of X chromosome breakpoints in premature ovarian failure. Mol Cytogenet 5:32-8166-5-32. doi:10.1186/1755-8166-5-32; 10.1186/1755-8166-5-32

    Article  Google Scholar 

  • Bink RJ, Habuchi H, Lele Z, Dolk E, Joore J, Rauch GJ, Geisler R, Wilson SW, den Hertog J, Kimata K, Zivkovic D (2003) Heparan sulfate 6-o-sulfotransferase is essential for muscle development in zebrafish. J Biol Chem 278:31118–31127. doi:10.1074/jbc.M213124200

    Article  CAS  PubMed  Google Scholar 

  • Bishop JR, Schuksz M, Esko JD (2007) Heparan sulphate proteoglycans fine-tune mammalian physiology. Nature 446:1030–1037. doi:10.1038/nature05817

    Article  CAS  PubMed  Google Scholar 

  • Buresh RA, Kuslak SL, Rusch MA, Vezina CM, Selleck SB, Marker PC (2010) Sulfatase 1 is an inhibitor of ductal morphogenesis with sexually dimorphic expression in the urogenital sinus. Endocrinology 151:3420–3431. doi:10.1210/en.2009-1359

    Article  CAS  PubMed  Google Scholar 

  • Buresh-Stiemke RA, Malinowski RL, Keil KP, Vezina CM, Oosterhof A, Van Kuppevelt TH, Marker PC (2012) Distinct expression patterns of Sulf1 and Hs6st1 spatially regulate heparan sulfate sulfation during prostate development. Dev Dyn. doi:10.1002/dvdy.23886; 10.1002/dvdy.23886

    PubMed Central  PubMed  Google Scholar 

  • Cadwallader AB, Yost HJ (2006) Combinatorial expression patterns of heparan sulfate sulfotransferases in zebrafish: II. The 6-O-sulfotransferase family. Dev Dyn 235:3432–3437. doi:10.1002/dvdy.20990

    Article  CAS  PubMed  Google Scholar 

  • Chen E, Stringer SE, Rusch MA, Selleck SB, Ekker SC (2005) A unique role for 6-O sulfation modification in zebrafish vascular development. Dev Biol 284:364–376. doi:10.1016/j.ydbio.2005.05.032

    Article  CAS  PubMed  Google Scholar 

  • Conway CD, Price DJ, Pratt T, Mason JO (2011) Analysis of axon guidance defects at the optic chiasm in heparan sulphate sulphotransferase compound mutant mice. J Anat 219:734–742. doi:10.1111/j.1469-7580.2011.01432.x; 10.1111/j.1469-7580.2011.01432.x

    Article  CAS  PubMed  Google Scholar 

  • Davison RM, Fox M, Conway GS (2000) Mapping of the POF1 locus and identification of putative genes for premature ovarian failure. Mol Hum Reprod 6:314–318

    Article  CAS  PubMed  Google Scholar 

  • Ebner A, Kiefer FN, Ribeiro C, Petit V, Nussbaumer U, Affolter M (2002) Tracheal development in Drosophila melanogaster as a model system for studying the development of a branched organ. Gene 287:55–66

    Article  CAS  PubMed  Google Scholar 

  • Habuchi H, Habuchi O, Kimata K (1995) Purification and characterization of heparan sulfate 6-sulfotransferase from the culture medium of Chinese hamster ovary cells. J Biol Chem 270:4172–4179

    Article  CAS  PubMed  Google Scholar 

  • Habuchi H, Kobayashi M, Kimata K (1998) Molecular characterization and expression of heparan-sulfate 6-sulfotransferase. Complete cDNA cloning in human and partial cloning in Chinese hamster ovary cells. J Biol Chem 273:9208–9213

    Article  CAS  PubMed  Google Scholar 

  • Habuchi H, Tanaka M, Habuchi O, Yoshida K, Suzuki H, Ban K, Kimata K (2000) The occurrence of three isoforms of heparan sulfate 6-O-sulfotransferase having different specificities for hexuronic acid adjacent to the targeted N-sulfoglucosamine. J Biol Chem 275:2859–2868

    Article  CAS  PubMed  Google Scholar 

  • Habuchi H, Miyake G, Nogami K, Kuroiwa A, Matsuda Y, Kusche-Gullberg M, Habuchi O, Tanaka M, Kimata K (2003) Biosynthesis of heparan sulphate with diverse structures and functions: two alternatively spliced forms of human heparan sulphate 6-O-sulphotransferase-2 having different expression patterns and properties. Biochem J 371:131–142. doi:10.1042/BJ20021259

    Article  CAS  PubMed  Google Scholar 

  • Habuchi H, Habuchi O, Kimata K (2004) Sulfation pattern in glycosaminoglycan: does it have a code? Glycoconj J 21:47–52. doi:10.1023/B:GLYC.0000043747.87325.5e

    Article  CAS  PubMed  Google Scholar 

  • Habuchi H, Habuchi O, Uchimura K, Kimata K, Muramatsu T (2006) Determination of substrate specificity of sulfotransferases and glycosyltransferases (proteoglycans). Methods Enzymol 416:225–243. doi:10.1016/S0076-6879(06)16014-0

    Article  CAS  PubMed  Google Scholar 

  • Habuchi H, Nagai N, Sugaya N, Atsumi F, Stevens RL, Kimata K (2007) Mice deficient in heparan sulfate 6-O-sulfotransferase-1 exhibit defective heparan sulfate biosynthesis, abnormal placentation, and late embryonic lethality. J Biol Chem 282:15578–15588. doi:10.1074/jbc.M607434200

    Article  CAS  PubMed  Google Scholar 

  • Habuchi H, Kimata K (2010) Mice deficient in heparan sulfate 6-O-sulfotransferase-1. Prog Mol Biol Transl Sci 93:79–111. doi:10.1016/S1877-1173(10)93005-6

    Article  CAS  PubMed  Google Scholar 

  • Irie A, Yates EA, Turnbull JE, Holt CE (2002) Specific heparan sulfate structures involved in retinal axon targeting. Development 129:61–70

    CAS  PubMed  Google Scholar 

  • Izvolsky KI, Lu J, Martin G, Albrecht KH, Cardoso WV (2008) Systemic inactivation of Hs6st1 in mice is associated with late postnatal mortality without major defects in organogenesis. Genesis 46:8–18. doi:10.1002/dvg.20355

    Article  CAS  PubMed  Google Scholar 

  • Kamimura K, Fujise M, Villa F, Izumi S, Habuchi H, Kimata K, Nakato H (2001) Drosophila heparan sulfate 6-O-sulfotransferase (dHS6ST) gene. Structure, expression, and function in the formation of the tracheal system. J Biol Chem 276:17014–17021. doi:10.1074/jbc.M011354200

    Article  CAS  PubMed  Google Scholar 

  • Kamimura K, Koyama T, Habuchi H, Ueda R, Masu M, Kimata K, Nakato H (2006) Specific and flexible roles of heparan sulfate modifications in Drosophila FGF signaling. J Cell Biol 174:773–778. doi:10.1083/jcb.200603129

    Article  CAS  PubMed  Google Scholar 

  • Kamimura K, Maeda N, Nakato H (2011) In vivo manipulation of heparan sulfate structure and its effect on Drosophila development. Glycobiology 21:607–618. doi:10.1093/glycob/cwq202

    Article  CAS  PubMed  Google Scholar 

  • Kato H, Matsumine A, Wakabayashi T, Hasegawa M, Sudo A, Shintani K, Fukuda A, Kato K, Ide N, Orita S, Hasegawa T, Matsumura C, Furukawa M, Tasaki T, Sonoda H, Uchida A (2007) Large-scale gene expression profiles, differentially represented in osteoarthritic synovium of the knee joint using cDNA microarray technology. Biomarkers 12:384–402. doi:10.1080/13547500601162482

    Article  CAS  PubMed  Google Scholar 

  • Kleinschmit A, Koyama T, Dejima K, Hayashi Y, Kamimura K, Nakato H (2010) Drosophila heparan sulfate 6-O endosulfatase regulates wingless morphogen gradient formation. Dev Biol 345:204–214. doi:10.1016/j.ydbio.2010.07.006

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kobayashi T, Habuchi H, Nogami K, Ashikari-Hada S, Tamura K, Ide H, Kimata K (2010) Functional analysis of chick heparan sulfate 6-O-sulfotransferases in limb bud development. Dev Growth Differ 52:146–156. doi:10.1111/j.1440-169X.2009.01148.x

    Article  CAS  PubMed  Google Scholar 

  • Kotani N, Kitazume S, Kamimura K, Takeo S, Aigaki T, Nakato H, Hashimoto Y (2005) Characterization of Drosophila aspartic proteases that induce the secretion of a Golgi-resident transferase, heparan sulfate 6-O-sulfotransferase. J Biochem 137:315–322. doi:10.1093/jb/mvi034

    Article  CAS  PubMed  Google Scholar 

  • Kusche-Gullberg M, Kjellen L (2003) Sulfotransferases in glycosaminoglycan biosynthesis. Curr Opin Struct Biol 13:605–611

    Article  CAS  PubMed  Google Scholar 

  • Labbe E, Lock L, Letamendia A, Gorska AE, Gryfe R, Gallinger S, Moses HL, Attisano L (2007) Transcriptional cooperation between the transforming growth factor-beta and Wnt pathways in mammary and intestinal tumorigenesis. Cancer Res 67:75–84. doi:10.1158/0008-5472.CAN-06-2559

    Article  CAS  PubMed  Google Scholar 

  • Li P, Rossman TG (2001) Genes upregulated in lead-resistant glioma cells reveal possible targets for lead-induced developmental neurotoxicity. Toxicol Sci 64:90–99

    Article  CAS  PubMed  Google Scholar 

  • Lindahl U, Li JP (2009) Interactions between heparan sulfate and proteins-design and functional implications. Int Rev Cell Mol Biol 276:105–159. doi:10.1016/S1937-6448(09)76003-4

    Article  PubMed  Google Scholar 

  • Liu J, Thorp SC (2002) Cell surface heparan sulfate and its roles in assisting viral infections. Med Res Rev 22:1–25

    Article  PubMed  Google Scholar 

  • Mettenleiter TC, Zsak L, Zuckermann F, Sugg N, Kern H, Ben-Porat T (1990) Interaction of glycoprotein gIII with a cellular heparinlike substance mediates adsorption of pseudorabies virus. J Virol 64:278–286

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nagai N, Habuchi H, Esko JD, Kimata K (2004) Stem domains of heparan sulfate 6-O-sulfotransferase are required for Golgi localization, oligomer formation and enzyme activity. J Cell Sci 117:3331–3341. doi:10.1242/jcs.01191

    Article  CAS  PubMed  Google Scholar 

  • Nakato H, Kimata K (2002) Heparan sulfate fine structure and specificity of proteoglycan functions. Biochim Biophys Acta 1573:312–318

    Article  CAS  PubMed  Google Scholar 

  • Nogami K, Suzuki H, Habuchi H, Ishiguro N, Iwata H, Kimata K (2004) Distinctive expression patterns of heparan sulfate O-sulfotransferases and regional differences in heparan sulfate structure in chick limb buds. J Biol Chem 279:8219–8229. doi:10.1074/jbc.M307304200

    Article  CAS  PubMed  Google Scholar 

  • Plump AS, Erskine L, Sabatier C, Brose K, Epstein CJ, Goodman CS, Mason CA, Tessier-Lavigne M (2002) Slit1 and Slit2 cooperate to prevent premature midline crossing of retinal axons in the mouse visual system. Neuron 33:219–232

    Article  CAS  PubMed  Google Scholar 

  • Pratt T, Conway CD, Tian NM, Price DJ, Mason JO (2006) Heparan sulphation patterns generated by specific heparan sulfotransferase enzymes direct distinct aspects of retinal axon guidance at the optic chiasm. J Neurosci 26:6911–6923. doi:10.1523/JNEUROSCI.0505-06.2006

    Article  CAS  PubMed  Google Scholar 

  • Qu X, Carbe C, Tao C, Powers A, Lawrence R, van Kuppevelt TH, Cardoso WV, Grobe K, Esko JD, Zhang X (2011) Lacrimal gland development and Fgf10-Fgfr2b signaling are controlled by 2-O- and 6-O-sulfated heparan sulfate. J Biol Chem 286:14435–14444. doi:10.1074/jbc.M111.225003

    Article  CAS  PubMed  Google Scholar 

  • Sedita J, Izvolsky K, Cardoso WV (2004) Differential expression of heparan sulfate 6-O-sulfotransferase isoforms in the mouse embryo suggests distinctive roles during organogenesis. Dev Dyn 231:782–794. doi:10.1002/dvdy.20173

    Article  CAS  PubMed  Google Scholar 

  • Shah MM, Sakurai H, Gallegos TF, Sweeney DE, Bush KT, Esko JD, Nigam SK (2011) Growth factor-dependent branching of the ureteric bud is modulated by selective 6-O sulfation of heparan sulfate. Dev Biol 356:19–27. doi:10.1016/j.ydbio.2011.05.004

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Song K, Li Q, Peng YB, Li J, Ding K, Chen LJ, Shao CH, Zhang LJ, Li P (2011) Silencing of hHS6ST2 inhibits progression of pancreatic cancer through inhibition of Notch signalling. Biochem J 436:271–282. doi:10.1042/BJ20110297

    Article  CAS  PubMed  Google Scholar 

  • Stringer SE (2006) The role of heparan sulphate proteoglycans in angiogenesis. Biochem Soc Trans 34:451–453. doi:10.1042/BST0340451

    Article  CAS  PubMed  Google Scholar 

  • Sugaya N, Habuchi H, Nagai N, Ashikari-Hada S, Kimata K (2008) 6-O-sulfation of heparan sulfate differentially regulates various fibroblast growth factor-dependent signalings in culture. J Biol Chem 283:10366–10376. doi:10.1074/jbc.M705948200

    Article  CAS  PubMed  Google Scholar 

  • Tornberg J, Sykiotis GP, Keefe K, Plummer L, Hoang X, Hall JE, Quinton R, Seminara SB, Hughes V, Van Vliet G, Van Uum S, Crowley WF, Habuchi H, Kimata K, Pitteloud N, Bulow HE (2011) Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci USA 108:11524–11529. doi:10.1073/pnas.1102284108

    Article  CAS  PubMed  Google Scholar 

  • Townley RA, Bulow HE (2011) Genetic analysis of the heparan modification network in Caenorhabditis elegans. J Biol Chem 286:16824–16831. doi:10.1074/jbc.M111.227926

    Article  CAS  PubMed  Google Scholar 

  • Tran TH, Shi X, Zaia J, Ai X (2012) Heparan sulfate 6-O-endosulfatases (Sulfs) coordinate the Wnt signaling pathways to regulate myoblast fusion during skeletal muscle regeneration. J Biol Chem 287:32651–32664. doi:10.1074/jbc.M112.353243

    Article  CAS  PubMed  Google Scholar 

  • Trybala E, Bergstrom T, Spillmann D, Svennerholm B, Olofsson S, Flynn SJ, Ryan P (1996) Mode of interaction between pseudorabies virus and heparan sulfate/heparin. Virology 218:35–42. doi:10.1006/viro.1996.0163

    Article  CAS  PubMed  Google Scholar 

  • Waaijer CJ, de Andrea CE, Hamilton A, van Oosterwijk JG, Stringer SE, Bovee JV (2012) Cartilage tumour progression is characterized by an increased expression of heparan sulphate 6O-sulphation-modifying enzymes. Virchows Arch 461:475–481. doi:10.1007/s00428-012-1300-5; 10.1007/s00428-012-1300-5

    Article  CAS  PubMed  Google Scholar 

  • Wang W, Zhong B, Sun J, Cao J, Tian J, Zhong N, Zhao W, Tian L, Xu P, Guo D, Ju X, Ma W, Li M, Hou W, Lu S (2011) Down-regulated HS6ST2 in osteoarthritis and Kashin-Beck disease inhibits cell viability and influences expression of the genes relevant to aggrecan metabolism of human chondrocytes. Rheumatology (Oxford) 50:2176–2186. doi:10.1093/rheumatology/ker230

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Institute for Molecular Science of Medicine, Aichi Medical University, 480-1195, Nagakute, Aichi, Japan

    Dr. Naoko Nagai

  2. Advanced Medical Research Center, Aichi Medical University, 1-1 Yazakokarimata, 480-1195, Nagakute, Aichi, Japan

    Dr. Koji Kimata

Authors
  1. Dr. Naoko Nagai
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  2. Dr. Koji Kimata
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Corresponding author

Correspondence to Naoko Nagai .

Editor information

Editors and Affiliations

  1. RIKEN-Max-Planck Joint Research Center for Systems Chemical Biology, RIKEN, Wako, Saitama, Japan

    Naoyuki Taniguchi

  2. Department of Biochemistry, Kochi University, Medical School, Nankoku, Kochi, Japan

    Koichi Honke

  3. Sanford Burnham Medical Research Institute, La Jolla, California, USA

    Minoru Fukuda

  4. Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan

    Hisashi Narimatsu

  5. RIKEN-Max-Planck Joint Research Center for Systems Chemical Biology, RIKEN, Wako, Saitama, Japan

    Yoshiki Yamaguchi

  6. Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

    Takashi Angata

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Nagai, N., Kimata, K. (2014). Heparan-Sulfate 6-O-Sulfotransferase 1-3 (HS6ST1-3). In: Taniguchi, N., Honke, K., Fukuda, M., Narimatsu, H., Yamaguchi, Y., Angata, T. (eds) Handbook of Glycosyltransferases and Related Genes. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54240-7_68

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