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

  • Naoko Nagai
  • Koji Kimata
Reference work entry


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.


Heparan Sulfate Premature Ovarian Failure Kallmann Syndrome Retinal Ganglion Cell Axon Idiopathic Hypogonadotropic Hypogonadism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 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.6603747PubMedCentralPubMedCrossRefGoogle Scholar
  2. 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; 10.1186/1755-8166-5-32CrossRefGoogle Scholar
  3. 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.M213124200PubMedCrossRefGoogle Scholar
  4. Bishop JR, Schuksz M, Esko JD (2007) Heparan sulphate proteoglycans fine-tune mammalian physiology. Nature 446:1030–1037. doi:10.1038/nature05817PubMedCrossRefGoogle Scholar
  5. 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.2009-1359PubMedCrossRefGoogle Scholar
  6. 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.23886PubMedCentralPubMedGoogle Scholar
  7. 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.20990PubMedCrossRefGoogle Scholar
  8. 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.2005.05.032PubMedCrossRefGoogle Scholar
  9. 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.xPubMedCrossRefGoogle Scholar
  10. Davison RM, Fox M, Conway GS (2000) Mapping of the POF1 locus and identification of putative genes for premature ovarian failure. Mol Hum Reprod 6:314–318PubMedCrossRefGoogle Scholar
  11. 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 287:55–66PubMedCrossRefGoogle Scholar
  12. 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 270:4172–4179PubMedCrossRefGoogle Scholar
  13. 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 273:9208–9213PubMedCrossRefGoogle Scholar
  14. 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 275:2859–2868PubMedCrossRefGoogle Scholar
  15. 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/BJ20021259PubMedCrossRefGoogle Scholar
  16. 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.0000043747.87325.5ePubMedCrossRefGoogle Scholar
  17. 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)16014-0PubMedCrossRefGoogle Scholar
  18. 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.M607434200PubMedCrossRefGoogle Scholar
  19. 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)93005-6PubMedCrossRefGoogle Scholar
  20. Irie A, Yates EA, Turnbull JE, Holt CE (2002) Specific heparan sulfate structures involved in retinal axon targeting. Development 129:61–70PubMedGoogle Scholar
  21. 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.20355PubMedCrossRefGoogle Scholar
  22. 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.M011354200PubMedCrossRefGoogle Scholar
  23. 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.200603129PubMedCrossRefGoogle Scholar
  24. 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/cwq202PubMedCrossRefGoogle Scholar
  25. 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:10.1080/13547500601162482PubMedCrossRefGoogle Scholar
  26. 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.2010.07.006PubMedCentralPubMedCrossRefGoogle Scholar
  27. 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.xPubMedCrossRefGoogle Scholar
  28. 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/mvi034PubMedCrossRefGoogle Scholar
  29. Kusche-Gullberg M, Kjellen L (2003) Sulfotransferases in glycosaminoglycan biosynthesis. Curr Opin Struct Biol 13:605–611PubMedCrossRefGoogle Scholar
  30. 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-06-2559PubMedCrossRefGoogle Scholar
  31. Li P, Rossman TG (2001) Genes upregulated in lead-resistant glioma cells reveal possible targets for lead-induced developmental neurotoxicity. Toxicol Sci 64:90–99PubMedCrossRefGoogle Scholar
  32. 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)76003-4PubMedCrossRefGoogle Scholar
  33. Liu J, Thorp SC (2002) Cell surface heparan sulfate and its roles in assisting viral infections. Med Res Rev 22:1–25PubMedCrossRefGoogle Scholar
  34. 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 64:278–286PubMedCentralPubMedGoogle Scholar
  35. 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.01191PubMedCrossRefGoogle Scholar
  36. Nakato H, Kimata K (2002) Heparan sulfate fine structure and specificity of proteoglycan functions. Biochim Biophys Acta 1573:312–318PubMedCrossRefGoogle Scholar
  37. 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.M307304200PubMedCrossRefGoogle Scholar
  38. 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 33:219–232PubMedCrossRefGoogle Scholar
  39. 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.0505-06.2006PubMedCrossRefGoogle Scholar
  40. 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.M111.225003PubMedCrossRefGoogle Scholar
  41. 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.20173PubMedCrossRefGoogle Scholar
  42. 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.2011.05.004PubMedCentralPubMedCrossRefGoogle Scholar
  43. 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/BJ20110297PubMedCrossRefGoogle Scholar
  44. Stringer SE (2006) The role of heparan sulphate proteoglycans in angiogenesis. Biochem Soc Trans 34:451–453. doi:10.1042/BST0340451PubMedCrossRefGoogle Scholar
  45. 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.M705948200PubMedCrossRefGoogle Scholar
  46. 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.1102284108PubMedCrossRefGoogle Scholar
  47. 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.M111.227926PubMedCrossRefGoogle Scholar
  48. 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.M112.353243PubMedCrossRefGoogle Scholar
  49. 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.1996.0163PubMedCrossRefGoogle Scholar
  50. 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/s00428-012-1300-5PubMedCrossRefGoogle Scholar
  51. 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/ker230CrossRefGoogle Scholar

Copyright information

© Springer Japan 2014

Authors and Affiliations

  1. 1.Institute for Molecular Science of MedicineAichi Medical UniversityNagakuteJapan
  2. 2.Advanced Medical Research CenterAichi Medical UniversityNagakuteJapan

Personalised recommendations