Heparan sulfate proteoglycans: Structure, protein interactions and cell signaling

Anais da Academia Brasileira de Ciencias

Volumn 81, Issue 3, 2009, Pages 409-429

  Dreyfuss, Juliana L ^a   Regatieri, Caio V ^a   Jarrouge, Thais R ^a   Cavalheiro, Renan P ^a   Sampaio, Lucia O ^a   Nader, Helena B ^a  

^a FEDERAL UNIVERSITY OF SÃO PAULO   (Brazil)

Author keywords

Cell cycle; Cell proliferation; Extracellular matrix; Focal adhesion; Glycosaminoglycans and protein interactions; Growth factors

Indexed keywords

ANIMALIA;

EID: 70349322683     PISSN: 00013765     EISSN: 16782690     Source Type: Journal    
DOI: 10.1590/S0001-37652009000300007     Document Type: Review

References (222)

1. Abramsson A et al. 2007. Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development. Genes Dev 21: 316-331.
2. Alexopoulou AN, Multhaupt HA and Couchman JR. 2007. Syndecans in wound healing, inflammation and vascular biology. Int J Biochem Cell Biol 39: 505-528.
3. Alliel PM, Perin JP, Jolles P and Bonnet FJ. 1993. Testican, a multidomain testicular proteoglycan resem- bling modulators of cell social behaviour. Eur J Biochem 214: 347-350.
4. Almeida PC, Nantes IL, Chagas JR, Rizzi CC, Faljoni-Alario A, Carmona E, Juliano L, NADER HB and Tersariol IL. 2001. Cathepsin B activity regulation. Heparin-like glycosaminogylcans protect human cathepsin B from alkaline pH-induced inactivation. J Biol Chem 276: 944-951.
5. Aricescu AR, McKinnell IW, Halfter W AND Stoker AW. 2002. Heparan sulfate proteoglycans are ligands for receptor protein tyrosine phosphatase sigma. Mol Cell Biol 22: 1881-1892.
6. Ashikari-Hada S, Habuchi H, Kariya Y and Kimata K. 2005. Heparin regulates vascular endothelial growth factor165-dependent mitogenic activity, tube formation, and its receptor phosphorylation of human endothelial cells. Comparison of the effects of heparin and modified heparins. J Biol Chem 280: 31508-31515.
7. Athanassiades A and Lala PK. 1998. Role of placenta growth factor (PIGF) in human extravillous trophoblast proliferation, migration and invasiveness. Placenta 19: 465-473.
8. Aviezer D and Yayon A. 1994. Heparin-dependent binding and autophosphorylation of epidermal growth factor (EGF) receptor by heparin-binding EGF-like growth factor but not by EGF. Proc Natl Acad Sci USA 91: 12173-12177.
9. Baeg GH, Lin X, Khare N, Baumgartner S AND Perrimon N. 2001. Heparan sulfate proteoglycans are critical for the organization of the extracellular distribution of Wingless. Development 128: 87-94.
10. Baker AB, Ettenson DS, Jonas M, Nugent MA, Iozzo RV and Edelman ER. 2008. Endothelial cells provide feedback control for vascular remodeling through a mechanosensitive autocrine TGF-beta signaling pathway. Circ Res 103: 289-297.
11. Bartlett AH, Hayashida K and Park PW. 2007. Molecular and cellular mechanisms of syndecans in tissue injury and inflammation. Mol Cells 24: 153-166.
12. Beauvais DM and Rapraeger AC. 2004. Syndecans in tumor cell adhesion and signaling. Reprod Biol Endocrinol 2: 3.
13. Beckett K, Franch-Marro X and Vincent JP. 2008. Glypican-mediated endocytosis of Hedgehog has opposite effects in flies and mice. Trends Cell Biol 18: 360- 363.
14. Belford DA, Hendry IA and Parish CR. 1992. Ability of different chemically modified heparins to potentiate the biologicalactivityofheparin-bindinggrowthfactor1: lack of correlation with growth factor binding. Biochemistry 31: 6498-6503.
15. BELLIN R, CAPILA I, LINCECUM J, PARK PW, REIZES O and Bernfield MR. 2002. Unlocking the secrets of syndecans: transgenic organisms as a potential key. Glycoconj J 19: 295-304.
16. Belting M. 2003. Heparan sulfate proteoglycan as a plasma membrane carrier. Trends Biochem Sci 28: 145-151.
17. Ben-Zaken O, Tzaban S, Tal Y, Horonchik L, Esko JD, Vlodavsky I and Taraboulos A. 2003. Cellular heparan sulfate participates in the metabolism of prions. J Biol Chem 278: 40041-40049.
18. BERNFIELD M, Gotte M, Park PW, Reizes O, Fitzgerald ML, Lincecum J and Zako M. 1999. Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem 68: 729-777.
19. Bezakova G and Ruegg MA. 2003. New insights into the roles of agrin. Nat Rev Mol Cell Biol 4: 295-308.
20. Blackhall FH, Merry CL, Lyon M, Jayson GC, Folkman J, Javaherian K and Gallagher JT. 2003. Binding of endostatin to endothelial heparan sulphate shows a differential requirement for specific sulphates. Biochem J 375: 131-139.
21. 1 transition. Proc Natl Acad Sci USA 84:6770-6774.
22. Caizergues-Ferrer M, Dousseau F, Gas N, Bouche G, Stevens B and Amalric F. 1984. Induction of new proteins in the nuclear matrix of CHO cells by a heat shock: detection of a specific set in the nucleolar matrix. Biochem Biophys Res Commun 118: 444-450.
23. Campbell EJ and Owen CA. 2007. The sulfate groups of chondroitin sulfate- and heparan sulfate-containing pro- teoglycans in neutrophil plasma membranes are novel binding sites for human leukocyte elastase and cathepsin G. J Biol Chem 282: 14645-14654.
24. Cano-Gauci DF et al. 1999. Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmelsyndrome. J Cell Biol 146: 255-264.
25. Capila I and Linhardt RJ. 2002. Heparin-protein interactions. Angew Chem Int Ed Engl 41: 391-412.
26. Capila I, Vandernoot VA, Mealy TR, Seaton BA and Linhardt RJ. 1999. Interaction of heparin with annexin V. FEBS Lett 446: 327-330.
27. Capila I, Hernaiz MJ, Mo YD, Mealy TR, Campos B, Dedman JR, Linhardt RJ and Seaton BA. 2001. Annexin V-heparin oligosaccharide complex suggests heparan sulfate-mediated assembly on cell surfaces. Structure 9: 57-64.
28. Capurro MI, Xu P, Shi W, Li F, Jia A and Filmus J. 2008. Glypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding. Dev Cell 14: 700-711.
29. Cardin AD and Weintraub HJ. 1989. Molecular modeling of protein-glycosaminoglycan interactions. Arteriosclerosis 9: 21-32.
30. Carnero A, Blanco-Aparicio C, Renner O, Link W and Leal JF. 2008. The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr Cancer Drug Targets 8: 187-198.
31. Cassaro CM andDietrich CP. 1977. Distribution of sulfated mucopolysaccharides in invertebrates. J Biol Chem 252: 2254-2261.
32. Casu B, Choay J, Ferro DR, Gatti G, Jacquinet JC, Petitou M, Provasoli A, Ragazzi M, Sinay P and Torri G. 1986. Controversial glycosaminoglycan conformations. Nature 322: 215-216.
33. Chavante SF, Santos EA, Oliveira FW, Guerrini M, Torri G, Casu B, Dietrich CP and Nader HB. 2000. A novel heparan sulphate with high degree of N- sulphation and high heparin cofactor-II activity from the brine shrimp Artemia franciscana. Int J Biol Macromol 27: 49-57.
34. Chen CL, Huang SS and Huang JS. 2006. Cellular heparan sulfate negatively modulates transforming growth factor-beta1 (TGF-beta1) responsiveness in epithelial cells. J Biol Chem 281: 11506-11514.
35. Cheng F, Mani K, van den Born J, Ding K, Belting M and Fransson LA. 2002. Nitric oxide-dependent processing of heparan sulfate in recycling S-nitrosylated glypican-1 takes place in caveolin-1-containing endosomes. J Biol Chem 277: 44431-44439.
36. 1H NMR experiments. Anal Chem 73: 2310-2316.
37. Cohen MM Jr. 2003. The hedgehog signaling network. Am J Med Genet A 123A: 5-28.
38. Cole GJ, Loewy A and Glaser L. 1986. Neuronal cell- cell adhesion depends on interactions of N-CAM with heparin-like molecules. Nature 320: 445-447.
39. Conrad HE. 2001. Degradation of heparan sulfate by nitrous acid. Methods Mol Biol 171: 347-351.
40. Coombe DR, Watt SM and Parish CR. 1994. Mac-1 (CD11b/CD18) and CD45 mediate the adhesion of hematopoietic progenitor cells to stromal cell elements via re- cognition of stromal heparan sulfate. Blood 84: 739-752.
41. Crown SE, Yu Y, Sweeney MD, Leary JA and Handel TM. 2006. Heterodimerization of CCR2 Chemo- kines and Regulation by Glycosaminoglycan Binding. J Biol Chem 281: 25438-25446
42. Czubayko F, Liaudet-Coopman ED, AIGNER A, Tuveson AT, Berchem GJ andWellstein A.1997. A secreted FGF-binding protein can serve as the angiogenic switch in human cancer. Nat Med 3: 1137-1140.
43. Deangelis PL. 2002. Evolution of glycosaminoglycans and their glycosyltransferases: Implications for the extracellular matrices of animals and the capsules of pathogenic bacteria. Anat Rec 268: 317-326.
44. Derksen PW, Keehnen RM, Evers LM, van Oers MH, Spaargaren M and Pals ST. 2002. Cell surface proteogly can syndecan-1mediateshepatocytegrowth factor binding and promotes Met signaling in multiple myeloma. Blood 99: 1405-1410.
45. Dietrich CP, Sampaio LO, Toledo OM and Cassaro CM. 1977. Cell recognition and adhesiveness: a possible biological role for the sulfated mucopolysaccharides. Biochem Biophys Res Commun 75: 329-336.
46. Dietrich CP, Sampaio LO, Montes de Oca H and Nader HB. 1980. Role of sulfated mucopolysaccharides incellrecognitionandneoplastictransformation. AnAcad Bras Cienc 52: 179-186.
47. Dietrich CP, Nader HB and Straus AH. 1983. Structural differences of heparan sulfates according to the tissue and species of origin. Biochem Biophys Res Commun 111: 865-871.
48. Dietrich CP, Tersariol IL, Toma L, Moraes CT, Porcionatto MA, Oliveira FW and Nader HB. 1998. Structure of heparan sulfate: identification of variable and constant oligosaccharide domains in eight heparan sulfates of different origins. Cell Mol Biol (Noisy- le-grand) 44: 417-429.
49. Dietrich CP, Paiva JF, Castro RA, Chavante SF, Jeske W, Fareed J, Gorin PA, Mendes A and Nader HB. 1999. Structural features and anticoagulant activities of a novel natural low molecular weight heparin from the shrimp Penaeus brasiliensis. Biochim Biophys Acta 1428: 273-283.
50. Dietz F, Franken S, Yoshida K, Nakamura H, Kappler J and Gieselmann V. 2002. The family of hepatoma-derived growth factor proteins: characterization of a new member HRP-4 and classification of its subfamilies. Biochem J 366: 491-500.
51. Duchesne L, Tissot B, Rudd TR, Dell A and Fernig DG. 2006. N-glycosylation of fibroblast growth factor receptor 1 regulates ligand and heparan sulfate co-receptor binding. J Biol Chem 281: 27178-27189.
52. Escriba PV, Wedegaertner PB, Goni FM and Vogler O. 2007. Lipid-protein interactions in GPCR- associated signaling. Biochim Biophys Acta 1768: 836-852.
53. Fan TC, Chang HT, Chen IW, Wang HY and Chang MD. 2007. A heparan sulfate-facilitated and raft-dependent macropinocytosis of eosinophil cationic protein. Traffic 8: 1778-1795.
54. Farach-Carson MC and Carson DD. 2007. Perlecan - a multifunctional extracellular proteoglycan scaffold. Glycobiology 17: 897-905.
55. Farach-Carson MC, Brown AJ, Lynam M, SAFRAN JB and Carson DD. 2008. A novel peptide sequence in perlecan domain IV supports cell adhesion, spreading and FAK activation. Matrix Biol 27: 150-160.
56. Fears CY and Woods A. 2006. The role of syndecans in disease and wound healing. Matrix Biol 25: 443-456.
57. Fedarko NS and Conrad HE. 1986. A unique heparan sulfate in the nuclei of hepatocytes: structural changes with the growth state of the cells. J Cell Biol 102: 587-599.
58. Ferreira TM, Medeiros MG, Dietrich CP AND Nader HB. 1993. Structure of heparan sulfate from the fresh water mollusc Anomantidae sp: sequencing of its disaccharide units. Int J Biochem 25: 1219-1225.
59. Ferro DR, Provasoli A, Ragazzi M, Casu B, TORRI G, Bossennec V, PERLY B, Sinay P, Petitou M AND Choay J. 1990. Conformer populations of Liduronic acid residues in glycosaminoglycan sequences. Carbo- hydr Res 195: 157-167.
60. FEYZI E, Lustig F, FAGER G, Spillmann D, LINDAHL U and Salmivirta M. 1997. Characterization of heparin and heparan sulfate domains binding to the long splice variant of platelet-derived growth factor A chain. J Biol Chem 272: 5518-5524.
61. Filmus J. 2002. The contribution of in vivo manipulation of gene expression to the understanding of the function of glypicans. Glycoconj J 19: 319-323.
62. Filmus J, Capurro M and Rast J. 2008. Glypicans. Genome Biol 9: 224.
63. Fjeldstad K andKolset SO. 2005. Decreasing the metastatic potential in cancers-targeting the heparan sulfate proteoglycans. Curr Drug Targets 6: 665-682.
64. Fox AN and Zinn K. 2005. The heparan sulfate proteogly- can syndecan is an in vivo ligand for the Drosophila LAR receptor tyrosine phosphatase. Curr Biol 15: 1701-1711.
65. Franco CR, Rocha HA, Trindade ES, Santos IA, Leite EL, Veiga SS, Nader HB and Dietrich CP. 2001. Heparan sulfate and control of cell division: adhesion and proliferation of mutant CHO-745 cells lacking xylosyl transferase. Braz J Med Biol Res 34: 971-975.
66. Fransson LA. 2003. Glypicans. Int J Biochem Cell Biol 35: 125-129.
67. Franssonl A, Belting M, Cheng F, Jonsson M, MANI K and Sandgren S. 2004. Novel aspects of glypican glycobiology. Cell Mol Life Sci 61: 1016-1024.
68. Fuki IV, Kuhn KM, Lomazov IR, Rothman VL, Tuszynski GP, Iozzo RV, Swenson TL, Fisher EA and Williams KJ. 1997. The syndecan family of proteoglycans. Novel receptors mediating internalization of atherogenic lipoproteins in vitro. J Clin Invest 100: 1611-1622.
69. Fuki IV, Iozzo RV and Williams KJ. 2000. Perlecan heparan sulfate proteoglycan: a novel receptor that medi- ates a distinct pathway for ligand catabolism. J Biol Chem 275: 25742-25750.
70. Furukawa K and Bhavanandan VP. 1983. Influences of anionic polysaccharides on DNA synthesis in isolated nuclei and by DNA polymerase alpha: correlation of ob- served effects with properties of the polysaccharides. Biochim Biophys Acta 740: 466-475.
71. Gagliardi M, Piddini E and Vincent JP. 2008. En- docytosis: a positive or a negative influence on Wnt signalling? Traffic 9: 1-9.
72. Gallagher JT. 2006. Multiprotein signalling complexes: regional assembly on heparan sulphate. Biochem Soc Trans 34: 438-441.
73. Gambarini AG, Miyamoto CA, Lima GA, Nader HB and Dietrich CP. 1993. Mitogenic activity of acidic fibroblast growth factor is enhanced by highly sulfated oligosaccharides derived from heparin and heparan sul- fate. Mol Cell Biochem 124: 121-129.
74. Giros A, Morante J, Gil-Sanz C, Fairen A and Costell M. 2007. Perlecan controls neurogenesis in the developing telencephalon. BMC Dev Biol 7: 29
75. Gitay-Goren H, Soker S, Vlodavsky I and Neufeld G. 1992. The binding of vascular endothelial growth fac- tor to its receptors is dependent on cell surface-associated heparin-like molecules. J Biol Chem 267: 6093-6098.
76. Glass DJ, Dechiara TM, Stitt TN, Distefano PS, Valenzuela DM and Yancopoulos GD. 1996. The receptor tyrosine kinase MuSK is required for neuromuscular junction formation and is a functional receptor for agrin. Cold Spring Harb Symp Quant Biol 61: 435-444.
77. Gomes PB and Dietrich CP. 1982. Distribution of heparin and other sulfated glycosaminoglycans in vertebrates. Comp Biochem Physiol B 73: 857-863.
78. Grunert M, Nurcombe V and Cool SM. 2008. Stem cell fate decisions: the role of heparan sulfate in the control of autocrine and paracrine signals. Curr Stem Cell Res Ther 3: 1-8.
79. Guerrini M, Bisio A and Torri G. 2001. Combined quantitative (1)H and (13)C nuclear magnetic resonance spectroscopy for characterization of heparin preparations. Semin Thromb Hemost 27: 473-482.
80. Guerrini M, Raman R, Venkataraman G, Torri G, Sasisekharan R and Casu B. 2002. A novel com- putational approach to integrate NMR spectroscopy and capillary electrophoresis for structure assignment of heparin and heparan sulfate oligosaccharides. Glycobiology 12: 713-719.
81. Gumienny TL, Macneil LT, Wang H, de Bono M, Wrana JL and Padgett RW. 2007. Glypican LON-2 is a conserved negative regulator of BMP-like signaling in Caenorhabditis elegans. Curr Biol 17: 159-164.
82. Habuchi H, Habuchi O and Kimata K. 2004. Sulfa- tion pattern in glycosaminoglycan: does it have a code? Glycoconj J 21: 47-52.
83. Hacker U, Nybakken K and Perrimon N. 2005. Hep- aran sulphate proteoglycans: the sweet side of develop- ment. Nat Rev Mol Cell Biol 6: 530-541.
84. Handel TM, Johnson Z, Crown SE, Lau EK and Proudfoot AE. 2005. Regulation of protein function by glycosaminoglycans - as exemplified by chemokines. Annu Rev Biochem 74: 385-410.
85. Harmer NJ. 2006. Insights into the role of heparan sulphate in fibroblast growth factor signalling. Biochem Soc Trans 34: 442-445.
86. Harrison CA, Gray PC, Vale WW and Robertson DM. 2005. Antagonists of activin signaling: mechanisms and potential biological applications. Trends Endocrinol Metab 16: 73-78.
87. Hausser HJ, Decking R and Brenner RE. 2004. Testi- can-1, an inhibitor of pro-MMP-2 activation, is expressed in cartilage. Osteoarthritis Cartilage 12: 870-877.
88. Henke CA, Roongta U, Mickelson DJ, Knutson JR and McCarthy JB. 1996. CD44-related chondroitin sulfate proteoglycan, a cell surface receptor implicated with tumor cell invasion, mediates endothelial cell migration on fibrinogen and invasion into a fibrin matrix. J Clin Invest 97: 2541-2552.
89. Hileman RE, Fromm JR, Weiler JM and Linhardt RJ. 1998. Glycosaminoglycan-protein interactions: definition of consensus sites in glycosaminoglycan binding proteins. Bioessays 20: 156-167.
90. Hsia E, Richardson TP and Nugent MA. 2003. Nuclear localization of basic fibroblast growth factor is me- diated by heparan sulfate proteoglycans through protein kinase C signaling. J Cell Biochem 88: 1214-1225.
91. Huber R, Mazzarella R, Chen CN, Chen E, Ireland M, Lindsay S, Pilia G and Crisponi L. 1998. Glypican 3 and glypican 4 are juxtaposed in Xq26.1. Gene 225: 9-16.
92. Iozzo RV. 2005. Basement membrane proteoglycans: from cellar to ceiling. Nat Rev Mol Cell Biol 6: 646-656.
93. Iozzo RV and San Antonio JD. 2001. Heparan sulfate proteoglycans: heavy hitters in the angiogenesis arena. J Clin Invest 108: 349-355.
94. Ishihara M, Fedarko NS and Conrad HE. 1986. Transport of heparan sulfate into the nuclei of hepato- cytes. J Biol Chem 261: 13575-13580.
95. Ishihara M, Guo Y, Wei Z, Yang Z, Swiedler SJ, Orellana A and Hirschberg CB. 1993. Regula- tion of biosynthesis of the basic fibroblast growth factor binding domains of heparan sulfate by heparan sulfate-N- deacetylase/N-sulfotransferase expression. J Biol Chem 268: 20091-20095.
96. Ishitsuka R, Kojima K, Utsumi H, Ogawa H and Matsumoto I. 1998. Glycosaminoglycan binding prop- erties of annexin IV, V, and VI. J Biol Chem 273: 9935- 9941.
97. Jastrebova N, Vanwildemeersch M, Rapraeger AC, Gimenez-Gallego G, Lindahl U and Spillmann D. 2006. Heparan sulfate-related oligosaccharides in ternary complex formation with fibroblast growth factors 1 and2andtheirreceptors. JBiolChem281: 26884-26892.
98. Jeronimo SM, Sales AO, Fernandes MZ, Melo FP, Sampaio LO, Dietrich CP and Nader HB. 1994. Glycosaminoglycan structure and content differ according to the origins of human tumors. Braz J Med Biol Res 27: 2253-2258.
99. Jiang X and Couchman JR. 2003. Perlecan and tumor angiogenesis. J Histochem Cytochem 51: 1393-1410.
100. Johnson KG etal. 2006. TheHSPGsSyndecanandDally- like bind the receptor phosphatase LAR and exert distinct effects on synaptic development. Neuron 49: 517-531.
101. Johnson Z, Proudfoot AE and Handel TM. 2005. In- teraction of chemokines and glycosaminoglycans: a new twist in the regulation of chemokine function with opportunities for therapeutic intervention. Cytokine Growth Factor Rev 16: 625-636.
102. Jury EC, Eldridge J, Isenberg DA and Kabouridis PS. 2007. Agrin signalling contributes to cell activation andisoverexpressedinTlymphocytesfromlupuspatients. J Immunol 179: 7975-7983.
103. Kayed H, Kleeff J, Keleg S, Jiang X, Penzel R, Giese T, Zentgraf H, Buchler MW, Korc M and Friess H. 2006. Correlation of glypican-1 expression with TGF-beta, BMP, and activin receptors in pancreatic ductal adenocarcinoma. Int J Oncol 29: 1139-1148.
104. Kemp LE, Mulloy B and Gherardi E. 2006. Signalling by HGF/SF and Met: the role of heparan sulphate coreceptors. Biochem Soc Trans 34: 414-417.
105. Kirkpatrick CA and Selleck SB. 2007. Heparansulfate proteoglycans at a glance. J Cell Sci 120: 1829-1832.
106. Knox SM and Whitelock JM. 2006. Perlecan: how does one molecule do so many things? Cell Mol Life Sci 63: 2435-2445.
107. Koopmann W, Ediriwickrema C and Krangel MS. 1999. Structure and function of the glycosaminoglycan binding site of chemokine macrophage - inflammatory protein-1 beta. J Immunol 163: 2120-2127.
108. Kreuger J, Spillmann D, LI JP and Lindahl U. 2006. Interactions between heparan sulfate and proteins: the concept of specificity. J Cell Biol 174: 323-327.
109. Krilleke D, Deerkenez A, Schubert W, Giri I, Robinson GS, Ng YS and Shima DT. 2007. Molecular mapping and functional characterization of the VEGF- 164 heparin-binding domain. J Biol Chem 282: 28045-28056.
110. Lau EK, Allen S, Hsu AR and Handel TM. 2004. Chemokine-receptor interactions: GPCRs, glycosamino- glycans and viral chemokine binding proteins. Adv Protein Chem 68: 351-391.
111. Leicht DT, Balan V, Kaplun A, Singh-Gupta V, Kaplun L, Dobson M and Tzivion G. 2007. Raf kinases: function, regulation and role in human cancer. Biochim Biophys Acta 1773: 1196-1212.
112. Lewis KA, Gray PC, Blount AL, MacConell LA, Wiater E, Bilezikjian LM and VALE W. 2000. Be- taglycan binds inhibin and can mediate functional antagonism of activin signalling. Nature 404: 411-414.
113. Lindner JR, Hillman PR, Barrett AL, Jackson MC, Perry TL, Park Y and Datta S. 2007. The Drosophila Perlecan genetrol regulates multiple signaling path- ways in different developmental contexts. BMC Dev Biol 7: 121.
114. Loo BM, Kreuger J, Jalkanen M, Lindahl U AND Salmivirta M. 2001. Binding of heparin/heparan sulfate to fibroblast growth factor receptor 4. J Biol Chem 276: 16868-16876.
115. Lopes CC, Dietrich CP and Nader HB. 2006a. Specific structural features of syndecans and heparan sulfate chains are needed for cell signaling. Braz J Med Biol Res 39: 157-167.
116. Lopes CC, Toma L, Pinhal MA, Porcionatto MA, Sogayar MC, Dietrich CP and Nader HB. 2006b. EJ-ras oncogene transfection of endothelial cells upregulates the expression of syndecan-4 and downregulates heparan sulfate sulfotransferases and epimerase. Biochimie 88: 1493-1504.
117. Lortat-Jacob H, Grosdidier A and Imberty A. 2002. Structural diversity of heparan sulfate binding domains in chemokines. Proc Natl Acad Sci USA 99: 1229-1234.
118. Ma YQ and Geng JG. 2000. Heparan sulfate-like proteoglycans mediate adhesion of human malignant melanoma A375 cells to P-selectin under flow. J Immunol 165: 558- 565.
119. Miyazono K. 1997. TGF-beta receptors and signal transduction. Int J Hematol 65: 97-104.
120. Mobli M, Nilsson M and Almond A. 2008. The structural plasticity of heparan sulfate NA-domains and hence their role in mediating multivalent interactions is con- firmed by high-accuracy (15)N-NMR relaxation studies. Glycoconj J 25: 401-414.
121. Mohammadi M, Olsen SK and Goetz R. 2005a. A protein canyon in the FGF-FGF receptor dimer selects from an a la carte menu of heparan sulfate motifs. Curr Opin Struct Biol 15: 506-516.
122. Mohammadi M, Olsen SK and Ibrahimi OA. 2005b. Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev 16: 107-137.
123. Mongiat M, Taylor K, Otto J, Aho S, Uitto J, Whitelock JM and IOZZO RV. 2000. The protein core of the proteoglycan perlecan binds specifically to fibroblast growth factor-7. J Biol Chem 275: 7095-7100.
124. Moreira CR, Lopes CC, Cuccovia IM, Porcionatto MA, Dietrich CP and Nader HB. 2004. Heparan sulfate and control of endothelial cell proliferation: increased synthesis during the S phase of the cell cycle and inhibition of thymidine incorporation induced by orthonitrophenyl-beta-D-xylose. Biochim Biophys Acta 1673: 178-185.
125. Morgan MR, Humphries MJ and Bass MD. 2007. Synergistic control of cell adhesion by integrins and syndecans. Nat Rev Mol Cell Biol 8: 957-969.
126. Mulloy B. 2005. The specificity of interactions between proteins and sulfated polysaccharides. An Acad Bras Cienc 77: 651-664.
127. Mulloy B and Forster MJ. 2000. Conformation and dynamics of heparin and heparan sulfate. Glycobiology 10: 1147-1156.
128. Mulloy B and Linhardt RJ. 2001. Order out of complexity-protein structures that interact with heparin. Curr Opin Struct Biol 11: 623-628.
129. Murray AJ. 2008. Pharmacological PKA inhibition: all may not be what it seems. Sci Signal 1: re4.
130. Nader HB, Takahashi HK, Straus AH and Dietrich CP. 1980. Selective distribution of the heparin in mammals: conspicuous presence of heparin in lymphoid tissues. Biochim Biophys Acta 627: 40-48.
131. Nader HB, Ferreira TM, Paiva JF, Medeiros MG, Jeronimo SM, PAIVA VM and Dietrich CP. 1984. Isolation and structural studies of heparan sulfates and chondroitin sulfates from three species of molluscs. J Biol Chem 259: 1431-1435.
132. Nader HB, Dietrich CP, Buonassisi V and Colburn P. 1987. Heparin sequences in the heparan sulfate chains of an endothelial cell proteoglycan. Proc Natl Acad Sci USA 84: 3565-3569.
133. 13C NMR spectroscopy. J Biol Chem 265: 16807-16813.
134. Nader HB et al. 1999a. Heparan sulfates and heparins: similar compounds performing the same functions in vertebrates and invertebrates? Braz J Med Biol Res 32: 529-538.
135. Nader HB, Kobayashi EY, Chavante SF, Tersariol IL, Castro RA, Shinjo SK, Naggi A, Torri G, Casu B and Dietrich CP. 1999b. New insights on the specificity of heparin and heparan sulfate lyases from Flavobacterium heparinum revealed by the use of synthetic derivatives of K5 polysaccharide from E. coli and 2-O-desulfated heparin. Glycoconj J 16: 265-270.
136. Nakada M, Miyamori H, Yamashita J and Sato H. 2003. Testican 2 abrogates inhibition of membrane-type matrix metalloproteinases by other testican family proteins. Cancer Res 63: 3364-3369.
137. Nascimento FD, Rizzi CC, Nantes IL, Stefe I, Turk B, Carmona AK, Nader HB, Juliano L and Tersariol IL. 2005. Cathepsin X binds to cell surface heparan sulfate proteoglycans. Arch Biochem Biophys 436: 323-332.
138. Nascimento FD, Hayashi MA, Kerkis A, Oliveira V, Oliveira EB, Radis-Baptista G, Nader HB, Yamane T, Tersariol IL and Kerkis I. 2007. Crotamine mediates gene delivery into cells through the binding to heparan sulfate proteoglycans. J Biol Chem 282: 21349-21360.
139. Ng YS, Krilleke D and Shima DT. 2006. VEGF function in vascular pathogenesis. Exp Cell Res 312: 527-537.
140. Ngo ST, Noakes PG and Phillips WD. 2007. Neural agrin: a synaptic stabiliser. Int J Biochem Cell Biol 39: 863-867.
141. Noti C and Seeberger PH. 2005. Chemical approaches to define the structure-activity relationship of heparin-like glycosaminoglycans. Chem Biol 12: 731-756.
142. Nozik-Grayck E, Suliman HB and Piantadosi CA. 2005. Extracellular superoxide dismutase. Int J Biochem Cell Biol 37: 2466-2471.
143. Nugent MA and Iozzo RV. 2000. Fibroblast growth factor-2. Int J Biochem Cell Biol 32: 115-120.
144. nunes SS, Outeiro-Bernstein MA, Juliano L, Vardiero F, Nader HB, Woods A, Legrand C and Morandi V. 2008. Syndecan-4 contributes to endothelial tubulogenesis through interactions with two motifs inside the pro-angiogenic N-terminal domain of thrombospondin-1. J Cell Physiol 214: 828-837.
145. Oba-Shinjo SM et al. 2006. Melanocyte transformation associated with substrate adhesion impediment. Neoplasia 8: 231-241.
146. Oh ES and Couchman JR. 2004. Syndecans-2 and -4; close cousins, but not identical twins. Mol Cells 17: 181- 187.
147. Padera R, Venkataraman G, Berry D, Godavarti R and Sasisekharan R. 1999. FGF-2/fibroblast growth factor receptor/heparin-like glycosaminoglycan interactions: a compensation model for FGF-2 signaling. Faseb J 13: 1677-1687.
148. Pankonin MS, Gallagher JT and Loeb JA. 2005. Specific structural features of heparan sulfate proteoglycans potentiate neuregulin-1 signaling. J Biol Chem 280: 383-388.
149. Parish CR. 2006. The role of heparan sulphate in inflamma- tion. Nat Rev Immunol 6: 633-643.
150. Patel VN, Likar KM, Zisman-Rozen S, Cowherd SN, Lassiter KS, Sher I, Yates EA, Turnbull JE, Ron D and Hoffman MP. 2008. Specific heparan sulfate structures modulate FGF10-mediated submandibular gland epithelial morphogenesis and differentiation. J Biol Chem 283: 9308-9317.
151. Patey SJ, Edwards EA, Yates EA and Turnbull JE. 2008. Engineered heparins: novel beta-secretase inhib- itorsaspotentialAlzheimer'sdiseasetherapeutics. Neuro- degener Dis 5: 197-199.
152. Pellegrini L, Burke DF, Von Delft F, Mulloy B and Blundell TL. 2000. Crystal structure of fibrob last growth factor receptor ectodomain bound to ligand and heparin. Nature 407: 1029-1034.
153. Peretti T, Waisberg J, Mader AM, De Matos LL, Da Costa RB, Conceição GM, Lopes AC, Nader HB and PINHAL MA. 2008. Heparanase-2, syndecan-1, and extracellular matrix remodeling in colorectal carci- noma. Eur J Gastroenterol Hepatol 20: 756-765.
154. Poon GM and Gariepy J. 2007. Cell-surface proteogly- cans as molecular portals for cationic peptide and polymer entry into cells. Biochem Soc Trans 35: 788-793.
155. Porcionatto MA, Pinto CR, Dietrich CP and Nader HB. 1994. Heparan sulfate proteoglycan and control of cell proliferation: enhanced synthesis induced by phorbol ester (PMA) during G(1)-phase. Braz J Med Biol Res 27: 2185-2190.
156. Porcionatto MA, Moreira CR, Lotfi CF, Armelin HA, Dietrich CP and Nader HB. 1998. Stimulation of heparan sulfate proteoglycan synthesis and secretion during G1 phase induced by growth factors and PMA. J Cell Biochem 70: 563-572.
157. Porcionatto MA, Nader HB and Dietrich CP. 1999. Heparan sulfate and cell division. Braz J Med Biol Res 32: 539-544.
158. Powell AK, Yates EA, Fernig DG and Turnbull JE. 2004. Interactions of heparin/heparan sulfate with proteins: appraisal of structural factors and experimental approaches. Glycobiology 14: 17R-30R.
159. Powers CJ, McLeskey SW and Wellstein A. 2000. Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer 7: 165-197.
160. Presta M, Dell'era P, Mitola s, Moroni E, Ronca R and Rusnati M. 2005. Fibroblast growth factor/fibro- blast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 16: 159-178.
161. Quarto N and Amalric F. 1994. Heparan sulfate proteoglycans as transducers of FGF-2 signalling. J Cell Sci 107 (Pt 11): 3201-3212.
162. Ragazzi M, Ferro DR, Provasoli A, Pumilia P, Cassinari A, Torri G, Guerrini M, Casu B, Nader HB and Dietrich CP. 1993. Conformation of the Un saturated Uronic Acid Residues of Glycosaminoglycan Disaccharides. J Carbohy Chem 12: 513-535.
163. Raman R, Sasisekharan V and Sasisekharan R. 2005. Structural insights into biological roles of protein- glycosaminoglycaninteractions. ChemBiol12: 267-277.
164. Rapraeger AC, Krufka A and Olwin BB. 1991. Requirement of heparan sulfate for bFGF-mediated fibro- blast growth and myoblast differentiation. Science 252: 1705-1708.
165. Rapraeger AC, Guimond S, Krufka A and Olwin BB. 1994. Regulation by heparan sulfate in fibroblast growth factor signaling. Methods Enzymol 245: 219-240.
166. Rider CC. 2006. Heparin/heparan sulphate binding in the TGF-beta cytokine superfamily. Biochem Soc Trans 34: 458-460.
167. Rohde LH, Janatpore MJ, McMaster MT, Fisher S, Zhou Y, Lim KH, French M, Hoke D, Julian J and Carson DD. 1998. Complementary expression of HIP, a cell-surface heparan sulfate binding protein, and perlecan at the human fetal-maternal interface. Biol Reprod 58: 1075-1083.
168. Rolny C, Spillmann D, Lindahl U and Claesson- Welsh L. 2002. Heparin amplifies platelet-derived growth factor (PDGF)- BB-induced PDGF alpha-receptor but not PDGF beta-receptor tyrosine phosphorylation in heparan sulfate-deficient cells. Effects on signal transduc- tion and biological responses. J Biol Chem 277: 19315- 19321.
169. Rubin JS, Day RM, Breckenridge D, Atabey N, Tay- lor WG, Stahl SJ, Wingfield PT, Kaufman JD, Schwall R and Bottaro DP. 2001. Dissociation of heparan sulfate and receptor binding domains of hepatocyte growth factor reveals that heparan sulfate-c-met interaction facilitates signaling. J Biol Chem 276: 32977- 32983.
170. Ruhrberg C, Gerhardt H, Golding M, Watson R, Ioannidou S, Fujisawa H, Betsholtz C and Shima DT. 2002. Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev 16: 2684-2698.
171. Saito Y et al. 2007. A peptide derived from tenascin-C induces beta1 integrin activation through syndecan-4. J Biol Chem 282: 34929-34937.
172. Saksela O, Moscatelli D, Sommer A and Rifkin DB. 1988. Endothelial cell-derived heparan sulfate binds basic fibroblast growth factor and protects it from proteolytic degradation. J Cell Biol 107: 743-751.
173. Sampaio L, Tersariol I, Lopes C, Bouças R, Nasci- mento F, Rocha H and Nader H. 2006. Heparins and heparans sulfates. Structure, distribution and protein interactions. In: Verli H (Ed), Insights into CARBOHYDRATESTRUCTUREANDBIOLOGICALFUNCtion. Transworld Research Network, Kerala, p. 1-24.
174. Sanderson RD and Yang Y. 2008. Syndecan-1: a dynamic regulator of the myeloma microenvironment. Clin Exp Metastasis 25: 149-159.
175. Sasaki S et al. 1999. Ligand-induced recruitment of a histone deacetylase in the negative-feedback regulation of the thyrotropin beta gene. Embo J 18: 5389-5398.
176. Sasaki N et al. 2008. Heparan sulfate regulates self-renewal and pluripotency of embryonic stem cells. J Biol Chem 283: 3594-3606.
177. Sasisekharan R, Shriver Z, Venkataraman G and Narayanasami U. 2002. Roles of heparan-sulphate glycosaminoglycans in cancer. Nat Rev Cancer 2: 521- 528.
178. Schnepp A, Komp Lindgren P, Hulsmann H, Kroger S, Paulsson M and Hartmann U. 2005. Mouse testican-2. Expression, glycosylation, and effects on neurite outgrowth. J Biol Chem 280: 11274-11280.
179. Schwall RH, Chang LY, Godowski PJ, Kahn DW, Hillan KJ, Bauer KD and Zioncheck TF. 1996. Heparin induces dimerization and confers proliferative activity onto the hepatocyte growth factor antagonists NK1 and NK2. J Cell Biol 133: 709-718.
180. 2+ exchanger and reduce the cytosolic calcium of smooth muscle cell lines. Requirement of C4- C5 unsaturation and 1 → 4 glycosidic linkage for activity. J Biol Chem 277: 48227-48233.
181. Smirnov SP, Barzaghi P, McKee KK, Ruegg MA and Yurchenco PD. 2005. Conjugation of LG domains of agrins and perlecan to polymerizing laminin-2 promotes acetylcholine receptor clustering. J Biol Chem 280: 41449-41457.
182. SoncinF, StrydomDJ andShapiroR.1997. Interaction of heparin with human angiogenin. J Biol Chem 272: 9818-9824.
183. Song HH, Shi W, Xiang YY and Filmus J. 2005. The loss of glypican-3 induces alterations in Wnt signaling. J Biol Chem 280: 2116-2125.
184. Spivak-Kroizman T, Lemmon MA, Dikic I, Ladbury JE, Pinchasi D, Huang J, Jaye M, Crumley G, Schlessinger J and Lax I. 1994. Heparin-induced oligomerization of FGF molecules is responsible for FGF receptor dimerization, activation, and cell proliferation.Cell 79: 1015-1024.
185. Stigliano I, Puricelli L, Filmus J, Sogayar MC, Bal De Kier Joffe E and Peters MG. 2003. Glypican-3 regulates migration, adhesion and actin cytoskeleton organization in mammary tumor cells through Wnt signaling modulation. Breast Cancer Res Treat 114(2): 251-262.
186. Straus AH, Nader HB, Takahashi HK and Dietrich CP. 1982. Ontogeny of heparin in mammals: a correlation with the appearance of mast cells in tissues. An Acad Bras Cienc 54: 439-448.
187. Stringer SE. 2006. The role of heparan sulphate proteo- glycans in angiogenesis. Biochem Soc Trans 34: 451-453.
188. Su G, Blaine SA, Qiao D and Friedl A. 2007. Shedding of syndecan-1 by stromal fibroblasts stimulates hu- man breast cancer cell proliferation via FGF2 activation. J Biol Chem 282: 14906-14915.
189. Suarez ER, Nohara AS, Mataveli FD, DE Matos LL, Nader HB and Pinhal MA. 2007. Glycosaminogly- can synthesis and shedding induced by growth factors are cell and compound specific. Growth Factors 25: 50-59.
190. Sugaya N, Habuchi H, Nagai N, Ashikari-Hada S and 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.
191. Sulpice E, Bryckaert M, Lacour J, Contreres JO and Tobelem G. 2002. Platelet factor 4 inhibits FGF2- induced endothelial cell proliferation via the extracellular signal-regulated kinase pathway but not by the phos- phatidylinositol 3-kinase pathway. Blood 100: 3087-3094.
192. Tantravahi RV, Stevens RL, Austen KF and Weis JH. 1986. A single gene in mast cells encodes the core peptides of heparin and chondroitin sulfate proteoglycans. Proc Natl Acad Sci USA 83: 9207-9210.
193. Taylor KR and Gallo RL. 2006. Glycosaminoglycans and their proteoglycans: host-associated molecular patterns for initiation and modulation of inflammation. Faseb J 20: 9-22.
194. Telci D, Wang Z, Li X, Verderio EA, Humphries MJ, Baccarini M, Basaga H and Griffin M. 2008. Fibronectin-Tissue Transglutaminase Matrix Rescues RGD-impaired Cell Adhesion through Syndecan-4 andbeta1IntegrinCo-signaling. JBiolChem283: 20937-20947.
195. Tersariol IL, Dietrich CP and Nader HB. 1992. Interaction of heparin with myosin ATPase: possible invol- vement with the hemorrhagic activity and a correlation with antithrombin III high affinity-heparin molecules.Thromb Res 68: 247-258.
196. Tersariol IL, Ferreira TM, Medeiros MG, Porcionatto MA, Moraes CT, Abreu LR, Nader HB and Dietrich CP. 1994. Sequencing of heparan sul- fate proteoglycans: identification of variable and constant oligosaccharide regions in eight heparan sulfate proteoglycans of different origins. Braz J Med Biol Res 27: 2097-2102.
197. Tkachenko E, Lutgens E, Stan RV and Simons M. 2004. Fibroblast growth factor 2 endocytosis in endothe- lial cells proceed via syndecan-4-dependent activation of Rac1 and a Cdc42-dependent macropinocytic pathway. J Cell Sci 117: 3189-3199.
198. Tkachenko E, Rhodes JM and Simons M. 2005. Syndecans: new kids on the signaling block. Circ Res 96: 488-500.
199. Toledo OM and Dietrich CP. 1977. Tissue specific distribution of sulfated mucopolysaccharides in mammals. Biochim Biophys Acta 498: 114-122.
200. Tourovskaia A, Li N and Folch A. 2008. Localized acetylcholine receptor clustering dynamics in response to microfluidic focal stimulation with agrin. Biophys J 95: 3009-3016.
201. Traister A, Shi W and Filmus J. 2008. Mammalian Notum induces the release of glypicans and other GPI- anchored proteins from the cell surface. Biochem J 410: 503-511.
202. Utani A, Nomizu M, Matsuura H, Kato K, Kobayashi T, Takeda U, Aota S, Nielsen PK andShinkai H. 2001. A unique sequence of the laminin alpha 3 G domain binds to heparin and promotes cell adhesion through syndecan-2 and -4. J Biol Chem 276: 28779-28788.
203. Veiga SS, Elias M, Gremski W, Porcionatto MA, da Silva R, Nader HB and Brentani RR. 1997. Post-translationalmodificationsofalpha5beta1integrinby glycosaminoglycan chains. The alpha5beta1 integrin is a facultativeproteoglycan. JBiolChem272: 12529-12535.
204. Veugelers M, Vermeesch J, Reekmans G, Steinfeld R, Marynen P and David G. 1997. Characterization of glypican-5 and chromosomal localization of human GPC5, a new member of the glypican gene family. Genomics 40: 24-30.
205. Veugelers M, De CAT B, Ceulemans H, Bruystens AM, Coomansc, Durrj, Vermeesch J, Marynen PAND DAVID G. 1999. Glypican-6, a new member of the glypican family of cell surface heparan sulfate proteoglycans. J Biol Chem 274: 26968-26977.
206. Vives RR, Crublet E, Andrieu JP, Gagnon J, Rousselle P and Lortat-Jacob H. 2004. A novel strategy for defining critical amino acid residues involved in protein/glycosaminoglycan interactions. J Biol Chem 279: 54327-54333.
207. Vlodavsky I, Goldshmidt O, Zcharia E, Atzmon R, Rangini-Guatta Z, Elkin M, Peretz T and Friedmann Y. 2002. Mammalian heparanase: involvement in cancer metastasis, angiogenesis and normal development. Semin Cancer Biol 12: 121-129.
208. Walker A, Turnbull JE and Gallagher JT. 1994. Specific heparan sulfate saccharides mediate the activity of basic fibroblast growth factor. J Biol Chem 269: 931-935.
209. Watt SM, Williamson J, Genevier H, Fawcett J, Simmons DL, Hatzfeld A, Nesbitt SA and Coombe DR. 1993. The heparin binding PECAM-1 adhesion molecule is expressed by CD34+ hematopoietic precursor cells with early myeloid and B-lymphoid cell phenotypes. Blood 82: 2649-2663.
210. Whitelock JM, Murdoch AD, Iozzo RV and Under- wood PA. 1996. The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin, and heparanases. J Biol Chem 271: 10079-10086.
211. Wiedlocha A and Sorensen V. 2004. Signaling, inter- nalization, and intracellular activity of fibroblast growth factor. Curr Top Microbiol Immunol 286: 45-79.
212. Wilcox-Adelman SA, Denhez F and Goetinck PF. 2002. Syndecan-4 modulates focal adhesion kinase phosphorylation. J Biol Chem 277: 32970-32977.
213. Wilkins-Port CE and McKeown-Longo PJ. 1996. Heparan sulfate proteoglycans function in the binding and degradation of vitronectin by fibroblast monolayers. Biochem Cell Biol 74: 887-897.
214. Williams S, Ryan C and Jacobson C. 2008. Agrin and neuregulin, expandingrolesandimplicationsfortherapeu- tics. Biotechnol Adv 26: 187-201.
215. Wojtal KA, Hoekstra D and VAN Ijzendoorn SC. 2008. cAMP-dependent protein kinase A and the dynamics of epithelial cell surface domains: moving membranes to keep in shape. Bioessays 30: 146-155.
216. Woods A and Couchman JR. 2001. Syndecan-4andfocal adhesion function. Curr Opin Cell Biol 13: 578-583.
217. Wu DQ, Kan MK, Sato GH, Okamoto T and Sato GH, Okamoto T and Sato JD 1991. Characterization and molecular cloning of a putative binding protein for heparin-binding growth factors. J Biol Chem 266: 16778-16785.
218. Yates EA, Guimond SE and Turnbull JE. 2004. Highly diverse heparan sulfate analogue libraries: provid- ing access to expanded areas of sequence space for bio- activity screening. J Med Chem 47: 277-280.
219. Yayon A, Klagsbrun M, Esko JD, Leder P and Ornitz DM. 1991. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 64: 841-848.
220. Yu WH AND WOESSNER JF JR. 2000. Heparan sulfateproteoglycans as extracellular docking molecules for matrilysin (matrix metalloproteinase 7). J Biol Chem 275: 4183-4191.
221. Yu WH, Yu S, Meng Q, Brew K and Woessner JF Jr. 2000. TIMP-3 binds to sulfated glycosaminoglycans of the extracellular matrix. J Biol Chem 275: 31226-31232.
222. Zhang F, McLellan JS, Ayala AM, Leahy DJ and Linhardt RJ. 2007. Kinetic and structural studies on interactions between heparin or heparan sulfate and pro- teins of the hedgehog signaling pathway. Biochemistry 46: 3933-3941.