Heparan sulfate oligosaccharides require 6-O-sulfation for promotion of basic fibroblast growth factor mitogenic activity.

2.50
Hdl Handle:
http://hdl.handle.net/10541/92717
Title:
Heparan sulfate oligosaccharides require 6-O-sulfation for promotion of basic fibroblast growth factor mitogenic activity.
Authors:
Pye, David A; Vivès, Romain R; Turnbull, Jeremy E; Hyde, Patricia; Gallagher, John T
Abstract:
The interaction of heparan sulfate (HS) with basic fibroblast growth factor (bFGF) is influential in enabling the growth factor to bind to its cell surface tyrosine kinase receptor. In this study, we have investigated further the structural properties of HS required to mediate the activity of bFGF in a mitogenic assay. We have prepared a library of heparinase III-generated HS oligosaccharides fractionated by both their size (dp6-dp12) and sulfate content. The ability of these oligosaccharides to activate bFGF in a mitogenic assay was then correlated with their length and disaccharide composition. All octa- and hexasaccharide fractions tested were unable to activate bFGF. Dodeca- and decasaccharide fractions were found to contain both activating and non-activating oligosaccharides, and showed a clear correlation between total sulfate content and the level of activatory activity. Disaccharide analysis of a range of dodeca- and decasaccharide fractions showed that both activating and non-activating oligosaccharides were composed mainly of N-sulfated and IdoA(2S)-containing disaccharides. The only significant difference between activating and non-activating oligosaccharides was the content of 6-O-sulfated disaccharides, in particular the disaccharide IdoA(2S)alpha1,4GlcNSO3(6S). These results show that there is a requirement for 6-O-sulfation of N-sulfated glucosamine residues, in addition to the 2-O-sulfation of IdoA, for the promotion of bFGF mitogenic activity by naturally occurring HS oligosaccharides. Analysis of the structure-activity relationships in the dodecasaccharide fractions in particular, suggests that a minimum bFGF activation sequence exists which is dependent on the positioning of at least one 6-O-sulfate group.
Affiliation:
CRC Department of Drug Development, Department of Medical Oncology, Paterson Institute for Cancer Research, Christie Hospital, Manchester, M20 4BX United Kingdom. DPlye@picr.man.ac.uk
Citation:
Heparan sulfate oligosaccharides require 6-O-sulfation for promotion of basic fibroblast growth factor mitogenic activity. 1998, 273 (36):22936-42 J. Biol. Chem.
Journal:
The Journal of Biological Chemistry
Issue Date:
4-Sep-1998
URI:
http://hdl.handle.net/10541/92717
PubMed ID:
9722514
Type:
Article
Language:
en
ISSN:
0021-9258
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorPye, David Aen
dc.contributor.authorVivès, Romain Ren
dc.contributor.authorTurnbull, Jeremy Een
dc.contributor.authorHyde, Patriciaen
dc.contributor.authorGallagher, John Ten
dc.date.accessioned2010-02-23T12:59:01Z-
dc.date.available2010-02-23T12:59:01Z-
dc.date.issued1998-09-04-
dc.identifier.citationHeparan sulfate oligosaccharides require 6-O-sulfation for promotion of basic fibroblast growth factor mitogenic activity. 1998, 273 (36):22936-42 J. Biol. Chem.en
dc.identifier.issn0021-9258-
dc.identifier.pmid9722514-
dc.identifier.urihttp://hdl.handle.net/10541/92717-
dc.description.abstractThe interaction of heparan sulfate (HS) with basic fibroblast growth factor (bFGF) is influential in enabling the growth factor to bind to its cell surface tyrosine kinase receptor. In this study, we have investigated further the structural properties of HS required to mediate the activity of bFGF in a mitogenic assay. We have prepared a library of heparinase III-generated HS oligosaccharides fractionated by both their size (dp6-dp12) and sulfate content. The ability of these oligosaccharides to activate bFGF in a mitogenic assay was then correlated with their length and disaccharide composition. All octa- and hexasaccharide fractions tested were unable to activate bFGF. Dodeca- and decasaccharide fractions were found to contain both activating and non-activating oligosaccharides, and showed a clear correlation between total sulfate content and the level of activatory activity. Disaccharide analysis of a range of dodeca- and decasaccharide fractions showed that both activating and non-activating oligosaccharides were composed mainly of N-sulfated and IdoA(2S)-containing disaccharides. The only significant difference between activating and non-activating oligosaccharides was the content of 6-O-sulfated disaccharides, in particular the disaccharide IdoA(2S)alpha1,4GlcNSO3(6S). These results show that there is a requirement for 6-O-sulfation of N-sulfated glucosamine residues, in addition to the 2-O-sulfation of IdoA, for the promotion of bFGF mitogenic activity by naturally occurring HS oligosaccharides. Analysis of the structure-activity relationships in the dodecasaccharide fractions in particular, suggests that a minimum bFGF activation sequence exists which is dependent on the positioning of at least one 6-O-sulfate group.en
dc.language.isoenen
dc.subjectHaematopoietic Stem Cellsen
dc.subject.meshCell Line-
dc.subject.meshDisaccharides-
dc.subject.meshDrug Interactions-
dc.subject.meshFibroblast Growth Factor 2-
dc.subject.meshHematopoietic Stem Cells-
dc.subject.meshHeparitin Sulfate-
dc.subject.meshLymphoid Tissue-
dc.subject.meshMitogens-
dc.subject.meshMitosis-
dc.subject.meshOligosaccharides-
dc.subject.meshPolysaccharide-Lyases-
dc.subject.meshSulfuric Acid Esters-
dc.titleHeparan sulfate oligosaccharides require 6-O-sulfation for promotion of basic fibroblast growth factor mitogenic activity.en
dc.typeArticleen
dc.contributor.departmentCRC Department of Drug Development, Department of Medical Oncology, Paterson Institute for Cancer Research, Christie Hospital, Manchester, M20 4BX United Kingdom. DPlye@picr.man.ac.uken
dc.identifier.journalThe Journal of Biological Chemistryen
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