Evidence that heparin saccharides promote FGF2 mitogenesis through two distinct mechanisms.

2.50
Hdl Handle:
http://hdl.handle.net/10541/67935
Title:
Evidence that heparin saccharides promote FGF2 mitogenesis through two distinct mechanisms.
Authors:
Goodger, Sarah J; Robinson, Christopher J; Murphy, Kevin J; Gasiunas, Nijole; Harmer, Nicholas J; Blundell, Tom L; Pye, David A; Gallagher, John T
Abstract:
Heparin-like saccharides play an essential role in binding to both fibroblast growth factors (FGF) and their receptors at the cell surface. In this study we prepared a series of heparin oligosaccharides according to their size and sulfation level. We then investigated their affinity for FGF2 and their ability to support FGF2 mitogenesis of heparan sulfate-deficient cells expressing FGFR1c. Tetra- and hexasaccharides bound FGF2, but failed to dimerize the growth factor. Nevertheless, these saccharides promoted FGF2-mediated cell growth. Furthermore, whereas enzymatic removal of the non-reducing end 2-O-sulfate group had little effect on the 1:1 interaction with FGF2, it eliminated the mitogenic activity of these saccharides. This evidence supports the symmetric two-end model of ternary complex formation. In contrast, even at very low concentrations, octasaccharide and larger heparin fragments conferred a potent mitogenic activity that was independent of terminal 2-O-sulfation. This correlated with the ability to dimerize FGF2 in an apparently cooperative manner. This data suggests that potent mitogenic signaling results from heparin-mediated trans-dimerization of FGF2, consistent with the asymmetric model of ternary complex formation. We propose that, depending on saccharide structure, there are different architectures and modes of ternary complex assembly that differ in stability and/or efficiency of transmembrane signaling.
Affiliation:
Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, UK.
Citation:
Evidence that heparin saccharides promote FGF2 mitogenesis through two distinct mechanisms. 2008, 283 (19):13001-8 J. Biol. Chem.
Journal:
The Journal of Biological Chemistry
Issue Date:
9-May-2008
URI:
http://hdl.handle.net/10541/67935
DOI:
10.1074/jbc.M704531200
PubMed ID:
18281281
Type:
Article
Language:
en
ISSN:
0021-9258
Appears in Collections:
All Paterson Institute for Cancer Research; Medical Oncology

Full metadata record

DC FieldValue Language
dc.contributor.authorGoodger, Sarah J-
dc.contributor.authorRobinson, Christopher J-
dc.contributor.authorMurphy, Kevin J-
dc.contributor.authorGasiunas, Nijole-
dc.contributor.authorHarmer, Nicholas J-
dc.contributor.authorBlundell, Tom L-
dc.contributor.authorPye, David A-
dc.contributor.authorGallagher, John T-
dc.date.accessioned2009-05-12T14:30:31Z-
dc.date.available2009-05-12T14:30:31Z-
dc.date.issued2008-05-09-
dc.identifier.citationEvidence that heparin saccharides promote FGF2 mitogenesis through two distinct mechanisms. 2008, 283 (19):13001-8 J. Biol. Chem.en
dc.identifier.issn0021-9258-
dc.identifier.pmid18281281-
dc.identifier.doi10.1074/jbc.M704531200-
dc.identifier.urihttp://hdl.handle.net/10541/67935-
dc.description.abstractHeparin-like saccharides play an essential role in binding to both fibroblast growth factors (FGF) and their receptors at the cell surface. In this study we prepared a series of heparin oligosaccharides according to their size and sulfation level. We then investigated their affinity for FGF2 and their ability to support FGF2 mitogenesis of heparan sulfate-deficient cells expressing FGFR1c. Tetra- and hexasaccharides bound FGF2, but failed to dimerize the growth factor. Nevertheless, these saccharides promoted FGF2-mediated cell growth. Furthermore, whereas enzymatic removal of the non-reducing end 2-O-sulfate group had little effect on the 1:1 interaction with FGF2, it eliminated the mitogenic activity of these saccharides. This evidence supports the symmetric two-end model of ternary complex formation. In contrast, even at very low concentrations, octasaccharide and larger heparin fragments conferred a potent mitogenic activity that was independent of terminal 2-O-sulfation. This correlated with the ability to dimerize FGF2 in an apparently cooperative manner. This data suggests that potent mitogenic signaling results from heparin-mediated trans-dimerization of FGF2, consistent with the asymmetric model of ternary complex formation. We propose that, depending on saccharide structure, there are different architectures and modes of ternary complex assembly that differ in stability and/or efficiency of transmembrane signaling.en
dc.language.isoenen
dc.subject.meshAnimals-
dc.subject.meshCell Line-
dc.subject.meshChromatography, High Pressure Liquid-
dc.subject.meshFibroblast Growth Factor 2-
dc.subject.meshHeparin-
dc.subject.meshMice-
dc.subject.meshMitosis-
dc.subject.meshReceptor, Fibroblast Growth Factor, Type 1-
dc.subject.meshSulfates-
dc.titleEvidence that heparin saccharides promote FGF2 mitogenesis through two distinct mechanisms.en
dc.typeArticleen
dc.contributor.departmentPaterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, UK.en
dc.identifier.journalThe Journal of Biological Chemistryen

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