Evidence that heparin saccharides promote FGF2 mitogenesis through two distinct mechanisms.
AuthorsGoodger, Sarah J
Robinson, Christopher J
Murphy, Kevin J
Harmer, Nicholas J
Blundell, Tom L
Pye, David A
Gallagher, John T
AffiliationPaterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, UK.
MetadataShow full item record
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.
CitationEvidence that heparin saccharides promote FGF2 mitogenesis through two distinct mechanisms. 2008, 283 (19):13001-8 J. Biol. Chem.
JournalThe Journal of Biological Chemistry
- Kinetic model for FGF, FGFR, and proteoglycan signal transduction complex assembly.
- Authors: Ibrahimi OA, Zhang F, Hrstka SC, Mohammadi M, Linhardt RJ
- Issue date: 2004 Apr 27
- Two hierarchies of FGF-2 signaling in heparin: mitogenic stimulation and high-affinity binding/receptor transphosphorylation.
- Authors: Krufka A, Guimond S, Rapraeger AC
- Issue date: 1996 Aug 27
- Oligomerization reduces heparin affinity but enhances receptor binding of fibroblast growth factor 2.
- Authors: Safran M, Eisenstein M, Aviezer D, Yayon A
- Issue date: 2000 Jan 1
- Novel mechanisms of fibroblast growth factor receptor 1 regulation by extracellular matrix protein anosmin-1.
- Authors: Hu Y, Guimond SE, Travers P, Cadman S, Hohenester E, Turnbull JE, Kim SH, Bouloux PM
- Issue date: 2009 Oct 23
- In vitro changes in plasma membrane heparan sulfate proteoglycans and in perlecan expression participate in the regulation of fibroblast growth factor 2 mitogenic activity.
- Authors: Guillonneau X, Tassin J, Berrou E, Bryckaert M, Courtois Y, Mascarelli F
- Issue date: 1996 Jan