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Pownall ME, Isaacs HV. FGF Signalling in Vertebrate Development. San Rafael (CA): Morgan & Claypool Life Sciences; 2010.

Cover of FGF Signalling in Vertebrate Development

FGF Signalling in Vertebrate Development.

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Heparan Sulphate Proteoglycans

FGF proteins are characterised by their ability to bind heparin, which is a highly sulphated form of heparan sulphate produced only by mast cells and well known for its activity as an anticoagulant. The high affinity of FGFs for heparin was key for the purification of FGF proteins. Heparan sulphate proteoglycans (HSPGs) are produced by virtually all cells and are present on the cell surface and in the extracellular matrix. They consist of a protein core to which long, unbranched chains of repeating disaccharides are attached. Heparan sulphate GAG chains are made up of the sugar subunits glucoronic acid and N-acetyl glucosamine; these subunits are highly modified by sulfation and epimerisation by specific enzymes present in the golgi. N-Deacetylase/N-sulfotransferase replaces the N-acetyl group of N-acetyl glucosamine with a sulphate group and then the glucuronic acid residues adjacent to N-sulphated glucosamine are epimerised to iduronic acid. After this, 2-O-sulfotransferase acts on iduronic acid and 6-O-sulfotransferase (6OST) on the glucosamine; a few are also modified by 3-O-sulfotransferase. However, not all of the available substrate is sulphated, which generates regions of high and low sulfation along the HS chain and results in an enormous amount of structural diversity in HSPGs. This rich heterogeneity allows HSPGs to bind many different proteins and among these proteins are growth factors and receptors including FGFs and FGFRs.

HSPGs are essential for FGF signalling in vivo (Lin et al., 1999). The crystal structure of FGF ligand bound to FGFR reveals heparin bridging to contact receptors and ligands, cross-linking and stabilising the signalling complex (Schlessinger et al., 2000). The 6-O-sulphate group on the glucosamine in heparin was found to be central in these interactions (Pye and Gallagher, 1999; Turnbull et al., 2001). This is important because enzymes that modify 6-O-sulfation of HSPGs have been found to play a role in the modulation of FGF signalling (Freeman et al., 2008; Sugaya et al., 2008; Wang et al., 2004).

Copyright © 2010 by Morgan & Claypool Life Sciences.
Bookshelf ID: NBK53165


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