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The morphogenic properties of oligomeric endostatin are dependent on cell surface heparan sulfate.
Clamp, A, Blackhall, FH, Blackhall, F, Henrioud, A, Jayson, G-, Javaherian, K, Esko, J, Gallagher, J, Gallagher, JT, Merry, C
J Biol Chem. 2006;281(21):14813-14822.
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Abstract
Endostatin has attracted considerable attention due to its ability to inhibit angiogenesis. This property of monomeric endostatin contrasts with that of the trimeric endostatin moiety generated from the intact C-terminal domain of collagen XVIII which induces a promigratory phenotype in endothelial cells. This activity is inhibited by monomeric endostatin. In this study we demonstrate that the effect of oligomeric endostatin can also be inhibited by exogenous glycoaminoglycans in a size-dependent manner, with heparin oligosaccharides containing more than twenty monosaccharide residues having optimal inhibitory activity. Oligomeric endostatin was also found to induce morphological changes in Chinese Hamster Ovary cells, an epithelial cell line. This novel observation allowed the utilisation of a panel of Chinese Hamster Ovary cell mutants with defined glycosaminoglycan biosynthetic defects. The action of oligomeric endostatin on these cells was shown to be dependent on cell surface glycosaminoglycans, principally heparan sulfate with N- and 6-O- sulfation of glucosamine residues rather than iduronate 2-O-sulfation being important for bioactivity. The responsiveness of a cell line (pgsE-606) with globally reduced HS sulfation and shortened S-domains however indicates that overall HS domain patterning is the key determinant of the bioactivity of oligomeric endostatin. Purified heparin-monomeric endostatin constructs generated by zero-length cross-linking techniques were found to be unable to inhibit the action of oligomeric endostatin. This indicates a mechanism for the perturbation of oligomeric endostatin action by its monomeric counterpart via competition for glycosaminoglycan attachment sites at the cell surface.