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Originally published In Press as doi:10.1074/jbc.M111345200 on January 17, 2002

J. Biol. Chem., Vol. 277, Issue 14, 12456-12462, April 5, 2002
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Hepatocyte Growth Factor/Scatter Factor Binds to Small Heparin-derived Oligosaccharides and Stimulates the Proliferation of Human HaCaT Keratinocytes*

Maryse Delehedde, Malcolm LyonDagger , Rishma Vidyasagar, Timothy J. McDonnell§, and David G. Fernig

From the School of Biological Sciences, Life Science Building, University of Liverpool, Crown Street, Liverpool L69 7ZB, the Dagger  Cancer Research Campaign Department of Medical Oncology, University of Manchester, Christie Hospital National Health Service Trust, Wilmslow Road, Manchester M20 4BX, United Kingdom, and the § Department of Molecular Pathology, the University of Texas, MD Anderson Cancer Center, Houston, Texas 77030

Hepatocyte growth factor/scatter factor (HGF/SF) acts via a dual receptor system consisting of the MET tyrosine kinase receptor and heparan sulfate or dermatan sulfate proteoglycans. In optical biosensor binding assays, competition by oligosaccharides for binding of HGF/SF to immobilized heparin showed that disaccharides failed to compete, whereas tetrasaccharides inhibited HGF/SF binding (IC50 8 µg/ml). The inhibitory potency of the oligosaccharides increased as their length increased by successive disaccharide units, to reach a maximum (IC50 1 µg/ml) at degree of polymerization (dp) 10. In binding assays, HGF/SF was found to bind directly to oligosaccharides as small as dp 4, and the binding parameters were similar for oligosaccharides of dp 4-14 (ka 2.2-45.3 × 106 M-1 s-1, kd 0.033-0.039 s-1, and Kd 9-16 nM). In human keratinocytes, HGF/SF stimulated DNA synthesis, and this was dependent on a sustained phosphorylation of p42/44MAPK. In chlorate-treated and hence sulfated glycosaminoglycan-deficient HaCaT cells, the stimulation of DNA synthesis by HGF/SF was almost abolished. Heparin-derived oligosaccharides from dp 2 to dp 24 were added together with HGF/SF to chlorate-treated cells to determine the minimum size of oligosaccharides able to restore HGF/SF activity. At restricted concentrations of oligosaccharides (4 ng/ml), HGF/SF required decasaccharides, whereas at higher concentrations (100 ng/ml) even tetrasaccharides were able to partly restore DNA synthesis. The results suggest that HGF/SF binds to a tetrasaccharide and that although this is sufficient to enable the stimulation of DNA synthesis, longer oligosaccharides are more efficient, perhaps by virtue of their ability to bind more easily other molecules.

* This work was supported by the Biotechnology and Biological Sciences Research Council, the Cancer and Polio Research Fund, the Cancer Research Campaign, NCI Grant P01 CA68233 from the National Institutes of Health, and the North West Cancer Research Fund.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: School of Biological Sciences, Life Sciences Bldg., Crown Street, University of Liverpool, Liverpool L69 7ZB, UK. Tel.: 44-151-794-4388; Fax: 44-151-794-4349; E-mail: dgfernig@liv.ac.uk.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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