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J. Biol. Chem., Vol. 279, Issue 42, 43560-43567, October 15, 2004
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¶
From the
Cancer Research UK and the Department of Medical Oncology, University of Manchester, Christie Hospital National Health Service Trust, Wilmslow Road, Manchester M20 4BX and the ||Growth Factors Group, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, United Kingdom
Full-length hepatocyte growth factor/scatter factor interacts with both heparan and dermatan sulfates and is critically dependent upon them as cofactors for activation of the tyrosine kinase receptor Met. Two C-terminally truncated variants (NK1 and NK2) of this growth factor also occur naturally. Their glycosaminoglycan binding properties are not clear. We have undertaken a comparative study of the heparan/dermatan sulfate binding characteristics of all three proteins. This has entailed the development of a modified gel mobility shift assay, utilizing fluorescence end-tagged oligosaccharides, that is also widely applicable to the analysis of many glycosaminoglycan-protein interactions. Using this we have shown that all three hepatocyte growth factor/scatter factor variants share identical heparan/dermatan sulfate binding properties and that both glycosaminoglycans occupy the same binding site. The minimal size of the oligosaccharide that binds with high affinity in all cases is a tetrasaccharide from heparan sulfate but a hexasaccharide from dermatan sulfate. These findings demonstrate that functional glycosaminoglycan binding is restricted to a binding site situated solely within the small N-terminal domain. The same minimal size fractions are also able to promote hepatocyte growth factor/scatter factor-mediated activation of Met and consequent downstream signaling in the glycosaminoglycan-deficient Chinese hamster ovary pgsA-745 cells. A covalent complex of heparan sulfate tetrasaccharide with monovalent growth factor is also active. The binding and activity of tetrasaccharides put constraints upon the possible interactions and molecular geometry within the ternary signaling complex.
Received for publication, July 27, 2004
* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Supported by a Programme Grant from Cancer Research UK.
** Supported by Programme Grant G9704528 from the Medical Research Council.
¶ To whom correspondence should be addressed: Dept. of Medical Oncology, Christie CRUK Research Centre, Christie Hospital NHS Trust, Wilmslow Rd., Manchester M20 4BX, United Kingdom. Tel.: 44-161-446-3202; Fax: 44-161-446-3269; E-mail: MLyon{at}picr.man.ac.uk.
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