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J. Biol. Chem., Vol. 277, Issue 2, 1040-1046, January 11, 2002
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From the Cancer Research Campaign & University of Manchester
Department of Medical Oncology, Christie Hospital NHS Trust,
Manchester M20 4BX, United Kingdom
Hepatocyte growth factor/scatter factor, in
addition to binding to its specific signal-transducing receptor, Met,
also interacts with both heparan and dermatan sulfates with high
affinity. We have investigated the comparative role of these two
glycosaminoglycans in the activation of Met by hepatocyte growth
factor/scatter factor. Using glycosaminoglycan-deficient CHO
pgsA-745 cells we have shown that growth factor activity is
critically dependent upon glycosaminoglycans, and that heparan sulfate
and dermatan sulfate are equally potent as co-receptors. Cross-linked
1:1 conjugates of growth factor and either heparan or dermatan sulfate
do not dimerize under physiological conditions and are biologically
active. This implies that a ternary signaling complex with Met forms
in vivo. Native Met isolated from CHO pgsA-745
cells shows only very weak intrinsic affinity for heparin in
vitro. Also, a heparin-derived hexasaccharide, which is the
minimal size for high affinity binding to the growth factor alone, is
sufficient to induce biological activity. Together these observations
imply that the role of these glycosaminoglycan may be primarily to
effect a conformational change in hepatocyte growth factor/scatter
factor, rather than to induce a necessary growth factor dimerization,
or to stabilize a ternary complex by additionally interacting with Met.
The Mode of Action of Heparan and Dermatan Sulfates in the
Regulation of Hepatocyte Growth Factor/Scatter Factor*
,
*
This work was supported by the Cancer Research Campaign,
United Kingdom.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: Dept. of Medical
Oncology, Christie CRC Research Center, Christie Hospital NHS Trust,
Wilmslow Road, Manchester M20 4BX, UK. Tel.: 44-0-161-446-3202; Fax:
44-0-161-446-3269; E-mail: MLyon@picr.man.ac.uk.
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