The mode of action of heparan and dermatan sulfates in the regulation of hepatocyte growth factor/scatter factor.

2.50
Hdl Handle:
http://hdl.handle.net/10541/84326
Title:
The mode of action of heparan and dermatan sulfates in the regulation of hepatocyte growth factor/scatter factor.
Authors:
Lyon, Malcolm; Deakin, Jon A; Gallagher, John T
Abstract:
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.
Affiliation:
Cancer Research Campaign & University of Manchester Department of Medical Oncology, Christie Hospital NHS Trust, Manchester M20 4BX, United Kingdom. MLyon@picr.man.ac.uk
Citation:
The mode of action of heparan and dermatan sulfates in the regulation of hepatocyte growth factor/scatter factor. 2002, 277 (2):1040-6 J. Biol. Chem.
Journal:
The Journal of Biological Chemistry
Issue Date:
11-Jan-2002
URI:
http://hdl.handle.net/10541/84326
DOI:
10.1074/jbc.M107506200
PubMed ID:
11689562
Type:
Article
Language:
en
ISSN:
0021-9258
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorLyon, Malcolmen
dc.contributor.authorDeakin, Jon Aen
dc.contributor.authorGallagher, John Ten
dc.date.accessioned2009-10-16T11:56:43Z-
dc.date.available2009-10-16T11:56:43Z-
dc.date.issued2002-01-11-
dc.identifier.citationThe mode of action of heparan and dermatan sulfates in the regulation of hepatocyte growth factor/scatter factor. 2002, 277 (2):1040-6 J. Biol. Chem.en
dc.identifier.issn0021-9258-
dc.identifier.pmid11689562-
dc.identifier.doi10.1074/jbc.M107506200-
dc.identifier.urihttp://hdl.handle.net/10541/84326-
dc.description.abstractHepatocyte 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.en
dc.language.isoenen
dc.subject.meshAnimals-
dc.subject.meshCHO Cells-
dc.subject.meshCell Movement-
dc.subject.meshCricetinae-
dc.subject.meshCross-Linking Reagents-
dc.subject.meshDermatan Sulfate-
dc.subject.meshHeparin-
dc.subject.meshHeparitin Sulfate-
dc.subject.meshHepatocyte Growth Factor-
dc.subject.meshMolecular Weight-
dc.subject.meshOligosaccharides-
dc.subject.meshProtein Structure, Tertiary-
dc.subject.meshProto-Oncogene Proteins c-met-
dc.subject.meshSignal Transduction-
dc.subject.meshTransferases (Other Substituted Phosphate Groups)-
dc.titleThe mode of action of heparan and dermatan sulfates in the regulation of hepatocyte growth factor/scatter factor.en
dc.typeArticleen
dc.contributor.departmentCancer Research Campaign & University of Manchester Department of Medical Oncology, Christie Hospital NHS Trust, Manchester M20 4BX, United Kingdom. MLyon@picr.man.ac.uken
dc.identifier.journalThe Journal of Biological Chemistryen
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