The mode of action of heparan and dermatan sulfates in the regulation of hepatocyte growth factor/scatter factor.
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.
Lyon
Malcolm
M
Cancer Research Campaign & University of Manchester Department of Medical Oncology, Christie Hospital NHS Trust, Manchester M20 4BX, United Kingdom. MLyon@picr.man.ac.uk
Deakin
Jon A
JA
Gallagher
John T
JT
D000818:Animals; D016466:CHO Cells; D002465:Cell Movement / Q000502:physiology; D006224:Cricetinae; D003432:Cross-Linking Reagents / Q000494:pharmacology; D003871:Dermatan Sulfate / Q000378:metabolism*; D006493:Heparin / Q000737:chemistry; D006497:Heparan Sulfate / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000737:chemistry / Q000378:metabolism*; D008970:Molecular Weight; D009844:Oligosaccharides / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics
D003432:Cross-Linking Reagents; D003871:Dermatan Sulfate; D006493:Heparin; D006497:Heparan Sulfate; D017228:Hepatocyte Growth Factor; D009844:Oligosaccharides; D019859:Proto-Oncogene Proteins c-met; D017855:Transferases (Other Substituted Phosphate Groups); C020676:CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase