Differential regulation of hepatocyte growth factor scatter factor by cellsurface proteoglycans and free glycosaminoglycan chains

Hepatocyte growth factor interacts with both heparan and dermatan sulphates , in addition to its specific signalling receptor, Met. However, the extent of glycosaminoglycan involvement in its biological activity remains uncert ain. We have investigated the effects of exogenous glycosaminoglycan additi on upon hepatocyte growth factor-stimulated motility of Madin-Darby canine kidney cells. Exogenous heparan/dermatan sulphate chains behave similarly a s either potentiators or inhibitors of cell motility (depending upon the as say), Specific heparan sulphate oligosaccharides, of octasaccharide or larg er, elicit similar effects, though with reduced potency, Additionally we ha ve investigated the motility of cells made completely deficient in function al proteoglycans by metabolic inhibition of glycosaminoglycan sulphation, u sing chlorate, Such cells are completely unresponsive to hepatocyte growth factor, both in terms of downstream phosphorylation of mitogen-activated pr otein kinase and actual cell motility, though they do remain responsive to phorbol ester, Interestingly, although cell responsiveness to hepatocyte gr owth factor is not restored by exogenous heparan/dermatan sulphate chains, it is by an immobilised heparan sulphate proteoglycan substratum, These fin dings suggest that hepatocyte growth factor activity is not only critically dependent upon the presence of glycosaminoglycan, but specifically require s an intact proteoglycan structure located in close apposition to cell surf ace Met.