Hepatocyte Growth Factor/Scatter Factor Binds with High Affinity to Dermatan Sulfate

Abstract

We have demonstrated by affinity chromatography that hepatocyte growth factor/scatter factor (HGF/SF) binds strongly to dermatan sulfate (DS), with a similar ionic strength dependence to that previously seen with heparan sulfate (HS). Analysis of binding kinetics on a biosensor yields an equilibrium dissociation constant, K D , of 19.7 nM. This corresponds to a 10 -100-fold weaker interaction than that with HS, primarily due to a faster dissociation rate of the complex. The smallest DS oligosaccharide with significant affinity for HGF/SF by affinity chromatography appears to be an octasaccharide. A sequence comprising unsulfated iduronate residues in combination with 4-O-sulfated N-acetylgalactosamine is sufficient for high affinity binding. The presence of 2-Osulfation on the iduronate residues does not appear to be inhibitory. These observations concur with our previous suggestions, from analyses of HS binding (Lyon, M., Deakin, J. A., Mizuno, K., Nakamura, T., and Gallagher, J.T. (1994) J. Biol. Chem. 269, 11216 -11223), that N-sulfation of hexosamines and 2-O-sulfation of iduronates are not absolute requirements for glycosaminoglycan binding to HGF/SF. This is the first described example of a high affinity interaction between a growth factor and DS, and is likely to have significant implications for the biological activity of this paracrine-acting factor.Hepatocyte growth factor/scatter factor (HGF/SF) 1 is a pleiotropic factor with the ability to influence the growth, motility, differentiation, and morphogenesis of its target cells (for a recent review, see Ref. 1). It acts in a paracrine manner, with the major secretors being fibroblasts, vascular smooth muscle cells, nonparenchymal liver cells, etc., whereas those cells that possess the requisite tyrosine kinase receptor (Met) are primarily epithelial and endothelial cells. Recent evidence suggests that multipotent and erythroid hemopoietic progenitor cells are also responsive to HGF/SF. The HGF/SF-Met system appears to operate primarily during the morphogenetic and differentiation events occurring in organogenesis, as well as in the repair of organ damage in the adult (reviewed in Ref. 1). Aberrant expression of HGF/SF and/or Met has been strongly implicated in tumor progression, particularly in the acquisition of an invasive malignant phenotype (2-5). This presumably results from its ability to directly stimulate the growth and motility of tumor cells, as well as increasing the secretion of matrix-degrading proteases (6), thereby facilitating invasion of the surrounding stroma. Additionally, its potent angiogenic action (7, 8) may contribute to the development of a tumor vasculature, which is essential for sustaining an expanding tumor mass.In addition to Met, HGF/SF also interacts in vitro with the heparan sulfate (HS) chains of heparan sulfate proteoglycans (HSPGs) (9). The latter probably constitute the more abundant, but relatively lower affinity, HGF/SF-binding sites present on most cells (10). The interaction of HGF/SF with cell surface HSPGs may ...

Pharmacokinetic Modeling of Hepatocyte Growth Factor in Experimental Animals and Humans

“…25 Dissociation constants K d,1 and K d,2 were taken to be fixed at 1615 and 2.62 ng/mL, respectively (assuming that the molecular weight of HGF is 82,000), for the association of HGF with heparin-like substance and c-Met, respectively. 26,27 In case of a single dose, V syn was assumed to be zero. During repeated dosing in monkeys, V syn was written follows, assuming negative feedback by HGF as reported for c-Met: 28 V syn = V syn0 (1 -C e / (IC 50 + C e )) (…”

“…S1. To minimize the number of parameters to be estimated in the fitting, the K d values for c-Met and heparin-like substance were fixed at the reported values 26,27 . In addition, V syn could not be determined by the fitting of single-dose data and therefore was fixed to be zero.…”

Syndecans: multifunctional cell-surface co-receptors

“…In every case where this has been examined, binding of the growth factors to syndecans is also observed [37,79,80]. Growth factors that demonstrate this characteristic include members of the heparinbinding-growth-factor family, of which bFGF is the best-studied example, but also hepatocyte growth factor (HGF) [81,82], a splice variant of PDGF [83], heparin-binding epidermal growth factor (EGF) [84,85], vascular endothelial growth factor [86], neuregulins [87] and others [88,89].…”

HSulf-1 modulates HGF-mediated tumor cell invasion and signaling in head and neck squamous carcinoma

“…The studies demonstrating the interaction of HGF with heparan sulfate are limited. However, the structural specificity of the HGF-HS interaction using HGF-binding oligosaccharides revealed the requirement of 6-O-sulfation of the glucosamine-6-sulfate residues than with sulfation at any other position (Lyon et al, 1994). Studies by Morimoto-Tomita et al (2002) indicated that HSulf-1 exhibits sulfatase activity with a preference for glucosamine-6-sulfate substrates, implicating HSulf-1 as one of the critical enzymes disrupting this interaction.…”