Abstract
Hepatocyte growth factor (HGF), also referred to as scatter factor (SF), is an important paracrine mediator of epithelial-mesenchymal cell interactions. It is secreted by mesenchymal cells and affects epithelial cell proliferation, motility and morphology. These diverse biological activities are a result of HGF/SF binding to and activating its high affinity (Kd=0.1-0.5nM) tyrosine kinase receptor called c-Met. The c-Met receptor is expressed in many epithelial and endothelial cell types but not in mesenchymal cells. In addition to c-Met, HGF/SF also binds heparin and heparan sulfate proteoglycans on cell surfaces, albeit with a 10-fold lower affinity (Kd=1-5nM). Both size and charge of heparan sulfate-derived oligosaccharides determine binding affinity to HGF. Furthermore, those binding determinants for HGF differ from those of FGF. Coincubation of soluble heparin and other heparin-like molecules with HGF/SF results in oligomerization of the growth factor and potentiation of its mitogenic activity in cell culture. Recent data indicate that the mitogenic response of cells to HGF/SF and its truncated variants called NK1 and NK2, may be determined by heparan sulfate proteoglygans expressed on the cell surface. Based on these data we propose a model, similar to that of fibroblast growth factor, where soluble heparinlike molecules (or cell surface heparan sulfate proteoglycans) can stabilize HGF/SF oligomers thus facilitating c-Met receptor-dimerization and cellular signaling.
