Dissociation of heparan sulfate and receptor binding domains of hepatocytegrowth factor reveals that heparan sulfate-c-Met interaction facilitates signaling

Hepatocyte growth factor (HGF) is a secreted, heparan sulfate (HS) glycosam inoglycan-binding protein that stimulates mitogenesis, motogenesis, and mor phogenesis in a wide array of cellular targets, including hepatocytes and o ther epithelial cells, melanocytes, endothelial cells, and hematopoietic ce lls. NK1 is an alternative HGF isoform that consists of the N-terminal (N) and first kringle (K1) domains of full-length HGF and stimulates all major HGF biological activities. Within NK1, the N domain retains the HS binding properties of full-length HGF and mediates HS-stimulated ligand oligomeriza tion but lacks significant mitogenic or motogenic activity. In contrast, K1 does not bind HS, but it stimulates receptor and mitogen-activated protein kinase activation, mitogenesis, and motogenesis, demonstrating that struct urally distinct and dissociable domains of HGF are the primary mediators of HS binding and receptor activation. Despite the absence of HS-K1 binding, K1 mitogenic activity in HS-negative cells is strictly dependent on added s oluble heparin, whereas K1-stimulated motility is not. We also found that, like the receptors for fibroblast growth factors, the HGF receptor c-Met bi nds tightly to HS. These data suggest that HS can facilitate HGF signaling through interaction with c-Met that is independent of HGF-HS interaction an d that the recruitment of specific intracellular effectors that mediate dis tinct HGF responses such as mitogenesis and motility is regulated by HS-c-M et interaction at the cell surface.