Dissociation of heparan sulfate and receptor binding domains of hepatocyte growth factor reveals that heparan sulfate-c-met interaction facilitates signaling.
Hepatocyte growth factor (HGF) is a secreted, heparan sulfate (HS) glycosaminoglycan-binding protein that stimulates mitogenesis, motogenesis, and morphogenesis in a wide array of cellular targets, including hepatocytes and other epithelial cells, melanocytes, endothelial cells, and hematopoietic cells. 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 oligomerization 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 structurally 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 soluble heparin, whereas K1-stimulated motility is not. We also found that, like the receptors for fibroblast growth factors, the HGF receptor c-Met binds tightly to HS. These data suggest that HS can facilitate HGF signaling through interaction with c-Met that is independent of HGF-HS interaction and that the recruitment of specific intracellular effectors that mediate distinct HGF responses such as mitogenesis and motility is regulated by HS-c-Met interaction at the cell surface.
Rubin
J S
JS
Laboratory of Cellular and Molecular Biology, Division of Basic Sciences, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Day
R M
RM
Breckenridge
D
D
Atabey
N
N
Taylor
W G
WG
Stahl
S J
SJ
Wingfield
P T
PT
Kaufman
J D
JD
Schwall
R
R
Bottaro
D P
DP
D000818:Animals; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004285:Dogs; D006497:Heparan Sulfate / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000737:chemistry* / Q000494:pharmacology*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007668:Kidney; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D010446:Peptide Fragments / Q000494:pharmacology; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D004247:DNA; D006497:Heparan Sulfate; D017228:Hepatocyte Growth Factor; D010446:Peptide Fragments; D020033:Protein Isoforms; D019859:Proto-Oncogene Proteins c-met