Collagens in the liver extracellular matrix bind hepatocyte growth factor.
OBJECTIVE
Hepatocyte growth factor (HGF), a potent mitogen for hepatocytes, binds to heparan sulfate. Because immunoreactive HGF can be detected in the interstitial extracellular matrix (ECM), where little heparan sulfate is found, the aim of this study was to investigate binding of HGF to several collagens and noncollagenous ECM proteins in vitro.


METHODS
125I-labeled HGF was incubated with collagens I-VI, single collagen chains and their cyanogen bromide peptides, with fibronectin, fibrinogen, and laminin that were either immobilized on polystyrene or blotted to nitrocellulose after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Biological activity of collagen-bound HGF was investigated in cell culture.


RESULTS
HGF displayed binding of moderate affinity (Kd approximately 10(-9) mol/L) to immobilized collagen types I, III, IV, V, and VI. Binding of HGF to all collagens could be inhibited by single chains of either collagens I, III, or VI. Fragmentation with cyanogen bromide indicated unique collagenous peptides mediating the interaction. Collagen-bound HGF induced primary hepatocyte proliferation and MDCK cell scattering in a dose-dependent manner.


CONCLUSIONS
Interstitial collagens I, III, V, and VI serve as abundant, low-affinity binding sites for HGF in the ECM. This interaction is mediated by unique collagenous peptides, opening the potential to modulate HGF availability and activity by collagen-derived peptide analogues.
Schuppan
D
D
Department of Gastroenterology and Hepatology, Klinikum Benjamin Franklin, Free University of Berlin, Germany.
Schmid
M
M
Somasundaram
R
R
Ackermann
R
R
Ruehl
M
M
Nakamura
T
T
Riecken
E O
EO
D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000166:cytology* / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding
D017228:Hepatocyte Growth Factor; D003094:Collagen