Properties and structure-function relationship of HGF-SF.
HGF-SF is a cytokine independently isolated and characterized for its activities as a mitogen for liver cells in culture (hepatocyte growth factor, HGF) and as a factor which enhances the movement and induces the dissociation of epithelial colonies (scatter factor, SF). The factor is composed of two subunits (A and B) with a M(r) of approximately 57 K and approximately 30 K produced by proteolytic cleavage of a polypeptide precursor. Based on the complete conservation of critical cysteine residues, the domain structure of HGF-SF appears to be remarkably similar to the domain structures of plasminogen, (a blood protease involved in fibrinolysis) and the HGF-like protein (the translation product of a gene recently isolated and which shares extensive sequence identity with HGF-SF). The A subunit of HGF-SF consists of an N-terminal domain, homologous to plasminogen preactivation peptide (PAP), followed by four kringle domains. The B subunit has the basic structure of a serine protease domain although HGF-SF has no protease activity due to replacement substitutions in two of the three residues of the catalytic site. Experiments with a truncated form of HGF-SF generated by alternative splicing and with a series of deletion and point mutants generated by site-directed mutagenesis, have established that both the N-terminal and the kringle domains of the A chain and the B chain are all required for biological activity. Loss of mitogenic activity in the HGF-SF mutants is always associated with loss of motogenic activity and vice versa. Thus, the protein engineering experiments confirm the hypothesis that the mitogenic and motogenic responses to HGF-SF diverge at the post-receptor level.
Gherardi
E
E
Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.
Sharpe
M
M
Lane
K
K
D000595:Amino Acid Sequence; D000818:Animals; D017228:Hepatocyte Growth Factor / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
D046911:Macromolecular Substances; D017228:Hepatocyte Growth Factor