Hepatocyte growth factor (HGF) is the most potent
mitogen for mature hepatocytes and seems to act as a hepatotropic factor that has not been purified over the past 30 years. HGF was first purified from rat platelets in 1986. HGF is a hetrodimer molecule composed of 69-kDa alpha-subunit and 34-beta-subunit. In 1989, cDNAs of both human and rat HGF were cloned and primary structure of HGF was determined. HGF is derived from preproprecursor of of 728
amino acids, which is proteolytically processed to form mature HGF. The alpha-chain contains four kringle domains and it has 38% homology with
plasmin. HGF
mRNA and HGF activity increase markedly in the liver of rats after various liver
injuries such as
hepatitis,
ischemia, physical crush, and partial
hepatectomy. Production of HGF in the liver occurs in Kupffer cells and sinusoidal endothelial cells, but not in parenchymal hepatocytes. HGF
mRNA is also markedly increased even in the intact lung, kidney, and spleen after
injuries of the liver. Therefore, HGF may act as a trigger for liver regeneration through two mechanisms: a paracrine mechanism and an endocrine mechanism. Moreover, HGF
mRNA increases markedly in the kidney after various renal
injuries, thus it suggests that HGF may act not only as a hepatotropic factor but also as a
renotropic factor.
HGF receptor with a Kd of 20 to 30 pM is widely distributed in various epithelial cells including hepatocytes.
HGF receptor was recently identified as the product of c-met protooncogene, which encodes a 190-kDa transmembrane
protein possessing
tyrosine kinase domain. HGF has recently been shown to be a pleiotropic factor. HGF stimulates growth of various epithelial cells, including renal tubular cells (
Mitogen). It is worth noting that HGF strongly enhances motility of epithelial cells (Motogen) and induces epithelial tubule formation (Morphogen), while it strongly inhibits growth of several
tumor cells. All these findings indicate that HGF may have important roles in organogenesis, morphogenesis,
carcinogenesis, as well as in organ regeneration.