The hepatocyte growth factor (HGF) is thought to be a humoral mediator of liver regeneration. A 145-kD tyrosyl phosphoprotein observed in rapid response to HGF treatment of intact target cells was identified by immunoblot analysis as the beta subunit of the c- met protooncogene product, a membrane-spanning tyrosine kinase. Covalent cross-linking of radiolabeled ligand to cellular proteins of appropriate size that were recognized by c-met antibodies directly established the c-met product as the cell-surface receptor for HGF. HGF is structurally related to the family of serine proteases that includes plasminogen, prothrombin, urokinase, and tissue plasminogen activator. Urokinase and thrombin associate with a specific cell-surface receptor which bears no homology to the c-met protein or other tyrosine kinase receptors. The direct interaction of HGF with the c-met receptor tyrosine kinase suggests a biochemical mechanism of mitogenic signal transduction similar to that of other peptide growth factors, which diverges significantly from the signal transduction schemes typical of other serine protease family members. The met oncogene was originally identified in a chemical carcinogen-treated human osteogenic sarcoma cell line by transfection analysis in NIH/3T3 cells. The protooncogene product is a transmembrane receptor-like protein whose transcript is expressed in many tissues. A high proportion of spontaneous NIH/3T3 transformants overexpress c-met. Since this cell line produces HGF, an autocrine mechanism may provide the basis for transformation. Tyrosine phosphorylation of apparently normal c- met protein has been observed in certain human gastric carcinoma cell lines; whether autocrine stimulation is responsible for the constitutive activation of c-met kinase in these cell lines remains to be determined. Knowledge that the HGF receptor is the c-met kinase will provide the opportunity to explore the role of this ligand-receptor system in normal as well as disease states.
