Isoforms of human HGF and their biological activities

Hepatocyte growth factor (HGF) is a plasminogen-like protein thought to be a humoral mediator of liver regeneration. It is produced by stromal fibroblasts and acts as a mitogen for a variety of target cells. Scatter factor, a stimulant of epithelial and vascular endothelial cell motility, is the same as HGF. HGF mediates its effects by activation of a membrane-spanning tyrosine kinase, recently identified as the met proto-oncogene product. We purified a naturally occurring hepatocyte growth factor variant, whose predicted sequence extends only through the second kringle domain of this plasminogen-related molecule. This smaller molecule, derived from an alternative HGF transcript, lacked mitogenic activity but specifically inhibited HGF-induced mitogenesis. Cross-linking studies demonstrated that the truncated molecule competes with HGF for binding to the c-met proto-oncogene product. Thus, the same gene encodes both a growth factor and its direct antagonist.