Hepatocyte growth factor

"Hepatocyte growth factor" was originally identified as a hepatically produced mitogen in 1984. Independently of this, a protein was discovered in 1992 that was able to promote the dissemination of epithelial cells and was therefore named "scatter factor". Later sequencing of both factors showed that they are identical with each other. The term HGF has since become established.

The HGF gene is located in the region q21.1 of chromosome 7. It consists of 18 exons and encodes a precursor protein of the plasminogen family with a characteristic structure. It contains a so-called kringle domain (a double loop formed by three disulfide bonds), a serine protease domain, and an activation segment located between the other two domains, which is essential for the proteolytic cleavage of the precursor protein. It is triggered in particular by serine protease uroplasminogen and tissue type plasminogen activator (uPA or tPA) and leads to the formation of the mature HGF protein, an 82 kDa heterodimer consisting of a 60 kDa α chain and a 22 kDa β chain. The factor is synthesized by many (predominantly mesenchymal) cells and therefore has an ubiquitous distribution. It can be detected in muscular, neuronal, cardiac, hepatic and connective tissue cells.

Similar to VEGF, HGF plays an important role in angiogenesis processes.

The receptor of HGF is called c-Met. The binding of HGF to c-Met leads to dimerization and autophosphorylation of tyrosine residues of the intracellular catalytic, c-terminal domains of the receptor. This causes the recruitment of intracellular signalling molecules to the receptor and the activation of various enzymatic cascades, including the phosphatidylinositol-3-OH-(PI3)-dependent kinase cascade and the mitogen-activated signalling cascade (MAPK).

Activation of the HGF/c-Met signalling pathway promotes various cellular processes, including proliferation, invasion and migration. At the tissue and organ level, the system is involved in the growth and morphogenesis of tubular structures in particular, such as the blood vessel and bronchial system.

For example, HGF plays a crucial role in lung regeneration: damaged lung epithelium is restored in vivo by HGF-triggered stimulation of type 2 alveolar cells. This HGF-triggered regeneration mode is also known in hepatocytes: rats with experimental liver cirrhosis survive longer with HGF than without it. As a paracrine factor, HGF is thus essential for embryonic and adult posttraumatic hepatogenesis.

Onartuzumab binds to the extracellular domain of c-Met, preventing the ligand from binding. This inhibits activation of the c-Met pathway. This leads to cell death in c-Met-expressing tumor cells. HGF receptors are increasingly expressed in non-small cell lung carcinoma and in various solid gastrointestinal carcinomas.

1. Bussolini F et al (1992) Hepatocyte growth factor is a potent angiongenic factor which stimulates endothelial cell motility and growth. J Cell Biol 119: 629-641
2. Hecht M et al (2004) Hepatocyte growth factor/c-Met signaling promotes the progression of experimental human neuroblastomas. Cancer Res 64: 6109-18
3. Trusolino L et al (2002) Scatter-Factor and semaphorin receptors: cell signalling for invasive growth. Nature 2: 289-300