Hepatocyte Growth Factor And Its Receptor Cmet

HGF was originally identified in 1984, from the serum of partially hepatectomised animals, as a protein that was able to stimulate DNA synthesis and growth of hepatocytes (3-5). Soon after the initial discovery of HGF, a protein termed scatter factor (SF) was isolated by a separate group working within a different field. Scatter factor was identified as a fibroblast-derived protein that demonstrated the ability to scatter tightly packed colonies of epithelial cells (6). However, subsequent structural and functional studies revealed HGF and SF to be identical proteins (7-10).

HGF is synthesised as a single chain peptide of 728 amino acid residues. This biologically inactive form is known as pro-HGF and requires enzymatic processing to generate the active, heterodimeric form of HGF (11-13). The mature active form of HGF is composed of a 69kDa a-chain and a 34kDa serine protease-like P-chain (14) (Figure 1). The a-chain contains the N-terminal hairpin domain and four kringle domains that are essential for the correct biological functioning of the molecule (15, 16). HGF's domain structure and proteolytic mechanism of active-tion are similar to that of the serine protease known as plasminogen, although HGF is devoid of protease activity. Interestingly, HGF is thought to have evolved from the same ancestral gene as plasminogen and hepatocyte growth factor-like/macrophage stimulating protein (17). Under normal conditions, the active form of HGF plays a role in the development of the liver, placenta, skeletal muscle, and is also involved in the tissue regeneration process (18, 19).

Tumour-stromal interactions are known to facilitate the metastatic spread of cancer. In the last 15 years HGF has attracted considerable attention as a stromal-derived mediator of tumour-stromal interactions, particularly due to its key involvement in cancer invasion and metastasis.

Originally, HGF was considered to be produced by cells of mesenchymal origin and act on epithelial cells through a paracrine mechanism of stimulation (20, 21). However, increasing evidence suggests that this may not be the case in all tumours, as HGF production has also been detected in a variety of carcinoma tissues, including breast, thereby suggesting an autocrine mechanism of stimulation within tumours (22-26).

The various cellular responses to HGF are mediated through a cell surface receptor specific to HGF (Figure 2). This receptor is a protein encoded by the c-MET proto-oncogene, known as c-Met. c-Met is a receptor tyrosine kinase and is the prototype of a distinct subfamily, which also includes Ron and Sea, and was originally identified as an activated oncogene in an osteosarcoma cell line (27). The expression of c-Met by tumour cells has since been shown to be associated with tumour progression (26, 28-34).

Figure 1. Hepatocyte growth factor. Schematic representation of single chain inactive pro-HGF and the mature heterodimeric form of biologically active HGF.

The receptor protein arises from a single polypeptide precursor, which undergoes co- and post-translational glycosylation and endopro-teolytic cleavage (35). c-Met is a 190kDa heterodimer composed of two disulphide-linked chains, an extracellular 50kDa a-chain and a transmembrane 145kDa p-chain, both of which are necessary for c-Met biological activity. The a-chain is exposed at the cell surface whilst the

P-chain spans the cell membrane and possesses an intracellular tyrosine kinase domain (36, 37). HGF binds to the P-chain and induces receptor dimerisation, followed by trans-phosphorylation of regulatory tyrosines, whi ch is critical for receptor activation (38). The C-terminal domain is responsible for the biological activity and, upon phosphorylation of specific tyrosine residues, provides a docking site for multiple signal transducers and adaptors (39). The bulk of receptor signalling activity is funneled through this multifunctional docking site made of the tandemly arranged degenerate sequence YVH/NV. The SH2 domains of the PI 3 kinase (phosphatidylinositol 3-kinase), phospholipase C-y, c-AktShc, and pp60c- rc bind with quick association and dissociation rates to either of the phosphotyrosines in the sequence Y1349VHVNATY1356VNV, where both residues can be phosphorylated simultaneously (39-44). The Grb2-associated receptor (Gab 1) has been identified as a multisubstrate adapter protein that associates with c-Met to mediate epithelial morphogenesis (45), and also acts as an inhibitor to HGF signalling pathways, downstream of PI3K, for cell survival and DNA repair (46, 47).

The c-Met receptor is expressed by a wide variety of epithelial cells, whereas its ligand, HGF, is normally produced by the stromal tissues. Interestingly, possible autocrine signalling mechanisms have also been demonstrated in human carcinomas of the breast, lung, colon, and prostate through the co-expression of HGF and c-Met in the tumour tissue (26, 28, 48-52).

Figure 2. The c-Met receptor. The receptor is composed of two disulphide linked chains; a 50 kDa a-chain and a 145 kDa P-chain. The P-chain contains the tyrosine kinase domain and a docking site which interacts with signalling molecules upon HGF complexing.
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