HGF, also known as scatter factor and hepatopoietin A, is a pleiotropic protein in the plasminogen subfamily of S1 peptidases. It is a multidomain molecule that includes an N-terminal PAN/APPLE-like domain, four Kringle domains, and a serine proteinase-like domain that has no detectable protease activity (1 - 5) Human HGF is secreted as an inactive 728 amino acid (aa) single chain propeptide. It is cleaved after the fourth Kringle domain by a serine protease to form bioactive disulfide-linked HGF with a 60 kDa α and 30 kDa β chain. Alternate splicing generates human HGF isoforms that lack the proteinase-like domain and different numbers of the Kringle domains. Human HGF shares 91% - 94% aa sequence identity with bovine, canine, feline, mouse, and rat HGF. HGF binds heparan-sulfate proteoglycans and the widely expressed receptor tyrosine kinase, HGF R/c-MET (6, 7). HGF-dependent c-MET activation is implicated in the development of many human cancers (8). HGF regulates epithelial morphogenesis by inducing cell scattering and branching tubulogenesis (9, 10). HGF induces the upregulation of integrin α2β1 in epithelial cells by a selective increase in α2 gene transcription (11). This integrin serves as a collagen I receptor, and its blockade disrupts epithelial cell branching tubulogenesis (11, 12). HGF can also alter epithelium morphology by the induction of nectin-1α ectodomain shedding, an adhesion protein component of adherens junctions (13). In the thymus, HGF induces the proliferation, motility, and loss of differentiation markers of thyrocytes and inhibits TSH-stimulated iodine uptake (14). HGF promotes the motility of cardiac stem cells in damaged myocardium (15).
1. Karihaloo, A. et al., 2005, Nephron Exp. Nephrol. 100:e40.
2. Hammond, D.E. et al., 2004, Curr. Top. Microbiol. Immunol. 286:21.
3. Rosario, M. and Birchmeier, W., 2004, Dev. Cell 7:3.
4. Lesk, A.M. and Fordham, W.D., 1996, J. Mol. Biol. 258:501.
5. Nakamura, T. et al., 1989, Nature 342:440.
6. Mizuno, K., et al., 1994, J. Biol. Chem. 269:1131.
7. Gheradi, E. et al., 2003, Proc. Natl. Acad. Sci. 100:12039.
8. Corso, S. et al., 2005, Trends Mol. Med. 11:284.
9. Maeshima, A. et al., 2000, Kid. Int. 58:1511.
10. Montesano, R. et al., 1991, Cell 67:901.
11. Chiu, S-J. et al., 2002, J. Biomed. Sci. 9:261.
12. Saelman, E.U.M. et al., 1995, J. Cell Sci. 108:3531.
13. Tanaka, Y. et al., 2002, Biochem. Biophys. Res. Commun. 299:472.
14. Mineo, R. et al., 1994, Endocrinology 145:4355.
15. Urbanek, K. et al., 2005, Circ. Res. 97:663.