Met protooncogene
Hepatocyte growth factor receptor (HGFR) (Bottaro D.P. et al., 1991)
Cell lines:
- Following c-met activation by
HGF in tumour cells, phosphorylation of
beta-catenin occurs, together with loss of intercellular adhesion and a gain in the motile and invasive nature of the cell. It was shown that c-met is co-localised with
beta-catenin and
E-cadherin at regions of cell-cell contact in MCF7 and MDA MB 231 BCC lines. Immunoprecipitation studies demonstrated an association between c-met and members of the cadherin adhesion complex in these epithelial tumour cells, along with the membrane tyrosine protein phophatase, PTPmu (Hiscox S. and Jiang W.G., 1999).
- T47D BCC were transfected with human
HGF. The
HGF-positive clones exhibited different levels of biologically functional
HGF expression and up-regulation of endogenous Met (
HGF receptor) expression. In addition, a constitutive phosphorylation of the receptor on tyrosine residues was detected, establishing a Met-
HGF autocrine loop. The autocrine activation of Met caused marked inhibition in cell growth accompanied by cell accumulation at G
0/G
1. These cells underwent terminal cell differentiation as determined by morphological changes, synthesis of milk proteins such as beta-casein and alpha-lactalbumin, and production of lipid vesicles (Ronen D. et al., 1999).
Tumors:
- It has been shown that
HGF and c-met are overexpressed in breast carcinoma as compared with benign breast tissue, and that they tend to be coexpressed in cancerous tissue. These findings are consistent with the idea that the
HGF:c-met ligand:receptor pair may have a role in breast carcinoma progression (Jin L. et al., 1997).
- Activating MET mutations leading to increased levels of tyrosine phosphorylation and enhanced kinase activity toward an exogenous substrate when compared with wildtype MET could contribute to papillary renal carcinoma and other human malignancies. Mutant MET induced motility of Madin-Darby canine kidney cells and metastasis of NIH 3T3 cells while transgenic mice expressing the oncogenic form of MET developed metastatic mammary carcinoma (Jeffers M. et al., 1998).
Bottaro D.P. et al. (1991) Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 251, 802-804.
Cooper C.S. et al. (1984) Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature 311, 29-33.
Cooper C.S. (1992) The met oncogene: from detection by transfection to transmembrane receptor for hepatocyte growth factor. Oncogene 7, 3-7 (
Review).
Dean M. et al. (1985) The human met oncogene is related to the tyrosine kinase oncogenes. Nature 318, 385-388.
Hiscox S. and Jiang W.G. (1999) Association of the
HGF/SF receptor, c-met, with the cell-surface adhesion molecule,
E-cadherin, and catenins in human tumor cells. Biochem. Biophys. Res. Commun. 261, 406-411.
Jeffers M. et al. (1998) The mutationally activated Met receptor mediates motility and metastasis. Proc. Natl. Acad. Sci. USA 95, 14417-14422.
Jin L. et al. (1997) Expression of
scatter factor and c-met receptor in benign and malignant breast tissue. Cancer 79, 749-760.
Nagy J. et al. (1996)
Hepatocyte growth factor/scatter factor expression and c-met in primary breast cancer. Surg. Oncol. 5, 15-21.
Park M. et al. (1987) Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors. Proc. Natl. Acad. Sci. USA 84, 6379-6383.
Ronen D. et al. (1999) Met-
HGF/SF mediates growth arrest and differentiation in T47D breast cancer cells. Cell Growth Differ. 10, 131-140.
Tuck A.B. et al. (1997) Coexpression of
hepatocyte growth factor and receptor (Met) in human breast carcinoma. Am. J. Pathol. 148, 225-232.
