The receptor encoded by the human C‐MET oncogene is expressed in hepatocytes, epithelial cells and solid tumors

The human c‐MET oncogene encodes a transmembrane tyrosine kinase (p 190c‐met) with structural and functional features of a growth‐factor receptor. Monoclonal antibodies (MAbs) have been used to investigate the distribution of the c‐Met protein in human normal and neoplastic tissues. By immunofluorescence microscopy homogeneous expression was detected in normal hepatocytes as well as in epithelial cells lining the stomach, the small and the large intestine. Positive staining was also found in epithelial cells of the endometrium and ovary, and in basal keratinocytes of esophagus and skin. By Northern blot analysis, high levels of c‐met messenger RNA were detected in specimens of liver, gastro‐intestinal tract and kidney. c‐met‐specific mRNA was also found in thyroid, pancreas and placenta, in which organs c‐Met protein was barely detectable by immunofluorescence. The antibodies revealed expression of c‐MET protein in hepatomas (11/14), carcinomas of colon and rectum (19/21), stomach (11/22), kidney (16/19), ovary (9/17) and skin (7/17). Carcinomas of the lung (13/20), thyroid (11/13) and pancreas (5/7) were also positive. In these last cases (lung, thyroid and pancreas) tumor cells were homogeneously stained by the antibodies, whereas in their normal counterparts staining was barely detectable. These data suggest that the receptor encoded by c‐MET plays a physiological role in epithelial cell growth and that its expression is altered in human carcinomas.

[1]  A. Bardelli,et al.  Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor. , 1991, The EMBO journal.

[2]  P. Comoglio,et al.  c-met is amplified but not mutated in a cell line with an activated met tyrosine kinase. , 1991, Oncogene.

[3]  G. Michalopoulos,et al.  Hepatocyte growth factor (HGF) stimulates the tyrosine kinase activity of the receptor encoded by the proto-oncogene c-MET. , 1991, Oncogene.

[4]  J. Rubin,et al.  Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. , 1991, Science.

[5]  G. Michalopoulos,et al.  Hepatocyte growth factor/hepatopoietin A stimulates the growth of rat kidney proximal tubule epithelial cells (RPTE), rat nonparenchymal liver cells, human melanoma cells, mouse keratinocytes and stimulates anchorage-independent growth of SV-40 transformed RPTE. , 1991, Biochemical and biophysical research communications.

[6]  T. Hunter,et al.  cDNA cloning and characterization of eck, an epithelial cell receptor protein-tyrosine kinase in the eph/elk family of protein kinases , 1990, Molecular and cellular biology.

[7]  M. Sudol,et al.  Expression of cellular-yes protein in mammalian tissues. , 1990, Oncogene.

[8]  David A. Williams,et al.  Stem cell factor is encoded at the SI locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor , 1990, Cell.

[9]  P. Leder,et al.  The hematopoietic growth factor KL is encoded by the SI locus and is the ligand of the c-kit receptor, the gene product of the W locus , 1990, Cell.

[10]  D. Weiner,et al.  p185neu expression in human lung adenocarcinomas predicts shortened survival. , 1990, Cancer research.

[11]  R. Bast,et al.  Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer. , 1990, Cancer research.

[12]  A. Ullrich,et al.  Expression of the p185 encoded by her2 oncogene in normal and transformed human tissues , 1990, International journal of cancer.

[13]  G. Michalopoulos Liver regeneration: molecular mechanisms of growth control , 1990, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[14]  G. Woude,et al.  Specific proteolysis of the c-mos proto-oncogene product by calpain on fertilization of Xenopus eggs , 1989, Nature.

[15]  K. Tashiro,et al.  Molecular cloning and expression of human hepatocyte growth factor , 1989, Nature.

[16]  C. Cooper,et al.  Biosynthesis of the protein encoded by the c-met proto-oncogene. , 1989, Oncogene.

[17]  J. Enghild,et al.  NH2-terminal amino acid sequence of rabbit hepatopoietin A, a heparin-binding polypeptide growth factor for hepatocytes. , 1989, Biochemical and biophysical research communications.

[18]  M. Okigaki,et al.  Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor. , 1989, Biochemical and biophysical research communications.

[19]  W Godolphin,et al.  Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. , 1989, Science.

[20]  C. Cooper,et al.  Tyrosine kinase receptor indistinguishable from the c-met protein , 1989, Nature.

[21]  I. Weinstein,et al.  Amplification of the EGF receptor and c‐myc genes in human esophageal cancers , 1988, International journal of cancer.

[22]  P. Comoglio,et al.  p145, a protein with associated tyrosine kinase activity in a human gastric carcinoma cell line , 1988, Molecular and cellular biology.

[23]  M. Stratton,et al.  Structure of the met protein and variation of met protein kinase activity among human tumour cell lines. , 1988, British Journal of Cancer.

[24]  E. A. Deakin,et al.  Characterization of the mouse met proto-oncogene. , 1988, Oncogene.

[25]  J. Lillehaug,et al.  Expression of oncogenes in thyroid tumours: coexpression of c-erbB2/neu and c-erbB. , 1988, British Journal of Cancer.

[26]  M. J. van de Vijver,et al.  Immunohistochemical detection of the neu protein in tissue sections of human breast tumors with amplified neu DNA. , 1988, Oncogene.

[27]  M. Braun,et al.  Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[28]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[29]  W. McGuire,et al.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. , 1987, Science.

[30]  C. Cooper,et al.  Amplification and overexpression of the met gene in spontaneously transformed NIH3T3 mouse fibroblasts. , 1986, The EMBO journal.

[31]  P. Comoglio,et al.  CAR-3, a monoclonal antibody-defined antigen expressed on human carcinomas. , 1985, Cancer research.

[32]  Charles J. Sherr,et al.  The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF 1 , 1985, Cell.

[33]  P. Echlin,et al.  Amplification and overexpression of the EGF receptor gene in primary human glioblastomas , 1985 .

[34]  C. Cooper,et al.  Molecular cloning of a new transforming gene from a chemically transformed human cell line , 1984, Nature.

[35]  E. Russell Hereditary anemias of the mouse: a review for geneticists. , 1979, Advances in genetics.

[36]  W. Silvers Dominant Spotting, Patch, and Rump-White , 1979 .