Hepatocyte growth factor (HGF) stimulates the tyrosine kinase activity of the receptor encoded by the proto-oncogene c-MET.
The human proto-oncogene c-MET encodes a heterodimeric 190 kDa transmembrane protein (p190c-met) with structural features of a tyrosine kinase receptor. The ligand for this putative receptor has not yet been identified. By Northern blot hybridization we found that, among a restricted number of human tissues, c-MET is highly expressed in the liver. This prompted us to test the hypothesis of a functional interaction between the c-MET receptor and Hepatocyte Growth Factor (HGF), a heparin-binding polypeptide consisting of heavy and light chains of 65 and 35 kDa. Nanomolar concentrations of highly purified HGF added to GTL-16 cells, which overexpress the c-MET receptor, enhanced the phosphorylation on tyrosine of the p190c-met kinase. Addition of other known growth factors or serum was ineffective. The kinase activity of the c-MET receptor was also stimulated by HGF in an in vitro assay, after detergent solubilization and partial purification of p190c-met. Moreover, elution of immunoprecipitates obtained with anti-MET antibodies from GTL-16 cell lysates yielded an HGF-responsive kinase activity. These results suggest that HGF, or a growth factor structurally related to HGF, is a candidate ligand for the receptor encoded by c-MET.
Naldini
L
L
Department of Biomedical Sciences & Oncology, University of Torino, School of Medicine, Italy.
Vigna
E
E
Narsimhan
R P
RP
Gaudino
G
G
Zarnegar
R
R
Michalopoulos
G K
GK
Comoglio
P M
PM
D000311:Adrenal Glands / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000502:physiology*; D017228:Hepatocyte Growth Factor; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D010053:Ovary / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D019859:Proto-Oncogene Proteins c-met; D012333:RNA, Messenger / Q000096:biosynthesis; D013154:Spleen / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism; D014599:Uterus / Q000378:metabolism
D006133:Growth Substances; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met