The tyrosine-phosphorylated hepatocyte growth factor/scatter factor receptor associates with phosphatidylinositol 3-kinase.
The receptor for hepatocyte growth factor, also known as scatter factor (HGF/SF), has recently been identified as the 190-kDa heterodimeric tyrosine kinase encoded by the MET proto-oncogene (p190MET). The signaling pathway(s) triggered by HGF/SF are unknown. In A549 cells, a lung epithelial cell line, nanomolar concentrations of HGF/SF induced tyrosine phosphorylation of the p190MET receptor. The autophosphorylated receptor coprecipitated with phosphatidylinositol 3-kinase (PI 3-kinase) activity. In GTL16 cells, a cell line derived from a gastric carcinoma, the p190MET receptor, overexpressed and constitutively phosphorylated on tyrosine, coprecipitated with PI 3-kinase activity and with the 85-kDa PI 3-kinase subunit. In these cells activation of protein kinase C or the increase of intracellular [Ca2+] inhibits tyrosine phosphorylation of the p190MET receptor as well as the association with both PI 3-kinase activity and the 85-kDa subunit of the enzyme. In an in vitro assay, tyrosine phosphorylation of the immobilized p190MET receptor was required for binding of PI 3-kinase from cell lysates. These data strongly suggest that the signaling pathway activated by the HGF/SF receptor includes generation of D-3-phosphorylated inositol phospholipids.
Graziani
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A
Department of Biomedical Sciences and Oncology, University of Torino Medical School, Italy.
Gramaglia
D
D
Cantley
L C
LC
Comoglio
P M
PM
D002460:Cell Line; D006133:Growth Substances / Q000302:isolation & purification / Q000378:metabolism*; D017228:Hepatocyte Growth Factor; D006801:Humans; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D008970:Molecular Weight; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism*; D019000:Phosphotyrosine; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met; D011519:Proto-Oncogenes; D011956:Receptors, Cell Surface / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis
D006133:Growth Substances; D017228:Hepatocyte Growth Factor; D046911:Macromolecular Substances; D019869:Phosphatidylinositol 3-Kinases; D010770:Phosphotransferases; D019000:Phosphotyrosine; D011493:Protein Kinase C; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met; D011956:Receptors, Cell Surface; D014443:Tyrosine; C000715470:MAS1 protein, human