Phosphatidylinositol 3-kinase activity is required for hepatocyte growth factor-induced mitogenic signals in epithelial cells.
Phosphatidylinositol (PI) 3-kinase is an important enzyme implicated in growth factor-stimulated intracellular signaling. In this study we have shown that hepatocyte growth factor (HGF) induces a rapid tyrosine phosphorylation of PI 3-kinase and association with HGF receptor/Met in Mv1Lu epithelial cells. Murine mammary carcinoma (SP1) cells, which co-express HGF and HGF receptor/Met, showed sustained phosphorylation of PI 3-kinase. Wortmannin, a potent inhibitor of PI 3-kinase, inhibited HGF-induced PI 3-kinase activity, proliferation of Mv1Lu cells, and spontaneous growth of SP1 cells in a dose-, and time-dependent manner. Transfection of a dominant negative mutant p85 (Deltap85) subunit of PI 3-kinase into SP1 cells strongly inhibited HGF-stimulated proliferation and PI 3-kinase activity. However, wortmannin did not influence HGF-induced c-Jun expression. Furthermore, HGF stimulated S6 kinase activity, but its activity was not required for HGF-induced proliferation. Overall, these results suggest that HGF-induced PI 3-kinase activity is important for the mitogenic action of HGF in epithelial cells and further demonstrate that expression of c-Jun is not influenced by inhibition of PI 3-kinase activity.
Rahimi
N
N
Department of Pathology, Cancer Research Laboratories, Queen's University, Kingston, Ontario K7L 3N6, Canada.
Tremblay
E
E
Elliott
B
B
D000818:Animals; D004789:Enzyme Activation; D015870:Gene Expression; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D051379:Mice; D008934:Mitogens / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D017228:Hepatocyte Growth Factor; D008934:Mitogens; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D017346:Protein Serine-Threonine Kinases; D016755:Proto-Oncogene Proteins c-jun; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D019893:Ribosomal Protein S6 Kinases; D014443:Tyrosine