Rahimi N, Tremblay E, Elliott B
Department of Pathology, Cancer Research Laboratories, Queen's University, Kingston, Ontario K7L 3N6, Canada.
J Biol Chem. 1996 Oct 4;271(40):24850-5. doi: 10.1074/jbc.271.40.24850.
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.
磷脂酰肌醇（PI）3激酶是一种参与生长因子刺激的细胞内信号传导的重要酶。在本研究中，我们发现肝细胞生长因子（HGF）可诱导Mv1Lu上皮细胞中PI 3激酶的快速酪氨酸磷酸化，并与HGF受体/Met结合。共表达HGF和HGF受体/Met的小鼠乳腺癌（SP1）细胞显示出PI 3激酶的持续磷酸化。渥曼青霉素是一种有效的PI 3激酶抑制剂，它以剂量和时间依赖性方式抑制HGF诱导的PI 3激酶活性、Mv1Lu细胞的增殖以及SP1细胞的自发生长。将PI 3激酶的显性负性突变体p85（Deltap85）亚基转染到SP1细胞中可强烈抑制HGF刺激的增殖和PI 3激酶活性。然而，渥曼青霉素并不影响HGF诱导的c-Jun表达。此外，HGF刺激S6激酶活性，但其活性对于HGF诱导的增殖并非必需。总体而言，这些结果表明HGF诱导的PI 3激酶活性对于HGF在上皮细胞中的促有丝分裂作用很重要，并进一步证明c-Jun的表达不受PI 3激酶活性抑制的影响。
