The mammalian target of rapamycin-p70 ribosomal S6 kinase but not phosphatidylinositol 3-kinase-Akt signaling is responsible for fibroblast growth factor-9-induced cell proliferation.
Fibroblast growth factor-9 (FGF9) is a potent mitogen that stimulates normal and cancer cell proliferation though the signaling mechanism is not fully understood. In this study, we aimed to unravel the signaling cascades mediate FGF9 actions in human uterine endometrial stromal cell. Our results demonstrate that the mitogenic effect of FGF9 is transduced via two parallel but additive signaling pathways involving mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase. Activation of mTOR by FGF9 induces p70 ribosomal S6 kinase (S6K1) phosphorylation, cyclin expression, and cell proliferation, which are independent of phosphatidylinositol 3-kinase and Akt. Coimmunoprecipitation analysis demonstrates that mTOR physically associates with S6K1 upon FGF9 treatment, whereas ablation of mTOR activity using RNA interference or pharmacological inhibitor blocks S6K1 phosphorylation and cell proliferation induced by FGF9. Further study demonstrates that activation of mTOR is regulated by a phospholipase Cgamma-controlled calcium signaling pathway. These studies provide evidence to demonstrate, for the first time, that a novel signaling cascade involving phospholipase Cgamma, calcium, mTOR, and S6K1 is activated by FGF9 in a receptor-specific manner.
Wing
Lih-Yuh C
LY
Department of Physiology, National Cheung Kung University, Tainan, Taiwan, Republic of China. wing@mail.ncku.edu.tw
Chen
Hsiu-Mei
HM
Chuang
Pei-Chin
PC
Wu
Meng-Hsing
MH
Tsai
Shaw-Jenq
SJ
D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004717:Endometrium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D051525:Fibroblast Growth Factor 9; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008934:Mitogens / Q000494:pharmacology; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins / Q000378:metabolism
D051525:Fibroblast Growth Factor 9; D005346:Fibroblast Growth Factors; D008934:Mitogens; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; C496459:FGF9 protein, human; C546842:MTOR protein, human; C494918:AKT1 protein, human