Extracellular ATP-induced Proliferation of Adventitial Fibroblasts Requires Phosphoinositide 3-Kinase, Akt, Mammalian Target of Rapamycin, and p70 S6 Kinase Signaling Pathways
| Autor: | Dwight J. Klemm, Doug A. Tucker, Evgenia V. Gerasimovskaya, Janet M. Wenzlau, Mary C.M. Weiser-Evans, Mark F. Banks, Kurt R. Stenmark |
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| Rok vydání: | 2005 |
| Předmět: |
P70-S6 Kinase 1
Protein Serine-Threonine Kinases Pulmonary Artery Biology Biochemistry Phosphatidylinositol 3-Kinases Adenosine Triphosphate Proto-Oncogene Proteins Extracellular Animals Molecular Biology Protein kinase B Cells Cultured PI3K/AKT/mTOR pathway TOR Serine-Threonine Kinases RPTOR Purinergic receptor Ribosomal Protein S6 Kinases 70-kDa Cell Biology Cell biology Phosphorylation Cattle Signal transduction Protein Kinases Proto-Oncogene Proteins c-akt Cell Division Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 280:1838-1848 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m409466200 |
| Popis: | Extracellular nucleotides are increasingly recognized as important regulators of growth in a variety of cell types. Recent studies have demonstrated that extracellular ATP is a potent inducer of fibroblast growth acting, at least in part, through an ERK1/2-dependent signaling pathway. However, the contributions of additional signaling pathways to extracellular ATP-mediated cell proliferation have not been defined. By using both pharmacologic and genetic approaches, we found that in addition to ERK1/2, phosphatidylinositol 3-kinase (PI3K), Akt, mammalian target of rapamycin (mTOR), and p70 S6K-dependent signaling pathways are required for ATP-induced proliferation of adventitial fibroblasts. We found that extracellular ATP acting in part through G(i) proteins increased PI3K activity in a time-dependent manner and transient phosphorylation of Akt. This PI3K pathway is not involved in ATP-induced activation of ERK1/2, implying activation of independent parallel signaling pathways by ATP. Extracellular ATP induced dramatic increases in mTOR and p70 S6K phosphorylation. This activation of the mTOR/p70 S6 kinase (p70 S6K) pathway in response to ATP is because of independent contributions of PI3K/Akt and ERK1/2 pathways, which converge on the level of p70 S6K. ATP-dependent activation of mTOR and p70 S6K also requires additional signaling inputs perhaps from pathways operating through Galpha or Gbetagamma subunits. Collectively, our data demonstrate that ATP-induced adventitial fibroblast proliferation requires activation and interaction of multiple signaling pathways such as PI3K, Akt, mTOR, p70 S6K, and ERK1/2 and provide evidence for purinergic regulation of the protein translational pathways related to cell proliferation. |
| Databáze: | OpenAIRE |
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