Distinct roles for PI3K in proliferation and survival of oligodendrocyte progenitor cells.
Phosphoinositol 3-kinase (PI3K) is a downstream effector for multiple ligand-activated receptors and modulates cell responses through activation of its target protein kinase B (Akt). We examined the roles of PI3K-Akt signaling in a primary glial (oligodendrocyte) progenitor cell culture system that is ligand-dependent for cell proliferation, survival, and prevention of differentiation. We demonstrate that PI3K and Akt (Ser-473 phosphorylation) are activated in response to platelet-derived growth factor but not basic fibroblast growth factor-2 (FGF2) and that distinct forms of PI3K are activated in early progenitors and later-maturation pro-oligodendroblasts as identified by their sensitivity to wortmannin. By establishing conditions to examine effects on cell proliferation and survival independently, we demonstrate that PI3K is necessary for a full mitogenic response and that PI3K is also necessary for early progenitor survival. Our results therefore demonstrate that PI3K-Akt signaling independently regulates proliferation and survival, that the form of PI3K is distinct in early progenitors and pro-oligodendroblasts, and that FGF2 does not activate this pathway in either primary glial cell population.
Ebner
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Departments of Surgery (Neurosurgery), Molecular Genetics, and Microbiology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
Dunbar
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McKinnon
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D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D008024:Ligands; D009836:Oligodendroglia / Q000166:cytology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D016222:Fibroblast Growth Factor 2; D008024:Ligands; D019869:Phosphatidylinositol 3-Kinases; D010982:Platelet-Derived Growth Factor; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; C494920:Akt1 protein, rat