IGF-1-stimulated protein synthesis in oligodendrocyte progenitors requires PI3K/mTOR/Akt and MEK/ERK pathways.
Insulin-like growth factor-1 (IGF-1) interacts with the Type I receptor to activate two main signaling pathways, the mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) and the phosphatidylinositol 3-kinase (PI3K)-Akt cascades, which mediate proliferation or survival of oligodendrocyte (OL) progenitors (OLPs). In other cellular systems, mammalian target of rapamycin (mTOR) and the p70 S6 kinase are downstream effectors that phosphorylate translation initiation factors (e.g. eIF-4E), their regulators (e.g. 4E-binding protein 1, 4E-BP1) and ribosomal protein S6 (S6). The aim of this study was to determine whether these pathways are involved in IGF-1-stimulated protein synthesis, important for growth and differentiation of OLs. Rat cultured OLPs were treated with IGF-1 with or without inhibitors of PI3K (LY294002 or Wortmannin), mTOR (rapamycin), MEK (PD98059), and Akt (III or IV), as well as an adenovirus encoding a dominant negative form of Akt. Protein synthesis, as assessed by [(35)S]-methionine incorporation, was stimulated by IGF-1 and required the upstream activation of PI3K, Akt, mTOR and MEK/ERK. Concordant with the experiments using protein kinase inhibitors, western blotting revealed that IGF-1 stimulates phosphorylation of Akt, mTOR, ERK, S6 and 4E-BP1. Activation of S6 and inactivation of 4E-BP1, necessary for protein synthesis to take place, were dependent on the upstream activation of PI3K and mTOR. Finally, IGF-1 consistently stimulated protein synthesis through mTOR in differentiating OLPs but mRNA transcription was not required at day 4, indicating a differential role of IGF-1 throughout OL development.
Bibollet-Bahena
Olivia
O
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Almazan
Guillermina
G
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003176:Complement C3 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases; D005699:Galactosylceramides / Q000378:metabolism; D005732:Gangliosides / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D004676:Myelin Basic Protein / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects*; D011494:Protein Kinases / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013234:Stem Cells / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases; D014162:Transfection
D003176:Complement C3; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D005699:Galactosylceramides; D005732:Gangliosides; D005904:Glial Fibrillary Acidic Protein; D007334:Insulin-Like Growth Factor I; D020928:Mitogen-Activated Protein Kinases; D004676:Myelin Basic Protein; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D011500:Protein Synthesis Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C002454:galactocerebroside; C062875:ganglioside A2B5; C546845:mTOR protein, rat