Early stimulation and late inhibition of extracellular signal-regulated kinase 1/2 phosphorylation by IGF-I: a potential mechanism mediating the switch in IGF-I action on skeletal muscle cell differentiation.
IGF-I has a unique biphasic effect on skeletal muscle cell differentiation. Initially, IGF-I inhibits differentiation and promotes proliferation of skeletal myoblasts. Subsequently, IGF-I switches to stimulating differentiation of these cells. The mechanisms responsible for this switch in IGF action remain unknown. We have examined the role of extracellular signal-regulated kinase (Erk)1/2 signaling in mediating the early inhibitory and late stimulatory effects of IGF-I on the gene expression of myogenin, a skeletal muscle-specific transcription factor essential for myogenic differentiation. We find that, concurrent with its early inhibitory and late stimulatory effects on myogenin mRNA, IGF-I has a biphasic but opposite effect on phosphorylation of Erk1/2: initially, IGF-I increases and subsequently decreases the phosphorylation of Erk1/2 in comparison to untreated cells. Cotreatment with an inhibitor of Erk1/2 activation prevents the early IGF-I-stimulation of Erk1/2 phosphorylation and partially reverses IGF-I-inhibition of myogenin mRNA. Conversely, preventing the late IGF-I-induced decrease in Erk1/2 phosphorylation blocks IGF-I-stimulation of myogenin mRNA. Our data indicate that the time-dependent, opposing effects of IGF-I on skeletal muscle cell differentiation are mediated, at least in part, by biphasic but opposite effects on activation of the Erk1/2 MAPK signaling pathway.
Adi
Saleh
S
Department of Pediatrics, University of California, San Francisco, California 94143-0434, USA.
Bin-Abbas
Bassam
B
Wu
Nan-Yan
NY
Rosenthal
Stephen M
SM
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects; D018008:Myogenin / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014638:Vanadates / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005419:Flavonoids; C503803:Myog protein, rat; D018008:Myogenin; D012333:RNA, Messenger; D014638:Vanadates; D007334:Insulin-Like Growth Factor I; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one