Dexamethasone enhances insulin-like growth factor-I effects on skeletal muscle cell proliferation. Role of specific intracellular signaling pathways.
IGF-I stimulation of cell proliferation and c-Fos expression in skeletal muscle cells is markedly enhanced by dexamethasone. The effect of dexamethasone is not mediated by changes in IGF-binding proteins, as evidenced by similar effects of dexamethasone on the actions of insulin, PDGF-BB, and the IGF-I analogue long R3IGF-I. Dexamethasone also does not alter autocrine IGF-II secretion by muscle cells. To investigate the mechanism of the augmentation of IGF-I action, the effects of dexamethasone on intracellular IGF-I signaling pathways were determined. In dexamethasone-treated cells, the levels of IGF-I receptor tyrosine phosphorylation and receptor-associated phosphatidylinositol 3-kinase activity were increased. Dexamethasone-treated cells also showed increased and prolonged tyrosine phosphorylation of the Shc proteins. In contrast, dexamethasone decreased both tyrosine phosphorylation and expression of insulin receptor substrate 1 (IRS-1) and IRS-1-associated phosphatidylinositol 3-kinase activity. Thus, distinct signaling pathways activated by the IGF-I receptor in skeletal muscle cells are differentially regulated by dexamethasone. Potentiation of IGF-I action correlates with increased IGF-I receptor-associated phosphatidylinositol 3-kinase activity and tyrosine phosphorylation of Shc, but appears to be independent of activation of the IRS-1/phosphatidylinositol 3-kinase signaling pathway.
Giorgino
F
F
Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Smith
R J
RJ
D000818:Animals; D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000502:physiology*; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins / Q000096:biosynthesis; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis; D019000:Phosphotyrosine; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis; D015398:Signal Transduction; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D016760:Proto-Oncogene Proteins c-fos; D019000:Phosphotyrosine; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D003907:Dexamethasone; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D020794:Receptor Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1