Insulin receptor substrate-1 mediates phosphatidylinositol 3'-kinase and p70S6k signaling during insulin, insulin-like growth factor-1, and interleukin-4 stimulation.
Insulin Receptor Substrate-1 (IRS-1) is an endogenous cellular protein that is tyrosine phosphorylated during stimulation of cells with insulin, IGF-1, and interleukin 4 (IL-4). Phosphorylated IRS-1 regulates multiple regulatory pathways by recruiting signaling molecules containing Src homology 2 domains (SH2 proteins). The 32D myeloid progenitor cell line contains few insulin receptors and no detectable IRS-1. Expression of the insulin receptor alone partially mediates insulin-stimulated microtubule-associated protein (MAP) kinase activation, and the addition of IRS-1 enhances this effect (Myers, M. G., Jr., Wang, L.-M., Sun, X. J., Zhang, Y., Yenush, L. P., Schlessinger, J., Pierce, J. H., and White, M. F. (1994) Mol. Cell. Biol. 14, 3577-3587). Alone, insulin receptors mediate phosphatidylinositol (PI) 3'-kinase and p70S6k activation poorly if at all during insulin stimulation. Expression of IRS-1 alone in 32D cells mediates the stimulation of p70S6k by insulin, IGF-1, or IL-4; addition of insulin receptor to these cells increases the sensitivity of the insulin response. In contrast, full insulin stimulation of PI 3'-kinase requires both the insulin receptor and IRS-1, suggesting that a high level of IRS-1 phosphorylation is required for insulin-stimulated PI 3'-kinase activation, whereas a low level of IRS-1 tyrosine phosphorylation transmits an essential signal to p70S6k. Both insulin receptors and IRS-1 are required for mitogenic signaling in 32D cells suggesting that MAP kinase or p70S6k alone are not sufficient, and that both or additional unknown IRS-1-mediated signals are necessary.
Research Division, Joslin Diabetes Center, Boston, Massachusetts 02115.
M G
MG
Myers
T C
TC
Grammer
L M
LM
Wang
X J
XJ
Sun
J H
JH
Pierce
J
J
Blenis
M F
MF
White
D002460:Cell Line; D004789:Enzyme Activation; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D008934:Mitogens / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction
D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I; D015847:Interleukin-4; D008934:Mitogens; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases