Mammalian target of rapamycin regulates IRS-1 serine 307 phosphorylation.
Insulin signaling can be negatively regulated by phosphorylation of serine 307 of the insulin receptor substrate (IRS)-1. Rapamycin, an inhibitor of the kinase mTOR, can prevent serine 307 phosphorylation and the development of insulin resistance. We further investigated the role of mTOR in regulating serine 307 phosphorylation, demonstrating that serine 307 phosphorylation in response to insulin, anisomycin, or tumor necrosis factor was quantitatively and temporally associated with activation of mTOR and could be inhibited by rapamycin. Amino acid stimulation activated mTOR and resulted in IRS-1 serine 307 phosphorylation without activating PKB or JNK. Okadaic acid, an inhibitor of the phosphatase PP2A, activated mTOR and stimulated the phosphorylation of serine 307 in a rapamycin-sensitive manner, indicating serine 307 phosphorylation requires mTOR activity but not PP2A, suggesting that mTOR itself may be responsible for phosphorylating serine 307. Finally, we demonstrated that serine 307 phosphorylated IRS-1 is detected primarily in the cytosolic fraction.
Carlson
Christian J
CJ
Insulin signaling, Metabolic Diseases Division, Global Pharmaceutical Research Division, Abbott Laboratories, Abbott Park, IL 60064, USA.
White
Morris F
MF
Rondinone
Cristina M
CM
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D002460:Cell Line; D003600:Cytosol / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010750:Phosphoproteins / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000502:physiology*; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D000596:Amino Acids; D004791:Enzyme Inhibitors; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D019319:Okadaic Acid; D012694:Serine; D000841:Anisomycin; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; D010749:Phosphoprotein Phosphatases; D020123:Sirolimus