Mammalian target of rapamycin pathway regulates insulin signaling via subcellular redistribution of insulin receptor substrate 1 and integrates nutritional signals and metabolic signals of insulin

A pathway sensitive to rapamycin, a selective inhibitor of mammalian target of rapamycin (mTOR), down-regulates effects of insulin such as activation of Akt (protein kinase B) via proteasomal degradation of insulin receptor s ubstrate 1 (LRS-1). We report here that the pathway also plays an important role in insulin-induced subcellular redistribution of IRS-1 from the low-d ensity microsomes (LDM) to the cytosol. After prolonged insulin stimulation , inhibition of the redistribution of IRS-1 by rapamycin resulted in increa sed levels of TRS-1 and the associated phosphatidylinositol (PI) 3-kinase i n both the LDM and cytosol, whereas the proteasome inhibitor lactacystin in creased the levels only in the cytosol. Since rapamycin but not lactacystin enhances insulin-stimulated 2-deoxyglucose (2-DOG) uptake, IRS-1-associate d PI 3-kinase localized at the LDM was suggested to be important in the reg ulation of glucose transport. The amino acid deprivation attenuated and the amino acid excess enhanced insulin-induced Ser/Thr phosphorylation and sub cellular redistribution and degradation of IRS-1 in parallel with the effec ts on phosphorylation of p70 S6 kinase and 4E-BP1, Accordingly, the amino a cid deprivation increased and the amino acid excess decreased insulin-stimu lated activation of Akt and 2-DOG uptake. Furthermore, 2-DOG uptake was aff ected by amino acid availability even when the degradation of IRS-1 was inh ibited by lactacystin. We propose that subcellular redistribution of IRS-1, regulated by the mTOR-dependent pathway, facilitates proteasomal degradati on of LRS-1, thereby down-regulating Akt, and that the pathway also negativ ely regulates insulin-stimulated glucose transport, probably through the re distribution of IRS-1. This work identifies a novel function of mTOR that i ntegrates nutritional signals and metabolic signals of insulin.