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MTOR inhibits IRS1. 49 / 58
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"On the other hand, chronic β-cell hyperfunction, a consequence of excessive leucine exposure, results in accelerated β-cell apoptosis and eventual secretory deficiency through a negative feedback loop involving the mTOR-dependent inhibition of IRS-1 [ xref ]."
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"MTOR dependent degradation of IRS-1 is required for the initiation of IGF-IR internalization."
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"In early studies mTOR inhibition led to p70 ribosomal protein S6 kinase (S6K) suppression, IRS1 upregulation, and PI3K-AKT activation 181."
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"Interestingly, inhibition of mTOR partially prevented the decrease in IRS1 protein (decrease to 74% compared to control)."
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"The cullin 7 complex, containing the E3 ligase Fbxw8, was shown to be activated by an mTOR-dependent negative feedback loop after which it could degrade IRS1 ( Xu et al., 2008 )."
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"Rapamycin has been reported to have alternate effects on Akt phosphorylation; prolonged rapamycin exposure has been shown to inhibit assembly of mTORC2, thereby inhibiting Akt, and mTOR inhibition has also been described to induce insulin receptor substrate-1 (IRS-1), leading to Akt activation."
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"Excess glucose also activates mTOR/S6K1, which inhibits the IRS-1 contribution to insulin resistance."
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"Although activation of mTOR is necessary and sufficient to induce IRS-1 degradation, our data suggest that the phosphorylation of mTOR did not differ between the two groups."
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"This suggests that inhibiting mTOR can promote IRS1 stabilization in CGNPs."
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"IRS-1 phosphoration is suppressed by mTOR/S6K signaling [28]."
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"Dual PI3K/mTOR inhibition using BE2235 was shown to induce IRS1-dependent activation of JAK2/STAT5 signalling, possibly via disruption of the mTORC1-IRS1 negative feedback ."
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"Current mTOR inhibition causes the upregulation of the Ras and Raf pathway and inhibition of the negative feedback loop of IRS1 while inhibition of IGF signaling has been shown to inhibit growth and induce death of cancer cells with upregulated PI3K."
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"For example, mTOR and its downstream S6K can inhibit the upstream insulin signaling molecule IRS-1 to regulate glucose uptake and protein synthesis [XREF_BIBR, XREF_BIBR]."
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"XREF_BIBR - XREF_BIBR Recent data suggest that the inhibition of mTOR relieves negative feedback regulation of IRS-1, resulting in increased IRS-1 expression and activation of AKT."
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"Additionally, it has been demonstrated that inhibition of mTOR by rapamycin prevents IRS-1 degradation and partially suppresses insulin resistance induced by chronic insulin treatment [37,44,45] ."
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"A 3–12-week-HFD was associated with elevated BNIP3L/NIX in rats [ xref ], whilst a later study investigating BNIP3L/NIX in C2C12 and primary human myotubes linked increased BNIP3L expression with impaired insulin signaling via mechanistic target of rapamycin kinase (mTOR)-dependent inhibition of insulin receptor substrate 1 (IRS-1) [ xref ]."
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"Inhibition of mTOR has been shown to inhibit proteasomal degradation of IRS-1 enhancing signaling through the PI-3 kinase and Akt pathway."
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"However, if BCAA contribute to insulin resistance, they may function through either mTOR-mediated suppression of insulin receptor substrate-1 (IRS-1) or through the accumulation of toxic BCAA cataboli[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"On the other hand, chronic beta-cell hyperfunction, a consequence of excessive leucine exposure, results in accelerated beta-cell apoptosis and eventual secretory deficiency through a negative feedback loop involving the mTOR dependent inhibition of IRS-1 [XREF_BIBR]."
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"UA agonizes signaling of insulin and IGF -1 receptor and elicits AMPK mediated p53 activation, which is abolished by mTOR mediated IRS-1 degradation downstream of IGF-1 receptor signaling [XREF_BIBR]."
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"43 Augmented mTOR/p70 S6K can inhibit the upstream IRS1 mediated signals initiating from other growth factor receptors rather than TGF‐β receptor I/II and thereby intensify the TGF‐β‐induced PI3K signalling."
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"Of critical importance, because mTOR inhibition quickly upregulates IRS-1 and PI3K (due to derepression of the p70S6K → IRS-1 feedback loop) [113], [114], [115], [116], it is imperative to simultaneously block the proximal portion of the IGF-1/PI3K/mTOR pathway (Fig. 1)."
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"Bose SK, Shrivastava S, Meyer K, Ray RB, Ray R. Hepatitis C virus activates the 32 mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance."
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"In addition to diabetes, mTOR/S6K1-mediated feedback inhibition of IRS1 and by extension the oncogenic PI3K/Akt pathway poses drawbacks for cancer therapy and limits the cytotoxic effects of rapamycin-based therapeutic approaches [75]."
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"By serine phosphorylation and insulin receptor substrate 1 (IRS1) inhibition by mTOR, activation of the mTOR signaling pathway has been shown to reduce insulin sensitivity [ xref ]."
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"Calorie restriction and/or GH resistance decreases mTOR signaling and phosphoSer inhibition of IRS-1 in skeletal muscle."
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"In addition, BNIP3L expression can impair insulin signaling in myotubes through MTOR-dependent inhibition of IRS1."
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"In addition, BNIP3L expression can impair insulin signaling in myotubes through MTOR-dependent inhibition of IRS1."
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"In these cells, Shh upregulates IRS-1 by interfering with mTOR mediated IRS-1 degradation, and by enhancing IRS-1 translation."
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"A negative feedback loop has been described, whereby mTOR and S6K1 activation attenuates PI3K signaling by suppressing insulin receptor substrate-1 (IRS1) function, a mediator of insulin receptor- dependent activation of PI3K."
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"Moreover, the genes up-regulated in Ptch1 +/- / Tis21 KO GCPs include : Depdc6 (Deptor), a subunit of the mTOR complex 1 (mTORC1) that can inhibit this complex and thus relieve the S6K and IRS1 feedback loop; the leucyl-tRNA synthetase Lars, that senses intracellular leucine concentration and initiates molecular events triggering mTORC1 activation, by binding Rraga GTPase; Rraga, a GTPase activator of mTORC1; and Dgkq, which is a mediator of the mTOR complex 2 (mTORC2)."
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"For example, mTOR can function in a negative feedback loop and potentially produce glucose intolerance by inhibiting the insulin receptor substrate 1 (IRS-1) [XREF_BIBR]."
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"This restoration of IRS-1 mRNA abundance by sustained rapamycin treatment is reversed by actinomycin D (XREF_FIG), indicating that mTOR and S6K1 signaling likely reduces IRS-1 mRNA abundance primarily at the level of gene transcription."
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"IRS-1 activity is not reflected by its expression level, which is elevated in mouse embryonic fibroblasts lacking mTORC2 (an mTOR isoform that promotes IRS-1 degradation); IRS-1 signaling capacity was[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"AMPK inhibits the mammalian target of rapamycin (mTOR), which in concert with protein kinase B/Akt (Akt) are proposed to reduce insulin signalling by inhibiting IRS-1 and IRS-2 in diabetes mellitus ( [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"MTOR can function in a negative feedback loop and produce glucose intolerance by inhibiting the insulin receptor substrate 1 (IRS-1)."
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"Moreover, mTOR hyper-activation is also among the known feedback mechanisms promoting IRS1 inhibition and insulin resistance development in AD [91,92,93,97]."
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"Therefore, mTOR inhibition will induce IRS-1 activation releasing the inhibition mediated by S6K1 and provoking the activation of AKT via an insulin growth factor receptor 1 (IGF-1R) dependent signaling process."
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"Mammalian target of rapamycin complex 1 (mTORC1) has the important role of managing excess of FFA and inducing differentiation of preadipocytes to white adipose tissue (WAT), leading to expansion of W[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Overactivation of mTOR can inhibit insulin receptor substrate 1, which leads to insulin resistance in hepatocytes."
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"Specifically , mTOR acts through S6 kinase to inhibit IRS-1 ( insulin receptor substrate ) ( Fig. 4C ) , leading to receptor signal resistance , including insulin resistance that contributes to type 2 diabetes ( Blagosklonny , 2006a ) ."
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"Leucine deprivation improves hepatic insulin sensitivity through activating general control nonderepressible 2 (GCN2), which reduces the inhibition of insulin receptor substrate 1 (IRS1) by the mammalian target of rapamycin (mTOR); therefore, enhancing downstream insulin signalling xref ."
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"In neurodegenerative diseases like Alzheimer’s, chronic mTOR overactivation disrupts insulin signaling by inhibiting IRS1, further impairing metabolic regulation [99]."
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"Therefore we tested, if CQ could modulate the RAD001-induced Akt activation in MCF7 cells.Previously, a negative feedback loop was described, whereby mTOR/S6K1 activation attenuated PI3K signaling by [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"For example, mTOR and its downstream S6K can inhibit the upstream insulin signaling molecule IRS-1 to regulate glucose uptake and protein synthesis [ xref , xref ]."
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"On the molecular level, the processes are mediated in part by increased de novo lipogenesis in the liver, reduced fat oxidation in mitochondria, accumulation of toxic ceramides and diacylglycerides, and activation of mTOR that ultimately degrade the insulin receptor substrate-1 (IRS-1) substrate and lead to malfunction of insulin-sensitive tissues [30]."
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"Thus, the CUL7 E3 appears to be responsible for mediating mTOR dependent degradation of IRS-1, thereby functioning as a critical component of the mTOR and IRS -1 negative feedback loop, which fine-tunes the PI3K activity in accordance with the magnitude and duration of mTOR and S6K activities."
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"Activation of mTOR signaling pathway has been found to suppress insulin sensitivity through serine phosphorylation and the inhibition of IRS1 by mTOR and its downstream effector, S6K1."
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"One well characterized negative feedback loop involves the tuberous sclerosis complex (TSC), the Rheb RAS superfamily member, the kinase mTOR, and the mTOR target p70 ribosomal S6 kinase (p70S6K) that inhibits insulin receptor substrate 1 (IRS1) and insulin-like growth factor receptor (IGFR) signaling ( xref ; xref ; xref )."
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