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MTOR phosphorylates IRS1. 58 / 59
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"Although S6K1 is an effector of growth, recent reports show that amino acids also negatively affect insulin signaling through mTOR and S6K1 phosphorylation of IRS1."
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"MTOR induced the serine phosphorylation of IRS-1 (Ser-636/639), and such phosphorylation was inhibited by rapamycin."
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"Prompted by the results from intravenous amino acid infusion studies in people that demonstrated that amino acids blunt insulin-mediated glucose disposal ( xref , xref ) and studies conducted in cultured myotubes and isolated rat skeletal muscles that demonstrated that leucine can impair insulin-mediated glucose uptake ( xref , xref ), presumably mediated by mTOR-p70S6K phosphorylation and subsequent serine phosphorylation of insulin receptor substrate-1 ( xref ), we tested the hypothesis that protein ingestion impairs insulin-mediated glucose disposal by leucine-mediated muscle mTOR signaling in people."
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"Amino acid-induced mammalian target of rapamycin complex-1 (mTORC1) activation causes phosphorylation of insulin receptor substrate-1 (IRS-1), leading to the occurrence of insulin resistance; (4) glucocorticoids promote gluconeogenesis in liver and cause hyperglycemia; and (5) non-specific binding of glucocorticoids to its receptor in the kidneys causes an increase in sodium retention, potassium excretion, water retention, and plasma volume concomitantly with elevation of blood pressure [ xref , xref , xref ]."
27708685
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"However, mTOR inhibition abolishes IRS-1 phosphorylation, thus allowing IRS-1 to complex with IGF-1R and promote Akt signaling XREF_BIBR, and thereby generating a mechanism for escape from selective mTOR inhibition."
25556614
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"When IRS1 is phosphorylated by S6K and mTOR, it is degraded and cells become unresponsive to insulin [133]."
32899412
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"Phosphorylation of IRS-1 (Ser312) by P-mTOR promotes conformational changes and subsequent detachment from the receptor and degradation [ xref ], and inhibits potentiation of Akt by IGF-1R/IRS-1 signaling [ xref ]."
20863384
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"This impairment correlated with increased phosphorylation of mTOR, p70S6K and serine phosphorylation of IRS-1 [ xref ]."
32230718
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"TNF-alpha produced by obesity induced inflammation stimulates IKK XREF_BIBR, JNK XREF_BIBR, and mTOR and S6K XREF_BIBR XREF_BIBR, which enhance serine phosphorylation of insulin receptor substrate-1 (IRS-1)."
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"This specific serine site on IRS-1 can be phosphorylated by p44/p42 MAPK ( xref ) and mTOR ( xref )."
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"Amino acid induced mammalian target of rapamycin complex-1 (mTORC1) activation causes phosphorylation of insulin receptor substrate-1 (IRS-1), leading to the occurrence of insulin resistance; (4) glucocorticoids promote gluconeogenesis in liver and cause hyperglycemia; and (5) non specific binding of glucocorticoids to its receptor in the kidneys causes an increase in sodium retention, potassium excretion, water retention, and plasma volume concomitantly with elevation of blood pressure [XREF_BIBR, XREF_BIBR, XREF_BIBR]."
27708685
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"Other feedback or alternative signaling loops that mediate resistance involve an mTOR dependent serine phosphorylation of insulin receptor substrate-1 (IRS-1) that enhances insulin like growth factor-1 (IGF-1) signaling leading to downstream activation of PI3K and AKT."
23714559
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"Statins also induced mTOR dependent phosphorylation of insulin receptor substrate 1."
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"In contrast, sustained PI3K/Akt activation inhibits IRS1 activity by negative feedback through the activation of mTOR and p70S6K that phosphorylate IRS1 on its inhibitory domain (Ser 307 ) [ xref ]."
24735980
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"AMPK activity is suppressed by IIS via Akt, and activated AMPK inhibits IIS by phosphorylating insulin receptor substrate 1 (IRS), and mTOR signaling pathways through phosphorylation of TSC2 and raptor."
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"This interaction likely requires phosphorylation of IRS-1 by mTOR and S6K, because phosphorylation of IRS-1 by S6K at Ser307 stimulated its interaction with Fbw8 in vitro and the S307/S312/S527/S636/S[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Physiologic activation of the Akt pathway is regulated, in part, by a negative feedback loop involving phosphorylation of insulin receptor substrate 1 (IRS1) by the mTOR effector molecule S6 kinase 1 ( xref A) [ xref – xref ]."
18215105
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"Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1)."
16354680
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"There are also other kinases, such as mammalian target of rapamycin (mTOR), protein kinase R (PKR), and protein kinase theta (PKtheta) that can induce inhibitory phosphorylation of IRS-1, and thus contribute to nutrient and inflammation related disruption of insulin signaling [XREF_BIBR]."
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"The activation of mTOR by nutrients can cause phosphorylation of the insulin receptor substrate 1 (IRS1)."
27897193
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"Loss-of-function and pharmacological inhibition studies have shown that the mTOR target S6K1, for instance, inhibits and desensitizes insulin-PI3K signaling by phosphorylating IRS1 protein and suppressing IRS1 gene transcription."
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"It is now believed that the proteolytic turnover of IRS-1 constitutes a negative feedback loop that restrains the magnitude and/or duration of PI3K activation, xref via a mechanism requiring seryl phosphorylation of IRS-1 by mTOR and its effector kinase S6K (whose activities are stimulated by the PI3K/Akt cascade; see xref ) (reviewed in refs. xref – xref )."
18927510
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"The findings of the present study of diet-and obesity induced insulin resistance in murine models suggest that suppression of TSC1 by IKKbeta activates mTOR and S6K1, which in turn phosphorylate IRS1 at Ser636/639 and Ser307, thereby inhibiting IRS1 function)."
18949383
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"This process requires PI3-K and Akt-dependent activation of the small G protein Rheb, which activates mTOR and its downstream effector kinase S6K (the p70 S6 kinase) that serine phosphorylate IRS-1, t[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Furthermore, the mTOR inhibitor, rapamycin, also blocked chronic insulin‐induced IRS1 degradation () suggesting that serine phosphorylation of IRS1 by mTOR targets IRS1 for degradation ()."
17027525
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"In aortic endothelial cells, ANG II can stimulate mTOR and p70S6K activation that phosphorylates IRS1 and inhibits endothelial nitric oxide synthase that not only may contribute to insulin resistance but also to vasoconstriction and hypertension [XREF_BIBR]."
22545721
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"Raptor binds the SAIN (Shc and IRS-1 NPXY binding) domain of insulin receptor substrate-1 (IRS-1) and regulates the phosphorylation of IRS-1 at Ser-636/639 by mTOR."
19561084
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"How Fbw8 is regulated and the compartment where it degrades IRS-1 has remained unclear but they have shown that the Fbw8 and IRS-1 interaction requires phosphorylation of IRS-1 by mTOR and S6K."
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"It is now believed that the proteolytic turnover of IRS-1 constitutes a negative feedback loop that restrains the magnitude and/or duration of PI3K activation, XREF_BIBR via a mechanism requiring seryl phosphorylation of IRS-1 by mTOR and its effector kinase S6K (whose activities are stimulated by the PI3K and Akt cascade; see XREF_FIG)."
18927510
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"Several signaling proteins have been shown to play roles in IRS1 degradation, including suppressor of cytokine signaling (SOCS) signaling, retinoic-acid mediated protein kinase C activation, and mTOR, which mediates IRS1 phosphorylation on S 636/639, to promote its degradation."
18755774
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"MTOR complex 1 (mTORC1)-S6K1 induced phosphorylation of insulin receptor substrate 1 (IRS1) provides a negative feedback mechanism to downregulate the insulin-like growth factor 1 receptor (IGF-1R) (11)."
32057715
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"In their pioneering study, Pan and colleagues XREF_BIBR reported that Cul7 ubiquitinates IRS-1 and that phosphorylation of IRS-1 by mTOR and S6K is important for Cul7 recognition of IRS-1."
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"When IRS1 is phosphorylated by S6K and mTOR, it is degraded and cells become unresponsive to insulin [ xref ]."
32899412
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"42 However, inhibition of mTOR by some chemicals, such as rapa, will promote AKT phosphorylation by blocking the phosphorylation of insulin receptor substrate 1 and p70 ribosoma S6 kinase, XREF_BIBR, XREF_BIBR which are known to be a part of a negative feedback mechanism of PI3K-AKT signal transduction."
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"The findings of the present study of diet-and obesity-induced insulin resistance in murine models suggest that suppression of TSC1 by IKKβ activates mTOR and S6K1, which in turn phosphorylate IRS1 at Ser636/639 and Ser307, thereby inhibiting IRS1 function)."
18949383
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"ERK, not MTOR and p70 S6K, mediates the phosphorylation of IRS1 in the liver extracts."
19801385
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"Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1)."
16354680
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"Leucine has also been implicated in muscle insulin resistance (via inhibitory phosphorylation of the insulin receptor substrate-1 by mTOR kinase) XREF_BIBR, XREF_BIBR, although this finding has not been fully supported by other studies XREF_BIBR."
25050624
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"We next sought to determine whether mTOR requires Raptor, an obligatory mTORC1 component, to phosphorylate IRS-1."
30240640
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"In case of genotype 1b, IRS-1 is down regulated by mTOR (mammalian target of Rapamycin) that causes the serine/threonine phosphorylation of IRS-1 and hampers normal insulin signaling."
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"28However, activation of the mTOR pathway promotes the serine/threonine phosphorylation of IRS-1 and IRS-2 that inhibits their function, promotes their degradation, and, possibly, inhibits their trans[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Physiologic activation of the Akt pathway is regulated, in part, by a negative feedback loop involving phosphorylation of insulin receptor substrate 1 (IRS1) by the mTOR effector molecule S6 kinase 1 (XREF_FIG A) [XREF_BIBR - XREF_BIBR]."
18215105
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"PP2A has been shown to dephosphorylate the mTOR substrate S6K1 and involved in mTOR-mediated phosphorylation of insulin receptor substrate 1 through modulation of PP2A activity by mTOR [28]."
34368369
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"Yoon and Chen [XREF_BIBR] found that mTOR activation can promote phosphorylation of insulin receptor substrate-1 and suppress cell differentiation of mouse C2C12."
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"Since both mTOR and S6K1 can phosphorylate IRS1 we wanted to determine the affects of Shh on the activation of S6K. Western blot analysis ( xref ) shows that S6K phosphorylation, an indicator of its activation by mTOR, is reduced in Shh-treated CGNPs."
18755774
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"* The HG/HI-induced serine phosphorylation of IRS-1 and activation of mTOR and p70S6K were attenuated by RE."
33471600
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"Since both mTOR and S6K1 can phosphorylate IRS1 we wanted to determine the affects of Shh on the activation of S6K."
18755774
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"Studies in cultured myotubes and isolated rat skeletal muscles suggest that Leu and BCAA can impair insulin-mediated glucose uptake through a negative-feedback loop (Iwanaka et al. 2010; xref ), presumably mediated by mTOR-S6K1 phosphorylation and subsequent serine phosphorylation and inactivation of IRS-1 (Iwanaka et al. 2010; xref )."
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"For example, TNF-activated signaling molecules such as IKK, JNK, S6 kinase, and mammalian target of rapamycin (mTOR) could potentially phosphorylate insulin receptor substrate 1 (IRS1) to attenuate insulin signaling and subsequently contribute to the development of insulin resistance ( xref ; xref ; xref ; xref ; xref ; xref )."
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"IRS1 is phosphorylated at S636/639 by the mTOR pathway [XREF_BIBR], keeping it from activating RTKs and further activating the PI3K pathway."
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"Increased BCAAs may increase activation of mTOR and S6K1 kinase pathway, which phosphorylates insulin receptor substrate 1 (IRS-1), with a subsequent decline in IRS-1 associated phosphatidylinositide 3-kinase (PI 3-kinase) activity."
25781947
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"However, by also inhibiting an mTOR-dependent serine phosphorylation of insulin receptor substrate-1 (IRS-1), they may enhance insulin-like growth factor-I (IGF-I) signaling and downstream phosphatidylinositol 3-kinase (PI3K)/AKT activation."
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"This suggests that activation of mTOR preceds loss of inhibitory IRS-1 phosphorylation, and that loss of IRS-1 inhibition, which was negatively correlated with phospho-S6 positivity in CAH and EC in the human disease, was associated with progression to hyperplasia in this rat model as well."
20179297
trips
"At the molecular level, Raptor binds the SAIN (Shc and IRS-1 NPXY binding) domain of IRS-1 and regulates the phosphorylation of IRS-1 at Ser-636/639 by mTOR."
19561084
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"MTOR complex 1 (mTORC1)-S6K1 induced phosphorylation of insulin receptor substrate 1 (IRS1) provides a negative feedback mechanism to downregulate the insulin-like growth factor 1 receptor (IGF-1R) ( xref )."
32057715
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"In addition, mTOR and S6K1 have been shown to induce serine/threonine phosphorylation of IRS1 to attenuate signal flow to downstream effectors, and thus play a role in insulin resistance [XREF_BIBR]."
20167101
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"In a similar fashion, it was shown that rapamycin induced mTOR inhibition decreased the serine phosphorylation of IRS-1, which was associated with a compensatory IGF-I downstream signaling via the PI3K and AKT pathway [XREF_BIBR]."
27661006
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"MTOR phosphorylates insulin receptor substrate 1 (IRS-1), causing insulin resistance by inhibition of insulin signalling."
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