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RPS6KB1 inhibits IRS1. 84 / 94
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"S6K1 inhibits IRS1 (insulin receptor substrate 1) by directly phosphorylating it, and is responsible for the inhibition of Akt that is caused by high mTORC1 activity."
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"However, inhibition of p70S6K does not restore IRS1 protein abundance and insulin sensitivity in hSkMC in which PRAS40 expression was silenced (Wiza et al., 2013a)."
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"Under overnutrient conditions, p70 inhibits insulin receptor substrate-1 (IRS-1) by phosphorylation at multiple sites, negatively regulating insulin signaling [ xref , xref ]."
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"Mechanistically, S6K1 inactivates IRS-1 through phosphorylation of the serine (S) residues 307 and 1101, which leads to negative feedback to the PI3K/mTOR pathway."
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"Activated S6K1 can phosphorylate and inhibit insulin-receptor substrate IRS1 and IRS2 [14] ."
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"It is possible that that these two points of interaction complete a regulatory loop that permits crosstalk between the two pathways by allowing signals from the ERK and MAPK pathway to feedback onto PI3K/AKT/mTOR through the inhibition of IRS-1 by p70S6K."
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"The phosphorylation of S6K1 inactivates IRS-1 which is required for insulin signaling through PI3K."
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"One mechanism by which this occurs appears to be through p70S6K dependent downregulation of IRS1."
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"Whereby S6K1 inhibits IRS-1 and prevents ERK1/EKR2 activation, ERK2 inhibition results in S6K1 downregulation ( xref )."
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"To be precise, S6K1 stimulates the degradation of insulin receptor substrate-1 (IRS-1), which results in the inhibition of mTORC2 and PI3K and Akt signaling."
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"In fact, inhibition of p-p70S6K1 by rapalog activates insulin receptor substrate 1 (IRS-1) and phosphatidylinositol 3 kinase (PI3K), by lifting negative feedback, resulting in the phosphorylated activation of Akt at Thr308 (Carracedo et al., 2008)."
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"In addition to decreasing IRS-1 protein stability by phosphorylation, S6K1 and 2 also appear able to downregulate IRS-1 transcription via an unknown mechanism, causing a decrease in IRS1 at the mRNA l[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"They were able to identify a cell line-specific feedback loop for inhibition of IRS1 by p70S6K in colorectal cell lines and to perform stimulations to identify ways to increase their sensitivity to TRIC ( TCP-1 ring complex) inhibitors."
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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 instance, p70S6K can inhibit IRS-1 as a negative feedback loop against overactivation [ xref , xref ]."
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"This is mediated by relief of the classical feedback loop in which mTORC1 and its substrate S6K1 promote IRS-1 degradation to dampen signaling through insulin and insulin like growth factors."
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"Mechanistically, S6K1 inactivates IRS-1 through phosphorylation of the serine (S) residues 307 and 1101, which leads to negative feedback to the PI3K/mTOR pathway."
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"In vivo, 18 h of extremely high S6K1 phosphorylation [up to 80-fold] and activity [up to 4-fold] following acute resistance type contractions do not decrease total IRS-1 or -2 levels immunoprecipated from muscle lysate."
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"There were also positive correlations between interventions in the insulin signalling pathway, particularly betweenIrs1 −/− andRps6kb1 −/− mutants, which is interesting considering that Rps6kb1 directly phosphorylates and inhibits Irs1 ( xref )."
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"Furthermore, rapamycin-induced inhibition of S6K1 abrogates negative feedback loops (S6K1/Rictor, S6K1/IRS1, etc.), leading to hyperactivation of the PI3K/Akt pathway."
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"Chronic ET-1 treatment inhibited insulin stimulated tyrosine phosphorylation of G alpha q/11 and IRS-1, as well as their association with PI3-kinase and blocked the activation of PI3-kinase activity and phosphorylation of AKT : In addition, chronic ET-1 treatment caused IRS-1 degradation, which could be blocked by inhibitors of PI3-kinase or p70 S6-kinase."
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"For example, mTOR signaling through the tuberous sclerosis complex (TSC1, hamartin / TSC2, tuberin) can inactivate IRS and phosphorylate p70S6K to block IRS1 activity by direct phosphorylation [XREF_BIBR]."
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"Although the detailed mechanism is unclear, the likely target of mTOR signalling responsible for the reduction in IRS-1 gene transcription seems to be S6K, because suppression of S6K1 and S6K2 by RNA [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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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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"Conversely, inhibition of mTORC1 relieves p70 S6 kinase mediated inhibition of IRS1, thereby promoting PI3K mediated activation of AKT and downstream survival signaling [XREF_BIBR]."
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"It is postulated that mTORC1 activation causes a negative feedback through S6K1 that reduce the activity of PI3K. The phosphorylation of S6K1 inactivates IRS-1 which is required for insulin signaling through PI3K ( xref )."
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"Mechanistically, a feedback loop has been established to indicate that S6K1 negatively regulates the stability of insulin receptor substrate 1 (IRS1) through directly phosphorylating the S307 and S636 and S639 residues under nutrient deprivation conditions [XREF_BIBR], as well as shuts down insulin or IGF-1 (insulin like growth factor) mediated activation of Akt by phosphorylating Grb10 (growth factor receptor bound protein 10) [XREF_BIBR, XREF_BIBR]."
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"In culture, high levels of mTORC1 and S6K1 activity reduce IRS-1 protein and mRNA levels, diminish its function, and through serine phosphorylation targets it for proteasomal degradation."
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"P70S6 kinase is known to negatively regulate IRS-1 through a feedback phosphorylation and inhibition of p70S6 kinase results in increased IGF receptor and PI3 kinase and AKT signaling [XREF_BIBR]."
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"In one such mechanism, S6K1 (which is directly activated by mTORC1) inactivates IRS-1 by phosphorylating IRS-1 at multiple serine residues ( xref ; xref ; xref ; xref )."
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"When mTOR is inhibited S6K1 does not inhibit IRS-1."
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"We have previously found that the inhibition of mTORC1 and S6K1 by rapamycin or adiponectin relieves the feedback inhibition of IRS1, resulting in increased PI3K and Akt2 activity."
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"Persistent mTORC1 activation is generally postulated to inhibit AKT via its downstream kinase, S6K1, which phosphorylates and inhibits either insulin receptor substrate-1 or members of the mTORC2 complex, rictor at Thr1135 and mSIN1 at Thr86 and Thr398."
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"In fact, S6K1 (activated by mTORC1) promotes also the phosphorylation and inactivation of IRS1, the insulin receptor substrate 1."
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"This result suggests that p70S6K-independent degradation of IRS-1 had a greater effect on the phosphorylation level of downstream signaling proteins (AKT and FOXO3a) than negative phosphorylation of t[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"For example, active mTORC1 phosphorylates S6K1, which in turn promotes degradation of IRS-1 leading to downregulation of PI3K/AKT signalling."
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"The inhibition of S6K1 by rapalogues can activate insulin receptor substrate 1 (IRS1), leading to a feedback loop mechanism that may reactivate AKT, 28 and preclinical evidence has shown that simultan[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"On the other hand, the mTORC1 substrate RPS6KB1 phosphorylates and inhibits IRS1 [ xref , xref ]."
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"mTORC1 activates S6K1, which inhibits IRS-1 through phosphorylation in serine 302 xref ."
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"The PI3K/AKT/mTOR signalling pathway is under the control of PTEN, but it may also be inactivated by a feedback loop in which S6K1 directly inhibits IRS1."
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"Further downstream, mTOR phosphorylates p70 S6 kinase (T389), a regulator of Ribosomal Protein S6 (RPS6) responsible for mRNA translation, and has been proposed to signal via 14-3-3 (tyrosine 3-monooxygenase), a required protein in Raf signaling, to inhibit IRS-1 in a negative feedback loop XREF_BIBR."
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"Excess glucose also activates mTOR/S6K1, which inhibits the IRS-1 contribution to insulin resistance."
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"mTORC1 activates S6K1, which inhibits IRS-1 through phosphorylation in serine 302 42."
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"Activated mTOR stimulates S6K1 to inhibit insulin receptor substrate-1 (IRS1), affecting the insulin pathway, causing insulin resistance [31–33]."
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"Activation and inhibition of Akt in gWAT and skeletal muscle may be related to the activity of other regulatory kinases or phosphatases and not necessarily results from the S6K1-induced IRS1 inhibition."
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"( 4 ) S6K1 inhibits IRS-1 , leading to subsequent ERK2 inhibition and consequent downregulation of S6K1 ."
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"Our results indicate that the mechanism that involves S6K1-induced inhibition of p-IRS1(S1101) is tissue-specific and partially contributes to systemic physiological IR in this critical developmental window of the rat."
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"As part of a negative feedback loop, S6K1 also phosphorylates and inhibits insulin receptor substrate 1 (IRS-1), leading to inhibition of AKT (protein kinase B)-mTOR and extracellular signal-regulated kinase (ERK) signaling."
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"Third, according to studies by Ono et al. 137 and Um, S. H et al. 138, activation of S6K1, a downstream effector of mTORC1, in hypothalamic neurons leads to hepatic insulin resistance because it decreases the stimulation of IRS-1 and AKT."
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"Thus, the inhibition of p70S6K can increase IRS-1 to feedback activate PI3K and AKT, which in turn drives tumor cells to acquire resistance to rapamycin."
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"Compelling evidence shows that S6K1 phosphorylates and inhibits the insulin-receptor substrate IRS1, an important mediator of insulin-receptor-dependent activation of PtdIns3K ( Figure 1 ) [65–68] ."
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"Therefore, S6K1 is unlikely to trigger IRS-1 degradation under physiological conditions like persistent insulin/IGF stimuli, although S6K1 mediates a negative feedback in ways other than IRS-1 degradation as reportedly shown in S6K1 knockout mice (Um et al., 2004)."
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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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"Suppression of either S6K1 or S6K2 mimics the effect of rapamycin treatment and restores IRS-1 mRNA to a level approaching that of TSC2 +/+ MEFs (XREF_FIG)."
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"S6K1 also phosphorylates and inactivates IRS1, thereby providing a negative feedback loop [ xref ]."
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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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"Even though S6K1 activity increases throughout muscle cell differentiation and IRS-1 levels decrease over this period, siRNA suggests that S6K1 is not mediating the decrease in IRS-1."
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"Under these conditions, the loss of S6K1 activation restores IRS-1/PI3K signaling potentiating insulin sensitivity."
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"Early work indicated that the rapamycin-sensitive mTOR pathway represses insulin/PI3K/Akt signaling [ 71–73 ] and it is now known that S6K1 inhibits IRS1 by directly phosphorylating it [ 74,75 ]."
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"Alternatively, increasing mTORC1 activates a negative feedback loop from p70S6K inhibiting IRS-1 by inhibiting the PI3-kinase-dependent activation of mTORC2."
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"It has been shown that p70S6K downstream of TORC1 can phosphorylate and inhibit the insulin receptor substrate IRS1 (Harrington et al. xref ) and that sustained activation of TORC1 leads to depletion of IRS1 and IRS2 and insulin resistance (Shah et al. xref )."
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"Normally, IGF stimulation results in activation of S6K1, which negatively regulates adaptor protein insulin receptor substrate-1 (IRS1) function by phosphorylation."
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"The PI3K/AKT/mTOR signalling pathway is under the control of PTEN, but it may also be inactivated by a feedback loop in which S6K1 directly inhibits IRS1."
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"Activation of S6K1 in Tsc2 −/− cells suppresses insulin receptor substrate 1 (IRS-1), both at the level of gene transcription and by coupling activated receptors to PI3K."
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"The persistent activity of S6K1 (mTORC1_S6K1 in the model) is known to negatively regulate the upstream insulin receptor substrate 1 (noted IRS1_PIK3CA in the model; Laplante & Sabatini, 2012)."
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"Since growth factor mediated differentiation is thought to involve IGF-II signaling through IRS-1 to PI3K and PKB, we further hypothesized that decreasing S6K1 would increase IRS-1 protein and result in greater IGF-II signaling and myoblast differentiation."
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"Lastly, S6K1 inhibits IRS-1 activity by phosphorylation at Ser318 XREF_BIBR."
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"Meanwhile, the inhibition of p70S6K also activates Akt by relieving the negative feedback produced by p70S6K which has been shown to inhibit the PI3K/Akt pathway by phosphorylation and inactivating in[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"For instance, p70S6K can inhibit IRS-1 as a negative feedback loop against overactivation [78, 79]."
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"Under overnutrient conditions, p70 inhibits insulin receptor substrate-1 (IRS-1) by phosphorylation at multiple sites, negatively regulating insulin signaling [44, 45]."
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"To be precise , S6K1 stimulates the degradation of insulin receptor substrate-1 ( IRS-1 ) , which results in the inhibition of mTORC2 and PI3K / Akt signaling ."
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"In particular, feedback inhibition of insulin receptor substrate 1 (IRS1) by the kinase p70S6K was predicted to confer resistance to EGFR inhibition, suggesting that disrupting this feedback may restore sensitivity to EGFR inhibitors in colorectal cancer cells."
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"It has been reported that in solid tumor models, activation of mTORC1 drives p70S6K mediated degradation of the IR/IGF-1R adaptor protein IRS-1, and is therefore a negative regulator of PI3K [XREF_BIBR]."
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"S6K1 can phosphorylate and inactivate IRS1, thereby allowing a feedback regulation of the IRS1/PI3K/AKT pathway [ xref , xref , xref ]."
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"Inactivation of S6K1 relieves the negative feedback on IRS-1, its stabilization, and upregulation of IGF-1R mediated signaling that activates AKT [154] ."
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"One of the best characterized is the S6K1-mediated negative feedback on pI3K. S6K1 inhibits IRS-1 by phosphorylating it at multiple sites, by inducing its degradation and by altering its localization,[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"The mTORC1 substrate p70S6 kinase 1 (S6K1) is involved in the regulation of protein synthesis and the growth of cell size, and active S6K1 inhibits IRS1 in a negative feedback loop [ xref ]."
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"mTORC1-activated S6K1 inactivates IRS-1 by phosphorylation on S422 [ xref ], leading to its proteasomal degradation [ xref ]."
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"Dong et al showed that eIF3a positively regulates RRM2 expression in HeLa and NIH3T3 cells. xref He et al also found that depletion of S6K1, another target of mTORC1, leads to up-regulation of RRM2. xref Raptor binds to the tor signaling motif within S6K1 for promoting interaction with mTOR and mediating phosphorylation. xref S6K1 has two downstream effectors, mTORC2 and insulin receptor substrate 1 (IRS1). xref , xref S6K1 is implicated in the phosphorylation and negative regulation of Rictor (sirolimus-insensitive companion of mTOR) within mTORC2, which phosphorylates and activates Akt. xref In addition to its role in the inhibition of mTORC2, S6K1 inhibits IRS1 through phosphorylation of serine of IRS1 xref , xref ; while the activated IRS1 with tyrosine phosphorylation activates PI3K/Akt/mTOR pathway. xref Forkhead box protein 3 (FoxP3), first found in regulatory T (Treg) cells, is a transcription factor involved in the development and function of Treg cells, xref and serves vital roles in cancers including breast cancer. xref The mTOR has the ability to block Foxp3 induction. xref Zhang et al also showed that FoxP3 positively regulates miR-150-5p/3p by binding to the mir-150 promoter, and miR-150-5p/3p directly targets IRS1 and IGF1R. xref This forms a feedback loop of FoxP3/miR-150/IGF1R-IRS1/PI3K/AKT/mTOR, like Akt/mTOC1/S6K1/mTOC2 and PI3K/Akt/mTOC1/S6K1/IRS1."
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"The ribosomal protein S6 kinase 1 (S6K1), a component of insulin signaling transduction, negatively regulates insulin receptor substrate 1 (IRS1)."
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"Growth factor activation of this pathway promotes VSMC de-differentiation and proliferation, while mTORC1 inhibition promotes differentiation, by relieving the classical S6K1 mediated negative feedback regulation of insulin receptor substrate-1 (IRS-1) signaling to PI3K and AKT XREF_BIBR."
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"In addition, BNIP3L can inhibit insulin signaling through activation of MTOR-RPS6KB/p70S6 kinase inhibition of IRS1, which is contingent on phosphatidic acids and RHEB."
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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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"Multiple mechanisms might contribute to such an augmented effect : (i) S6K1 has been shown to phosphorylate and negatively regulate IRS-1 signaling."
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