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RPS6KB1 phosphorylates IRS1. 207 / 240
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"It has been described that S6K1 phosphorylates insulin receptor substrate-1 (IRS-1) to avoid hyperactivation of mTORC1 [31]."
34258253
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"When mTORC1 is active, p70S6K phosphorylates the IRS-1 and -2 proteins on Ser residues, targeting them for proteasomal degradation [XREF_BIBR, XREF_BIBR]."
22564882
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"Wang C, Mao X, Wang L, et al. Adiponectin sensitizes insulin signaling by reducing p70 S6 kinase-mediated serine phosphorylation of IRS-1."
31359797
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"Rapamycin treatment also resulted in an increased mobility of IRS1, indicating that S6K1 contributes to the basal phosphorylation of IRS1."
23304509
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"An experiment using dominant negative S6K1 supports the essential role of S6K1 in the hyperosmolarity stimulated phosphorylation of IRS1."
18252807
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"The activated S6K1 phosphorylates IRS1 and Rictor in negative feedback loops [ xref ]."
27149630
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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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"In addition, S6K1 can directly phosphorylate insulin receptor substrate 1 (IRS-1) as part of the negative feedback loop, thereby reducing insulin-based PI3K activation xref ."
37489050
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"Activated S6K1 can phosphorylate and inhibit insulin-receptor substrate IRS1 and IRS2 [14] ."
16996801
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"Both mTORC1 and S6K1 could phosphorylate IRS-1 ()."
30240640
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"mTORC1 activation is postulated to cause a negative feedback loop through S6K1, which directly phosphorylates IRS-1 and finally induces its degradation XREF_BIBR."
22059905
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"It has been reported that ribosomal p70 S6 kinase (p70S6K) enhances IRS-1 serine phosphorylation, which lead to decreased Akt phosphorylation and causes insulin resistance."
18022395
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"Activation of mTORC1 can inhibit the PI3K/AKT pathway through a negative feedback loop mediated by p70S6K phosphorylation of insulin receptor substrate 1 ( xref ; xref )."
26233890
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"S6K1 and mTORC1 phosphorylate IRS-1 directly to induce its degradation, thus uncoupling the insulin receptor from PI3K."
25242279
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"In addition, when mTORC1 is activated, S6K1 could directly phosphorylate Insulin receptor substrate 1 (IRS1; S307 and S636/S639) and promote its degradation, which subsequently blunts phosphoinositide 3-kinase (PI3K)-AKT activation and its downstream effects such as glucose uptake and glycogen accumulation ( xref ; xref )."
33574765
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"S6K1 and mTORC1 phosphorylate IRS-1 directly to induce its degradation, thus uncoupling the insulin receptor from PI3K."
25242279
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"Furthermore, S6K1 can phosphorylate insulin receptor substrate 1 (IRS-1), which is part of the negative feedback loop xref ."
37489050
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"We observed that Ang II induced a transitory increase in IRS-1 Ser 636 /Ser 639 and S6K-1 Thr 421 /Ser 424 phosphorylation."
19879250
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"Importantly, greater mTORC1 activity can impede AKT activation through p70 S6K1 -mediated phosphorylation of Insulin receptor substrate 1 (IRS-1) [ xref ], thereby inhibiting downstream AKT activation."
36672183
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"Attenuation of insulin signaling is achieved through a negative feedback loop involving Akt-dependent stimulation of mTOR complex with Raptor mTORC1 and its effector kinase S6K1 which phosphorylates I[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
24815187
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"The observation of increased AKT phosphorylation upon dexamethasone treatment may indicate there is activation of the known negative feedback loop consisting of S6K1 phosphorylation and downregulation of IRS1 ( xref )."
26080839
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"Upon activation by growth factors, mTORC1 limits the extent of upstream growth factor signaling by a negative feedback loop through IRS-1 phosphorylation by S6K1[ xref , xref ]."
27033070
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"For example, the negative feedback loop in which S6K1 promotes the phosphorylation of IRS1 and this way reduces its stability [ xref ]."
25152703
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"For example, S6K1 can phosphorylate IRS-1 to inhibit insulin receptor signaling [XREF_BIBR]."
21805467
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"Adiponectin enhances insulin signaling by reducing p70 S6 kinase-mediated serine phosphorylation of IRS-1 [ xref ] but systemic adiponectin levels are not influenced by carbohydrate uptake."
17311679
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"S6K1 phosphorylates IRS-1 causing disruption in IR signal transduction."
31363792
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"Rapamycin inhibits S6K1-dependent IRS-1 serine phosphorylation, increases IRS-1 protein levels, and promotes association of tyrosine-phosphorylated IRS-1 with PI3K. A rapamycin-resistant S6K1 mutant prevents rapamycin-induced Akt activation and VSMC differentiation."
17908691
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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."
21962509
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"It is possible that PF-4708671-induced phosphorylation is a result of inhibiting the negative-feedback loop in which S6K1 phosphorylates IRS-1 (insulin receptor substrate-1)."
39408794
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"Negative regulation of mTORC1 by AMPK can increase insulin sensitivity by repressing p70S6K1 phosphorylation and inactivation of IRS1."
21723507
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"Numerous studies have demonstrated that activated p70S6K promotes insulin receptor substrate-1 ( IRS-1 ) phosphorylation at inhibitory serine sites (S636/639 and/or S312), leading to IRS-1 degradation[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
37394161
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"S6K1 also phosphorylates and inactivates IRS1, thereby providing a negative feedback loop [XREF_BIBR]."
24352740
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"On the other hand, the mTORC1 substrate RPS6KB1 phosphorylates and inhibits IRS1 [XREF_BIBR, XREF_BIBR]."
33544134
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"Notably, activated p70S6K can phosphorylate insulin receptor substrate IRS-1, an activator of PI3K, and induce IRS-1 degradation, followed by the suppression of PI3K activity."
26314828
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"The best-described negative feedback mechanism occurs through S6K1, which directly phosphorylates insulin receptor substrate 1 causing its mislocalization and degradation ( xref )."
20418915
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"Insulin activates mTORC1 and its substrate S6K1, which phosphorylates and inhibits the insulin receptor substrate 1 (IRS-1)."
25161886
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"Hence, identifying the regulatory mechanisms of insulin signaling and the pathogenesis of T2D had been focused on protein phosphorylation, especially a feedback phosphorylation of IRS1 by p70 ribosomal protein S6 kinase (S6K) ."
38212312
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"Akt mediated activation of mTOR results in activation of p70S6K, which phosphorylates IRS-1 resulting in inhibition of IRS1."
19690459
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"As shown in xref , p-S6K1 (T389) was increased in LKB1-deficient WAT whereas the levels of p-IRS1 (Ser636/639) in WAT from LKB1 −/− were reduced when compared with WT, suggesting that increased Akt inhibition in LKB1-deficient WAT was not due to increased phosphorylation of IRS1 by S6K1."
23396401
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"49 Active mTORC1 and S6K1 phosphorylate insulin receptor substrate 1 (IRS1), which is an adaptor protein that recruits key downstream effectors to the insulin receptor."
27534530
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"Irrespective of DNA damage, IRS1 can also be phosphorylated by p70S6K, leading to inhibition of IRS1, which provides a feedback response from an mTOR substrate to the upstream IGF1R signaling [254,255[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
21570395
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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."
16753575
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"Adiponectin sensitizes insulin signaling by reducing p70 S6 kinase-mediated serine phosphorylation of IRS-1."
19085255
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"Here we show that S6K1 directly phosphorylates IRS-1 Ser-1101 in vitro in the C-terminal domain of the protein and that mutation of this site largely blocks the ability of amino acids to suppress IRS-1 tyrosine and Akt phosphorylation."
17709744
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"Thus, phosphorylation of IRS1(Ser307, 1101) by hyperactive S6K1, and phosphorylation of IRS1(Ser636/639, 422) by hyperactive mTORC1, result in suppressing IRS tyrosines phosphorylation by the IR tyrosine kinase, followed by IRS ubiquitination and degradation [ xref – xref ]."
32128655
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"The best described negative feedback mechanism occurs through S6K1, which directly phosphorylates insulin receptor substrate 1 causing its mislocalization and degradation (XREF_FIG)."
20418915
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"Here, we show that MASTL/Greatwall, a cell cycle kinase that supports mitosis by phosphorylating the PP2A/B55 inhibitors ENSA/ARPP19, inhibits PI3K-AKT activity by sustaining mTORC1- and S6K1-dependent phosphorylation of IRS1 and GRB10."
36354735
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"S6K1-dependent serine phosphorylation of IRS-1."
29738527
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"As a negative-feedback loop exists in which S6K1 directly phosphorylates IRS1 (insulin receptor substrate protein 1) and blocks IGF-1 (insulin like growth factor 1) signaling to PI3K 107, a major drawback of selectively inhibiting mTOR is the consequent activation of PI3K, which can ultimately enhance tumor growth 108."
21110697
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"We show that in skeletal muscle, adiponectin promotes tyrosine phosphorylation of IRS1 and AKT phosphorylation via inhibiting p70 S6K phosphorylation and serine phosphorylation of IRS1, thereby increasing insulin sensitivity ( xref )."
26993044
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"P7170 induced upregulation of IRS-1 levels, which occurs as a result of inhibition of p70S6K-induced phosphorylation of IRS-1 that, in turn, slows IRS-1 degradation (reviewed in ref. [ xref ])."
25491778
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"Hyperglycemia upregulates the activity of mTOR/p70 ribosomal S6 protein kinase (p70S6K) (14), which stimulates IRS-1 Ser636/639 phosphorylation and suppresses IRS-1-associated PI3K/Akt signaling, and GSK-3 is activated (14)."
31702811
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"S6K1 phosphorylates inhibitory serine sites of IRS-1 leading to its degradation ( xref – xref ), whereas rapamycin prevents inhibitory IRS-1 phosphorylation, stabilizing IRS-1 and induces Akt activity by augmenting IGF-IR signaling to PI3K/Akt."
21294052
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"It is possible that PF-4708671-induced phosphorylation is a result of inhibiting the negative feedback loop in which p70S6K phosphorylates IRS-1 [15,16]."
22564017
sparser
"It is possible that PF-4708671-induced phosphorylation is a result of inhibiting the negative-feedback loop in which S6K1 phosphorylates IRS-1 (insulin receptor substrate-1)."
39408794
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"In addition, S6K1 can directly phosphorylate insulin receptor substrate 1 (IRS-1) as part of the negative feedback loop, thereby reducing insulin-based PI3K activation177."
37489050
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"Furthermore, S6K1 can phosphorylate insulin receptor substrate 1 (IRS-1), which is part of the negative feedback loop179."
37489050
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"Activated mTORC1 phosphorylates and activates its substrate S6K1, which directly phosphorylates IRS-1 to prevent activation of the PI3K/Akt pathway [33,34]."
36499271
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"Following activation, mTORC1 phosphorylates and activates its downstream target p70S6K, which then phosphorylates and inhibits IRS1, the upstream of PI 3-K [XREF_BIBR]."
21307646
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"S6K1 phosphorylates IRS1 in vitro on multiple residues showing strong preference for RXRXXS/T over S/T,P sites."
16914728
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"Increased activation of mTOR results in activation of p70S6K, which phosphorylates IRS1 resulting in inhibition of IRS1."
19435890
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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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"As plasma concentrations of amino acids are increased in obesity ( Felig et al., 1969, 1970, 1974 ) and amino acids drive S6K1 activation ( Hara et al., 1998; Iiboshi et al., 1999; Nobukuni et al., 20[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
16753575
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"Elevated mTORC1 activity upon insulin/ IGF-1signaling increases the activity of one of its direct effectors, S6K1 (see below), which in turn will phosphorylate insulin receptor substrate 1 (IRS1) on various negative regulatory sites, thereby inhibiting PI3K signaling and dampening mTORC2 [67]."
38862983
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"Akt indirectly activates p70S6K, which then phosphorylates IRS1, thereby suppressing PI3K activation."
27390173
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"This distinctive profile reflects the relief of a feedback loop where active S6K1 directly phosphorylates IRS1, resulting in the degradation of IRS1 and subsequent reduction of growth factor signaling from RTKs to downstream effectors such as AKT 1."
29416044
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"Moreover, genetic deletion of S6K1 in mice fed with a high fat diet prevented both insulin resistance and serine 1101 phosphorylation of IRS1 10."
33303821
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"Importantly, IRS1 phosphorylation by S6K1 targets it for proteasomal degradation and thereby hampers the ability of growth factors (insulin, insulin-like growth factor-1) to signal downstream of recep[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
25497227
sparser
"Wang C, Mao X, Wang L, Liu M, Wetzel MD, Guan KL et al. Adiponectin sensitizes insulin signaling by reducing p70 S6 kinase-mediated serine phosphorylation of IRS-1."
23043361
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"The results show that only in IRS-1 108–516 in which serines 302, 307, and 310 are mutated ( xref A, site 2) is IRS-1 not phosphorylated in vitro by S6K1 ( xref C, left panels)."
15249583
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"The anecdotal finding that inhibition of mTOR increased phosphorylation and activation of Akt in many cell lines thus raised the possibility that this feedback loop in which S6K1 phosphorylated and do[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
16530700
sparser
"This impairment correlated with increased phosphorylation of mTOR, p70S6K and serine phosphorylation of IRS-1 [ xref ]."
32230718
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"In a complementary pathway, S6K1 phosphorylates IRS-1 on serine residues leading to its degradation ( xref ) and also phosphorylates rictor, a protein unique to mTORC2 ( xref )."
24018049
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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 )."
33454277
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"Given that p70S6K phosphorylates IRS-1 and induces its degradation, we postulate that the inactivation of p70S6K by miR-200 in lung cancer cells may feedback activate AKT by increasing IRS-1 (XREF_FIG)."
26314828
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"A recent report showed that amino acids affect insulin signaling through mTOR/S6K1 phosphorylation of IRS1 ."
37696922
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"mTORC1’s downstream target p70S6K phosphorylates IRS-1 at multiple inhibitory sites, promoting degradation of this signaling adaptor, thereby contributing to insulin resistance, especially with increasing activation of mTORC1 ( xref )."
37457922
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"mTORC1 and S6K1 phosphorylate insulin receptor substrate 1 (IRS1), leading to the inactivation or degradation of IRS1."
40142329
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"Both leucine and insulin stimulate mTORC1, resulting in downstream activation of the p70S6K that is thought to phosphorylate insulin receptor substrate 1 (IRS-1) and reduce insulin sensitivity."
25926513
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"In turn, the activation of p70S6K by mTORC1 promotes the phosphorylation of IRS1 and reduces its stability, an auto-regulatory pathway or negative feedback loop that has been shown to have profound implications for both metabolic diseases and tumorigenesis [XREF_BIBR, XREF_BIBR]."
26536660
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"Moreover, impaired glucose uptake appears to be mediated through phosphorylation of IRS1 by S6K1 ( Tremblay et al., 2005 ), a system that may have evolved to suppress insulin signaling under condition[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
16753575
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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."
23607966
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"Specifically, mTORC1 activation negatively feeds back to PI3K by S6K1 phosphorylation of IRS1 and by regulating Grb10 stability via direct phosphorylation [XREF_BIBR - XREF_BIBR]."
25646773
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"These findings highlight the critical function of ribosomal protein S6 kinase beta 1 (S6K1), which is triggered by foods such as amino acids, in increasing IR via insulin receptor substrate-1 (IRS-1) phosphorylation."
38983814
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"The results show that only in IRS-1 108-516 in which serines 302, 307, and 310 are mutated (XREF_FIG A, site 2) is IRS-1 not phosphorylated in vitro by S6K1 (XREF_FIG C, left panels)."
15249583
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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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"Akt mediated activation of mTOR results in activation of p70S6K, which phosphorylates IRS-1 resulting in inhibition of IRS1."
19690459
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"It is important to underline here that p70S6K 1/2, when activated by mTORC1, directly phosphorylates the insulin receptor substrate-1 and -2 (IRS1 and IRS2), which promotes their degradation and reduces the ability of growth factors to signal downstream of receptor tyrosine kinases, such as insulin receptor (IR) or insulin like growthfactor-1 receptor (IGF-1R) [44,45]."
22686561
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"Whereas mTORC2 directly phosphorylates AKT, activated p70S6K phosphorylates and negatively regulates insulin receptor substrate 1. xref As insulin receptor substrate 1 is an important upstream activator of PI3K–AKT, phosphorylation of p70S6K, thus, evokes a physiological negative feedback loop toward AKT. xref Phosphorylation of AKT at Ser 473 was slightly attenuated in 3T3 cells expressing active mTOR mutants compared with that in those expressing the wild‐type protein (Fig. xref a), consistent with a previous observation. xref "
26432419
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"However, S6K1 has multiple substrates. xref For example, S6K1 phosphorylates eEF2K to enhance protein synthesis, xref and the cell growth regulator SKAR (S6K1 Aly/REF-like target) has also been identified as a substrate for S6K1, but not for S6K2. xref S6K1 also phosphorylates insulin receptor substrate 1 (IRS1) xref and mTOR xref in response to nutrients and growth factors, albeit in a feedback fashion."
25229342
sparser
"Notably, activated p70S6K can phosphorylate insulin receptor substrate IRS-1, an activator of PI3K, and induce IRS-1 degradation, followed by the suppression of PI3K activity."
26314828
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"The use of specific inhibitors to block AT 1 R-induced EGFR transactivation confirmed that Ang II/AT 1 R-induced S6K-1 Thr 421 /Ser 424 and IRS-1 Ser 636 /Ser 639 phosphorylation are dependent on activation of PKC, MMPs and EGFR transactivation ( xref )."
19879250
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"S6k1 can phosphorylate IRS-1, which leads to proteasome-mediated degradation, and it can phosphorylate and inactivate the proapoptotic protein Bad."
16844299
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"Irrespective of DNA damage, IRS1 can also be phosphorylated by p70S6K, leading to inhibition of IRS1, which provides a feedback response from an mTOR substrate to the upstream IGF1R signaling [254,255[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
21570395
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"S6K1 phosphorylates IRS-1 causing disruption in IR signal transduction."
31363792
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"Upon activation, mTORC1 activates p70S6 kinase (S6K1), a key mTORC1 substrate, which in turn phosphorylates IRS1 at multiple serine residues that disrupt IRS1 activity XREF_BIBR - XREF_BIBR."
29330362
sparser
"On the other hand, the mTORC1 substrate RPS6KB1 phosphorylates and inhibits IRS1 [ xref , xref ]."
33544134
sparser
"In fact, S6K1 (activated by mTORC1) promotes also the phosphorylation and inactivation of IRS1, the insulin receptor substrate 1."
25685786
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"In vitro studies demonstrated that S6K1 phosphorylates mouse (m) S302 and mS522 (human (h) S307 and hS527) of IRS-1 [XREF_BIBR], and mTORC1 phosphorylates mS632 (hS636) of IRS-1 [XREF_BIBR]."
29077002
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"As metformin treatment is known to induce glucose uptake in skeletal muscle, it was hypothesized that, at least in part, these effects are mediated by metformin induced activation of the AMPK-TSC1/2 axis and inhibition of mTORC1 and S6K1 phosphorylation of IRS1."
20444419
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"In our study, we speculate that Art-M's inhibition of p70S6K activity may reduce IRS-1 phosphorylation and stabilize IRS-1 , leading to increased AKT and ERK activities."
37394161
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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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"The insulin receptor substrate 1 (IRS1) is directly phosphorylated by S6K1 at multiple sites which impairs its function and leads to inhibitory effects on the insulin-PI3K-AKT pathway."
25505994
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"mTOR inhibition prevents negative feedback mechanisms; in one of these S6K1 phosphorylates IRS-1 (insulin receptor substrate-1) causing it to dissociate from tyrosine kinase receptors; in another mTORC1 phosphorylates GRB10 which suppresses insulin and IGF receptor kinase activity and facilitates their degradation; and in a third mTORC2 assembly is prevented by phosphorylation of Sin1, mediated by S6K or Akt depending on the cell type."
26793165
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"But beside its phosphorylation at this site, IRS-1 can be down-regulated through transcriptional repression 42 and phosphorylated at different residues by S6K1 as well as by other members of the pathway XREF_BIBR - XREF_BIBR."
19098454
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"Specifically, the mTORC1 substrate, S6K1, phosphorylates IRS-1 at S636/639 to promote its degradation, which in turn, reduces PI3K and Akt signaling."
31710966
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"It has been described that S6K1 phosphorylates insulin receptor substrate 1 (IRS-1), promoting its degradation."
20628002
sparser
"We report here that Ang II-induced IRS-1 Ser 636 /Ser 639 phosphorylation by S6K-1 is involved in the inhibition of Akt."
19879250
sparser
"Furthermore, S6K1 serine phosphorylates IRS1 and IRS2 thereby decreasing insulin signaling ( xref )."
19797661
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"Inhibition of S6K1 activity prevents phosphorylation of IRS-1 (S636/639), resulting in accumulation of IRS-1 and activation of its downstream kinases, such as PI3K and Akt, by a feedback regulating mechanism."
20628002
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"Activated S6K1 can phosphorylate and inhibit insulin-receptor substrate IRS1 and IRS2 [14] ."
16996801
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"However, we also need to consider that this would generate sustained p70S6K activation, which should phosphorylate IRS1, causing insulin desensitization and interrupted Akt activation, an apparent contradiction to what was reported in post-mortem AD brain."
28626421
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"However an alternate event, p70 S6 kinase phosphorylation of IRS-1 on S636/639, could also occur resulting in decreased IGF-1R signaling."
21980324
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"Adiponectin enhances insulin signaling by reducing p70 S6 kinase mediated serine phosphorylation of IRS-1 [XREF_BIBR] but systemic adiponectin levels are not influenced by carbohydrate uptake."
17311679
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"Activation of mTORC1 can inhibit the PI3K and AKT pathway through a negative feedback loop mediated by p70S6K phosphorylation of insulin receptor substrate 1."
26233890
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"mTORC1 and S6K1 phosphorylate insulin receptor substrate 1 (IRS1), leading to the inactivation or degradation of IRS1."
40142329
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"It is well known that chronic treatment with growth factors induces a negative feedback regulation on IRS1 via the mTOR/S6K1 pathway, leading to S6K1-dependent phosphorylation of IRS1."
23304509
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"XREF_BIBR - XREF_BIBR In addition, adiponectin has been shown to increase muscle insulin signaling by reducing p70 S6 kinase mediated serine phosphorylation of insulin receptor substrate 1."
23459195
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"However, suppression of S6K1 activity by mTOR inhibitors can prevent the phosphorylation of insulin receptor substrate 1 (IRS-1), thereby stabilizing IRS-1 and increasing IGF-IR and PI3K signaling to Akt [XREF_BIBR]."
25026290
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"Nonetheless, upon growth factor stimulation, mTORC1 activates S6K1, which in turn phosphorylates IRS-1 at the plasma membrane, and ultimately suppresses PI3K-mediated activation of AKT ( xref ; xref )."
21179025
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"Dyslipidemia and nutrient overload lead to overexpression of mTOR and S6K1, which phosphorylate IRS1; subsequently, the PI3K pathway is inhibited, leading to insulin resistance [41] ."
27295130
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"Importantly, greater mTORC1 activity can impede AKT activation through p70 -mediated phosphorylation of Insulin receptor substrate 1 (IRS-1) [165], thereby inhibiting downstream AKT activation."
36672183
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"S6K1 can phosphorylate and inactivate IRS1, thereby allowing a feedback regulation of the IRS1/PI3K/AKT pathway [XREF_BIBR, XREF_BIBR, XREF_BIBR]."
26999118
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"First, mTORC1 and its direct effector S6K1 phosphorylate insulin receptor substrate 1 (IRS1) to inhibit insulin signalling [51] ."
37217140
sparser
"S6K1, a major target of mTOR, is required for IRS1 phosphorylation in cells and can also directly phosphorylate IRS1 ( xref ; xref )."
18755774
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"For example, the negative feedback loop in which S6K1 promotes the phosphorylation of IRS1 and this way reduces its stability [XREF_BIBR]."
25152703
reach
"This distinctive profile reflects the S6K1-mediated feedback loop, where active mTORC1 substrate, S6K1, directly phosphorylates IRS1, resulting in its degradation and the subsequent reduction of growt[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
31231029
sparser
"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."
23607966
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"The observation of increased AKT phosphorylation upon dexamethasone treatment may indicate there is activation of the known negative feedback loop consisting of S6K1 phosphorylation and downregulation of IRS1."
26080839
sparser
"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
sparser
"When activated by mTORC1, S6K1 directly phosphorylates the insulin receptor substrate-1 (IRS1), which promotes IRS1 degradation and reduces the ability of growth factors to signal downstream of receptor tyrosine kinase (RTK) ( xref ; xref ) ( xref )."
22500797
sparser
"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] ."
16002336
sparser
"S6K1 promotes the inhibitory serine phosphorylation of insulin receptor substrate 1 (IRS1) [ xref , xref ]."
37242206
sparser
"As a negative-feedback loop exists in which S6K1 directly phosphorylates IRS1 (insulin receptor substrate protein 1) and blocks IGF-1 (insulin-like growth factor 1) signaling to PI3K xref , a major drawback of selectively inhibiting mTOR is the consequent activation of PI3K, which can ultimately enhance tumor growth xref ."
21110697
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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
reach
"Increased activation of mTOR results in activation of p70S6K, which phosphorylates IRS1 resulting in inhibition of IRS1."
19435890
sparser
"Phosphorylation of IRS-1 by S6K1 inhibits its interaction with insulin and IGF receptors and also promotes proteasomal degredation of IRS-1 ( xref ), thereby dampening PI3K signalling and reducing AKT activity."
27919797
sparser
"Insulin- and amino acid-mediated activation of mTOR/S6K via the PI3K pathway leads to a negative feedback loop resulting in the phosphorylation and downregulation of IRS1 by S6K1 and eventually insulin resistance and type 2 diabetes."
32054043
reach
"The inhibition of S6K1 activity may, therefore, prevent IRS-1 phosphorylation, resulting in accumulation of IRS-1 and activation of its downstream kinases by a feedback regulation mechanism."
34258253
trips
"S6K1 phosphorylates IRS1 in vitro on multiple residues showing strong preference for RXRXXS/T over S/T,P sites."
16914728
sparser
"Given that p70S6K phosphorylates IRS-1 and induces its degradation ( xref , xref ), we postulate that the inactivation of p70S6K by miR-200 in lung cancer cells may feedback activate AKT by increasing IRS-1 ( xref )."
26314828
sparser
"S6K1, which is activated by mTORC1, causes inhibitory phosphorylation of IRS1 and reduces the amount of IRS1 protein."
37513916
sparser
"Lastly, IR in AD brain is linked to inhibitory feedback phosphorylations of IRS-1 (S616 and S636) by pS6K [ xref , xref ]."
35061720
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"Insulin- and amino acid-mediated activation of mTOR/S6K via the PI3K pathway leads to a negative feedback loop resulting in the phosphorylation and downregulation of IRS1 by S6K1 and eventually insulin resistance and type 2 diabetes."
32054043
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"First, mTORC1 and its direct effector S6K1 phosphorylate insulin receptor substrate 1 (IRS1) to inhibit insulin signalling [51] ."
37217140
sparser
"In cell lines, it has been shown that IRS1 stability can be regulated by a negative feedback loop wherein S6K1 phosphorylates IRS1, targeting it for degradation by the proteasome ( xref )."
18755774
reach
"On the basis of current evidence, the most likely possibility is that S6K1 mediates a negative feedback via phosphorylation of IRS1 at Ser636/639, although the phosphorylation of tyrosine in IRS1 is n[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
24650522
sparser
"In our study, we found that mTORC2 deficiency could lead to increased mTORC1 activity under certain conditions [ xref , xref ] (data not shown), while over-activation of mTORC1 also restricts mTORC2 activity, either through the mTORC1-mediated phosphorylation and activation of Grb10, a negative regulator of insulin/IGF-1 receptor [ xref , xref ], or by S6K1 phosphorylation and degradation of insulin receptor substrate 1 (IRS1) to suppress mTORC2 activity [ xref ]."
34691993
reach
"21 S6K1 also phosphorylates insulin receptor substrate 1 (IRS1) 22 and mTOR 23 in response to nutrients and growth factors, albeit in a feedback fashion."
25229342
sparser
"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 )."
29728917
reach
"These apparent paradoxical events are linked to a negative feedback loop in which hyperactive S6K1 phosphorylates the insulin receptor substrate-1 (IRS-1), thereby leading to the internalization of th[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
29729422
reach
"It has been shown that p70S6K downstream of TORC1 can phosphorylate and inhibit the insulin receptor substrate IRS1 and that sustained activation of TORC1 leads to depletion of IRS1 and IRS2 and insulin resistance."
28643116
reach
"mTOR phosphorylates and activates S6K1, which in turn phosphorylates IRS-1 causing its internalization (Um et al., 2004)."
29729422
sparser
"Activated mTORC1 phosphorylates and activates its substrate S6K1, which directly phosphorylates IRS-1 to prevent activation of the PI3K/Akt pathway [ xref , xref ]."
36499271
reach
"Notably, rictor and IRS-1 phosphorylation by p70S6K1 attenuate insulin action through a negative feedback pathway."
27965359
reach
"This infection also down-regulates the TSC1/TSC2 complex and causes subsequent upregulation of mTOR/S6K1, which leads to Ser1101 phosphorylation of IRS-1 and its subsequent degradation."
39472817
reach
"Imidazole propionate is produced in the colon and causes decreased hepatic insulin signaling by activating mechanistic target of rapamycin complex 1 (mTORC1) and S6K1 phosphorylation which is leading to phosphorylation of insulin receptor substrate 1 (IRS1) and insulin receptor substrate 2 (IRS2) targeting them for degradation [8]."
36456963
reach
"In turn, S6K1 activation suppresses PI3K signaling through an intracellular negative feedback loop in which pS6K1 phosphorylates insulin receptor substrate 1 (IRS1) and targets it for degradation through ubiquitin mediated mechanisms, extinguishing its PI3K activating actions."
28099079
sparser
"Persistent inhibition of S6K1 has been shown to activate Akt via feedback inhibition of the PI3K pathway where S6K1 phosphorylates several sites on insulin receptor substrate-1 (IRS-1) and inhibits it ( xref – xref )."
21427355
sparser
"S6K1 also phosphorylates and inactivates IRS1, thereby providing a negative feedback loop [ xref ]."
24352740
reach
"It is now a well-supported conclusion that IRS1 phosphorylation by S6K1 (Figure 2), decreases insulin signaling through the insulin receptor substrate[61,100,103,110,111]."
34630911
sparser
"This distinctive profile reflects the relief of a feedback loop where active S6K1 directly phosphorylates IRS1, resulting in the degradation of IRS1 and subsequent reduction of growth factor signaling from RTKs to downstream effectors such as AKT xref ."
29416044
reach
"Accordingly, suppression of S6K1 activity by rapamycin and its analogs prevents IRS-1 phosphorylation, thus stabilizing IRS-1—the principal insulin-like growth factor-1 receptor (IGF-1R)-docking molec[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
25816698
reach
"mTOR can increase p70S6K, which in turn phosphorylates and inhibits insulin receptor substrate 1, a protein upstream of PI3K and AKT."
25933683
reach
"The insulin receptor substrate 1 (IRS1) is directly phosphorylated by S6K1 at multiple sites which impairs its function and leads to inhibitory effects on the insulin-PI3K-AKT pathway."
25505994
sparser
"S6k1 can phosphorylate IRS-1, which leads to proteasome-mediated degradation, and it can phosphorylate and inactivate the proapoptotic protein Bad."
16844299
sparser
"It has been described that S6K1 phosphorylates insulin receptor substrate 1 (IRS-1), promoting its degradation ( xref )."
20628002
sparser
"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 )."
28643116
reach
"S6K1, a major target of mTOR, is required for IRS1 phosphorylation in cells and can also directly phosphorylate IRS1."
18755774
reach
"Since both mTOR and S6K1 can phosphorylate IRS1 we wanted to determine the affects of Shh on the activation of S6K."
18755774
reach
"In cell lines, it has been shown that IRS1 stability can be regulated by a negative feedback loop wherein S6K1 phosphorylates IRS1, targeting it for degradation by the proteasome."
18755774
reach
"This effect was closely connected to the IGF-IR/IRS-1 system since S6K1, the down-stream intermediate of mTORC1, can prevent an inhibitory phosphorylation of IRS-1 [16,17] ."
20116405
sparser
"In humans, acute supplementation with protein has been shown to be insulinotropic. xref , xref , xref It has been suggested that the insulinotropic effect of leucine is mediated by stimulation of protein synthesis in pancreatic β cells by the mTOR signaling pathway. xref This pathway mediates insulin resistance by phosphorylation of IRS-1 by S6K1."
28969366
reach
"Consistent with previous studies [9] , knockdown of S6K1 increased the insulin-dependent Ser473 phosphorylation of Akt and significantly decreased IRS1 phosphorylation at S636/639 ( Fig. 4 B), reveali[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
22846606
reach
"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
reach
"In addition, it was reported that rapamycin inhibited mTORC1 and p70 S6 kinase induced serine phosphorylation of IRS-1 and promoted smooth muscle differentiation by potentiating IGF-1-induced Akt2 activation [XREF_BIBR]."
24694942
reach
"To control the extent of mTORC1 activation and restore TSC regulation after this stimulus, the mTORC1 substrate S6K1 then directly phosphorylates insulin receptor substrate 1 (IRS-1) as part of a negative feedback loop, blocking the further insulin mediated activation of the PI3K-AKT pathway [XREF_BIBR, XREF_BIBR]."
33572326
sparser
"P70S6K is activated in the insulin-signaling pathway via AKT phosphorylation of mTOR, which in turn phosphorylates and activates p70S6K. A well defined negative signaling pathway has been described involving negative phosphorylation of IRS-1 by p70S6K, leading to insulin induced degradation of IRS-1 ( xref ; xref )."
26868295
sparser
"S6K1 knockout mice are protected against obesity and insulin resistance due to elevated energy expenditure and the loss of IRS1 serine phosphorylation by S6K1[ xref , xref ]."
22391948
sparser
"Although it has been proposed that adiponectin may insulin sensitize through reduced serine phosphorylation of IRS1 by p70S6 kinase ( xref ), our in vivo data are not consistent with this model."
22989629
reach
"As shown in XREF_FIG, p-S6K1 (T389) was increased in LKB1 deficient WAT whereas the levels of p-IRS1 (Ser636/639) in WAT from LKB1 -/- were reduced when compared with WT, suggesting that increased Akt inhibition in LKB1 deficient WAT was not due to increased phosphorylation of IRS1 by S6K1."
23396401
sparser
"It is now a well-supported conclusion that IRS1 phosphorylation by S6K1 (Figure xref ), decreases insulin signaling through the insulin receptor substrate[ xref , xref , xref , xref , xref ]."
34630911
trips
"Notably, rictor and IRS-1 phosphorylation by p70S6K1 attenuate insulin action through a negative feedback pathway."
27965359
reach
"Nonetheless, upon growth factor stimulation, mTORC1 activates S6K1, which in turn phosphorylates IRS-1 at the plasma membrane, and ultimately suppresses PI3K mediated activation of AKT."
21179025
sparser
"However an alternate event, p70 S6 kinase phosphorylation of IRS-1 on S636/639, could also occur resulting in decreased IGF-1R signaling."
21980324
sparser
"Importantly, IRS1 phosphorylation by S6K1 targets it for proteasomal degradation and thereby hampers the ability of growth factors (insulin, insulin-like growth factor-1) to signal downstream of recep[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
25497227
reach
"This enhancement is associated with the activation of the mTOR/S6K1 kinase signaling pathway and subsequent phosphorylation of serine on IRS-1 residues, which further cause IR [ 36 ]."
37648074
reach
"In fact, S6K1 (activated by mTORC1) promotes also the phosphorylation and inactivation of IRS1, the insulin receptor substrate 1."
25685786
sparser
"S6K1 can phosphorylate and inactivate IRS1, thereby allowing a feedback regulation of the IRS1/PI3K/AKT pathway [ xref , xref , xref ]."
26999118
sparser
"It has been described that S6K1 phosphorylates insulin receptor substrate-1 (IRS-1) to avoid hyperactivation of mTORC1 [ xref ]."
34258253
sparser
"Upon activation, mTORC1 activates S6K1, which in turn phosphorylates inhibitory sites (i.e. Ser 636/639) on the insulin receptor substrate-1 (IRS-1), thereby suppressing IRS-1 mediated activation of t[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
20005306
reach
"There were also positive correlations between interventions in the insulin signalling pathway, particularly between Irs1 -/- and Rps6kb1 -/- mutants, which is interesting considering that Rps6kb1 directly phosphorylates and inhibits Irs1."
33454277
sparser
"The mTOR-activated kinase S6K1 phosphorylates and destabilizes the IRS1 and IRS2 proteins in insulin like growth factor (IGF) responsive cells."
21115426
reach
"XREF_BIBR - XREF_BIBR mTORC1 then activates S6 kinase 1 (S6K1) which phosphorylates IRS-1 on serines residues and inhibits insulin signaling."
23145367
reach
"When activated by mTORC1, S6K1 directly phosphorylates the insulin receptor substrate-1 (IRS1), which promotes IRS1 degradation and reduces the ability of growth factors to signal downstream of receptor tyrosine kinase (RTK) (XREF_FIG)."
22500797
reach
"Together, this may suggest that T-cad upregulation in SHR might be a characteristic feature of hypertensive and insulin resistant VSMC phenotype.Attenuation of insulin signaling is achieved through a [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
24815187
sparser
"When mTORC1 is activated, S6K1 could directly phosphorylate IRS1 (S307 and S636/S639) and promote its degradation, which subsequently blunts PI3K-AKT activation and its downstream effects such as glucose uptake, glycogen accumulation, etc. [ xref , xref ]."
30011848
sparser
"Here, we show that MASTL/Greatwall, a cell cycle kinase that supports mitosis by phosphorylating the PP2A/B55 inhibitors ENSA/ARPP19, inhibits PI3K-AKT activity by sustaining mTORC1- and S6K1-dependent phosphorylation of IRS1 and GRB10."
36354735
sparser
"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."
25999540
reach
"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] ."
16002336
reach
"IL-6 activates S6K1 in these cells, but unexpectedly, S6K1 is not involved in IL-6 inhibition of insulin signaling, since the effect of IL-6 persists in cells with drastically reduced S6K1 levels induced by RNA interference, suggesting that the function of mTOR signaling is through a mechanism different from the prevailing model of S6K1 phosphorylation of insulin receptor substrate-1."
17993646
sparser
"These apparent paradoxical events are linked to a negative feedback loop in which hyperactive S6K1 phosphorylates the insulin receptor substrate-1 (IRS-1), thereby leading to the internalization of the receptor and insulin resistance ( xref )."
29729422
reach
"It is well known that chronic treatment with growth factors induces a negative feedback regulation on IRS1 via the mTOR and S6K1 pathway, leading to S6K1 dependent phosphorylation of IRS1."
23304509
sparser
"The anecdotal finding that inhibition of mTOR increased phosphorylation and activation of Akt in many cell lines thus raised the possibility that this feedback loop in which S6K1 phosphorylated and do[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
16530700
reach
"S6K1 phosphorylates IRS1 in vitro on multiple residues showing strong preference for RXRXXS/T over S/T, P sites."
16914728
sparser
"Next, the resistance to insulin/IGF action that characterizes AD brain has been mechanistically linked to the inhibitory feedback phosphorylations of IRS-1 (S616 and S636) by pS6K [ xref , xref ]."
34215308
sparser
"Full-body S6K1 knockout mice are protected against obesity and insulin resistance owing to elevated energy expenditure and the loss of IRS1 serine phosphorylation by S6K1 [ 62,63 ]."
19683471