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RPS6KB1 phosphorylates IRS1 on serine. 62 / 69
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"It has been proposed that an S6K1 associated negative feedback loop results in the inhibitory serine phosphorylation of IRS1 in response to mTOR activation."
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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]"
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"Adiponectin sensitizes insulin signaling by reducing p70 S6 kinase mediated serine phosphorylation of IRS-1."
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"S6K1 phosphorylates inhibitory serine sites of IRS-1 leading to its degradation, whereas rapamycin prevents inhibitory IRS-1 phosphorylation, stabilizing IRS-1 and induces Akt activity by augmenting IGF-IR signaling to PI3K and Akt."
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"This was due to increased basal S6K1 activity which leads to IRS1 serine phosphorylation and disruption of PI 3-kinase activation, thereby limiting the effects of insulin on fatty acid uptake and lipolysis."
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"mTORC1 is able to impair insulin signaling via its substrates S6K1 which then phosphorylates serine residues of IRS1 causing downregulation of PI3K/Akt pathway (Harrington et al., xref ; Shah et al., xref )."
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"This is because activated mTORC1 and S6K1 phosphorylates serine residues of IRS-1 (S302, S307, S612, and S1101) (Gual et al., 2005)."
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"Recent studies demonstrate that the mTOR downstream target S6K1 directly phosphorylates IRS1 serine residues, including Ser-302/307 ( xref ), Ser-307/312 ( xref ), Ser-632/636 ( xref ), and Ser-1097/1101 ( xref )."
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"Additionally, it was demonstrated that p70S6K1 is able to directly phosphorylate IRS-1 on serine residues, reducing insulin-stimulated IRS-1 tyrosine phosphorylation [32] ."
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"In turn, p70S6K1 also phosphorylates the inhibiting serine residue of insulin receptor substrate (IRS1), blocking insulin signaling and thus providing a negative feedback loop on insulin action [34,35]."
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"In a complementary pathway, S6K1 phosphorylates IRS-1 on serine residues leading to its degradation and also phosphorylates rictor, a protein unique to mTORC2."
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"Adiponectin sensitizes insulin signaling by reducing p70 S6 kinase mediated serine phosphorylation of IRS-1."
23043361
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"Once activated by insulin, mTOR and p70S6K phosphorylates insulin receptor substrate-1 (IRS-1) on serine residues, resulting in its inhibition and reduction of insulin signaling."
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"A previous study demonstrated that increased activation of mTOR and S6 kinase beta-1 (S6K1) may promote serine phosphorylation of IRS-1, thus resulting in the pathogenesis of hepatic insulin resistance in obese rats."
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"In addition to stimulating muscle anabolism, activated mTORC1 and S6K1 can phosphorylate insulin receptor substrate 1 (IRS-1) on serine residues, which can lead to insulin resistance."
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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 – xref ."
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"This impairment correlated with increased phosphorylation of mTOR, p70S6K and serine phosphorylation of IRS-1 [XREF_BIBR]."
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"Activation of the cell nutrient sensor mTOR and S6K1 kinase causes serine phosphorylation of IRS-1, with a subsequent decline in the IRS1-associated PI3K activity."
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"The results show that targeted pharmacologic interventions with DPP-4 inhibitor could be useful in ameliorating pathophysiologic abnormalities in cardiac diastolic dysfunction and preventing the activation of insulin metabolic signaling molecules through enhanced mTOR/S6K1 activation and Ser phosphorylation of IRS-1 and IRS-2."
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"This led to phosphorylation of IRS-1 by S6K1 at multiple serine residues including Ser-270, Ser-307, Ser-636, and Ser-1101 in human IRS-1 (Ser-265, Ser-302, Ser-632, and Ser-1097, in rodent IRS-1)."
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"This is due to the fact that many inhibitors lead to irreversible degradation of a protein; An example would be the serine/threonine phosphorylation of the insulin receptor substrate-1 (IRS-1) by S6K1, among other serine kinases, which leads to ubiquitylation and degradation of IRS-1."
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"Others have looked at how S6K1 phosphorylates IRS-1 serine residues as reviewed (Nutrients."
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"S6K1 can further impair the phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) signaling pathway by phosphorylating insulin receptor substrate 1 (IRS1) serine residues, including Ser-302/307, Se[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Activated mTORC1/S6K1 phosphorylates serine residues of IRS-1 (Ser612) [60], leading to reduced glucose transport [11,12,14]."
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"Because S6Ks phosphorylate IRS-1 at several serine residues to promote inhibition of insulin signaling at the IRS-1 level ( xref )."
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"In addition, it has been shown that mTOR/S6K-1 negatively regulate IRS-1 by phosphorylating IRS-1 on serine residues."
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"This kind of feedback regulation is known to limit insulin signaling through the phosphorylation of IRS1 by p70 S6 kinase at Ser residues ( xref )."
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"XREF_BIBR In obese rodents, hyperactive mTORC1 and S6K1 induces IRS-1 phosphorylation at serine residues and consequent IRS-1 degradation, leading to the impairment of PI3K-Akt signaling."
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"In vitro studies with rapamycin suggest that mTOR and S6K1 overactivation contributes to elevated serine phosphorylation of IRS-1, leading to impaired insulin signaling to Akt in liver and muscle of this dietary model of obesity."
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"Under some conditions, p70S6K can also phosphorylate multiple serine residues of insulin receptor substrate-1 (IRS-1) as well as the serine phosphorylate rictor (a component of the mTORC2 complex that activates Akt)."
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"Indeed, mTOR and S6K1 are able to induce IRS-1 serine phosphorylation and affect IRS-1 protein turnover."
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"Ability of S6K1 to promote serine phosphorylation of IRS-1 has been suggested as a potential mechanism of insulin resistance [XREF_BIBR - XREF_BIBR, XREF_BIBR, XREF_BIBR]."
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"mTORC1 and its substrate S6K1 participate in a well-documented feedback loop xref in which growth factor and nutrient signaling limits the activity of the PI3K/Akt pathway: S6K1 phosphorylates IRS-1 on serine residues that promote its ubiquitination and degradation."
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"Adiponectin sensitizes insulin signaling by reducing p70 S6 kinase mediated serine phosphorylation of IRS-1."
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"Reduced mTOR and S6K1 signaling during chronic increases in physical activity may play an important regulatory role in the serine phosphorylation of IRS-1, which should be examined as a potential mechanism for attenuation of insulin resistance associated with increased IRS-1 serine phosphorylation."
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"For example, IL-6-dependent insulin resistance is mediated, at least in part, by induction of SOCS3 in insulin target cells, which inhibits tyrosine phosphorylation of IRS; TNFalpha is a potent activator of JNK, which in turn phosphorylates IRS-1 at Ser 307; adiponectin sensitizes insulin signaling by reducing p70 S6 kinase mediated serine phosphorylation of IRS-1."
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"The stability of IRS-1 was reduced by serine phosphorylation, and long-term insulin stimulation caused mTORC1 and S6K1 hyperactivation and markedly enhanced insulin induced IRS-1 serine phosphorylatio[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"However, the activation of mTOR leads to the activation of S6 protein kinase 1 (S6K1), which increases the phosphorylation of serine on IRS-1, creating a negative feedback loop by inhibiting IRS-1 and thus halting insulin 's signaling."
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"The inhibition of mTOR and p70S6K can inhibit serine phosphorylation of IRS-1(38), restore the insulin-mediated glucose transport of GLUT4(39), and improve insulin sensitivity and reduce obesity in mice (40)."
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"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_BIBR, XREF_BIBR]."
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"It has been reported that inhibition of mTORC1 signaling by rapamycin can abrogate S6K1 activity (Saitoh et al., 2002); we therefore used rapamycin to investigate whether mTORC1 and S6K1 directly part[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"P70S6K can also phosphorylate IRS1 on an inhibitory serine residue, thus causing negative feedback that inhibits insulin and IGF signaling to PI3K and AKT."
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"Persistent activation of mTORC1 and S6K1 induce serine phosphorylation of insulin receptor substrate 1 (IRS-1) and IRS-2."
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"As such, S6K1 phosphorylates IRS-1 proteins at several serine residues (S270, S307, S636, and S1101) of which S270 was found to be required for S6K1/IRS-1 interaction and subsequent phosphorylation of the other S6K1-specific residues [ xref ]."
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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."
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"A negative feedback regulation is provided by S6K1 which increases an inhibitory serine phosphorylation of IRS-1, leading to downregulation of insulin signaling [XREF_BIBR]."
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"Conversely, silencing of S6K1 using siRNAs was shown to decrease IRS-1 phosphorylation on several serine residues leading to an increase in PI3K and AKT signaling."
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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."
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"These findings support the model that S6K1 mediates IRS1 serine phosphorylation, disrupting its interaction with IR and leading to its degradation."
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"For example, activated S6K1 phosphorylates IRS1 on multiple serine residues. xref The serine - phosphorylated form of IRS1 is known to attenuate the signal from IGF1R to PI3K through inhibition of tyrosine phosphorylation of IRS1 and/or inhibition of tertiary complex formation including IGF1R, PI3K, and IRS1. xref , xref , xref In the present study, the level of the serine-phosphorylated form of IRS1 was significantly decreased within 3 h of exposure to ZSTK474 in all four cell lines examined, suggesting relief from the negative feedback program."
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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
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"This led to phosphorylation of IRS-1 by S6K1 at multiple serine residues including Ser 270, Ser 307, Ser 636, and Ser 1101 in human IRS-1 (Ser 265, Ser 302, Ser 632, and Ser 1097, in rodent IRS-1)."
18952604
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"In the state of nutrient excess, mTORC1/S6K1 signaling is chronically upregulated which in downstream promotes inhibitory serine phosphorylation as well as degradation of IRS1( Shah et al., 2004 )."
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"Adiponectin sensitizes insulin signaling by reducing p70 S6 kinase mediated serine phosphorylation of IRS-1."
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"mTORC1 and its substrate S6K1 participate in a well documented feedback loop 35 in which growth factor and nutrient signaling limits the activity of the PI3K and Akt pathway : S6K1 phosphorylates IRS-1 on serine residues that promote its ubiquitination and degradation."
21454807
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"P70S6K can also phosphorylate IRS1 on an inhibitory serine residue, thus causing negative feedback that inhibits insulin and IGF signaling to PI3K/AKT ( xref )."
27758884
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"mTORC1/S6K1 activation results in the inhibitory phosphorylation of serine residues of insulin receptor substrate-1 (IRS-1) (Ser636, Ser312, Ser616 in humans, and Ser632, Ser307 and Ser612 in mice) by S6K1."
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"In the liver, the serine phosphorylation of IRS-1 by mTORC1/S6K1 also leads to the impairment of PI3K-Akt metabolic pathway, thereby promoting gluconeogenesis."
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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."
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"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]."
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"For example, activated S6K1 phosphorylates IRS1 on multiple serine residues."
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"P70 S6 kinase directly binds to and phosphorylates IRS-1 via two different serine residues, S1101 and S270."
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