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MTOR phosphorylates IRS1 on serine. 36 / 38
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"Studies conducted in rodent models and cultured rat myocytes found that increased exposure of skeletal muscle cells to BCAA impairs insulin action in concert with activation of the mammalian target of rapamycin (mTOR), which causes serine phosphorylation of insulin receptor substrate-1 and disrupts insulin signaling."
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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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"The latter is because inhibition of an mTOR-dependent serine phosphorylation of insulin receptor substrate-1 by mTOR inhibitors such as rapamycin enhance insulin-like growth factor (IGF) I signaling a[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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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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"Cul7 can participate in the degradation of IRS-1 in a mTOR/S6K dependent manner, which induced Ser phosphorylation of IRS-1 [ 37 ]."
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"Additionally, p70 S6K, the downstream effector of mTOR, has been shown to cause serine phosphorylation of IRS-1, resulting in impaired insulin signaling and insulin resistance [XREF_BIBR]."
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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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"mTOR induced the serine phosphorylation of IRS-1 (Ser-636/639), and such phosphorylation was inhibited by rapamycin."
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"MTOR, along with other kinases such as JNK, phosphorylate IRS-1 on serine residues, leading ultimately to IRS-1 degradation."
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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]."
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"Such effect is achieved by an Downloaded by [University of Wisconsin - Madison] at 03:17 24 December 2017146 H. Al Dera et al.insulin-stimulated negative feedback loop in which mTOR and its downstream regulator, S6 kinase (S6K) 1, phosphorylate insulin receptor substrate-1 (IRS-1) on its serine residues, which blocks phosphatidylinositol 3-kinase (PI3K) activation (Carlson et al., 2004; Ozes et al., 2001)."
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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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"Given that dietary protein and amino acids can impair insulin signaling through mammalian target of rapamycin complex 1/S6 kinase 1 (mTORC1/S6K1) dependent phosphorylation of insulin receptor substrate 1 (IRS1) on multiple inhibitory serines residues xref – xref , we next tested whether our PM diet impacts metabolic health via this nutrient-sensing mechanism."
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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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"Indeed, mTOR and S6K1 are able to induce IRS-1 serine phosphorylation and affect IRS-1 protein turnover."
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"Increased BCAA leads to mitochondrial dysfunction and sustained activation of the mTOR signaling pathway, which increases Ser phosphorylation of IRS-1 and inhibits the GLUT4 transport of glucose, ultimately leading to insulin resistance [141]."
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"Notably, hyperactive S6K1 and mTOR negatively regulate Akt by inducing IRS-1 serine phosphorylation (S302 (human 307) [XREF_BIBR], S636/639 [XREF_BIBR], S1101 [XREF_BIBR], S307 (human 312) [XREF_BIBR, XREF_BIBR]), which disrupts its interaction with the insulin receptor, and results in degradation."
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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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"MTOR induced the serine phosphorylation of IRS-1 (Ser 636/639), and such phosphorylation was inhibited by rapamycin."
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"This inhibition is likely to be due to mTOR, which exerts a negative feedback loop on insulin signaling by phosphorylating IRS-1 on serine residues, as shown previously in different cell types, includ[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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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."
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"Moreover, it has been proposed that the mTOR-dependent IRS1 phosphorylation on serine residues could allow for its degradation [19,69,98,99] ."
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"In addition, constitutive activation of mTOR triggers ER stress and inhibition of insulin action through JNK-mediated serine phosphorylation of IRS1 ( Ozcan et al., 2008 )."
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"Recent studies demonstrate that the mTOR downstream target S6K1 directly phosphorylates IRS1 serine residues, including Ser 302/307, Ser 307/312, Ser 632/636, and Ser 1097/1101."
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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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"Elevated serine phosphorylation of IRS-1, driven by the overactive mTOR pathway, impairs the ability of IRS-1 to activate PI3K."
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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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"PA has been shown to activate p70 ribosomal S6 kinase 1 (S6K1) [9] , a downstream effector of mTOR, which leads to serine phosphorylation of IRS-1 [10] ."
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"Accordingly, the inhibition of mTOR by rapamycin was found to attenuate serine phosphorylation of IRS-1, restore insulin action on the PI3K and AKT pathway and prevent the insulin resistant effects of excess nutrients on insulin mediated glucose transport in muscle and adipose cells XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR."
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"Importantly, studies have shown that the Ser and Ser phosphorylation of IRS-1 is mediated by mTOR and its downstream target p706SK to reduce PI3K/Akt signaling and glucose uptake [62,70]."
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"The mammalian target of rapamycin (mTOR) is downstream of Akt and can phosphorylate IRS1 on serine residues, targeting it for degradation."
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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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"Overfeeding and metabolic stresses, including high levels of free fatty acids or inflammatory cytokines, enable activation of a number of endogenous protein kinases, such as mTOR, JNK, and IKKbeta, which can phosphorylate IRS1 and IRS2 at serine and threonine residues and which mediate IRS protein ubiquitination and degradation, resulting in insulin resistance [XREF_BIBR]."
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"Activation of mTOR signaling pathway has been found to suppress insulin sensitivity through serine phosphorylation and the inhibition of IRS1 by mTOR and its downstream effector, S6K1."
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"The mammalian target of rapamycin (mTOR) is downstream of Akt and can phosphorylate IRS1 on serine residues, targeting it for degradation ( xref )."
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