"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]."
"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."
"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)."
"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]."
"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."
"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."
"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."
"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."
"Using two cell culture models of the familial hamartoma syndrome, tuberous sclerosis, we show here that Raptor-mTOR and S6K1 are required for phosphorylation of IRS1 at a subset of serine residues frequently associated with insulin resistance, including S307, S312, S527, S616, and S636 (of human IRS1)."
"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."