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RPS6KB1 inhibits IRS1. 63 / 67
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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."
21980324
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"Therefore, S6K1 is unlikely to trigger IRS-1 degradation under physiological conditions like persistent insulin and IGF stimuli, although S6K1 mediates a negative feedback in ways other than IRS-1 deg[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
30240640
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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."
29738527
eidos
"( 4 ) S6K1 inhibits IRS-1 , leading to subsequent ERK2 inhibition and consequent downregulation of S6K1 ."
36133808
sparser
"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."
27879396
sparser
"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 ]."
27149630
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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)."
27613445
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"The phosphorylation of S6K1 inactivates IRS-1 which is required for insulin signaling through PI3K."
21216931
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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."
19372546
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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
signor
"Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin."
15306821
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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."
24961241
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"mTORC1 activates S6K1, which inhibits IRS-1 through phosphorylation in serine 302 42."
19098454
sparser
"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."
36224569
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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."
24961241
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
signor
"Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin."
15306821
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"One mechanism by which this occurs appears to be through p70S6K dependent downregulation of IRS1."
26536660
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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."
26314828
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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"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."
26957369
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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."
33684837
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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]."
22545721
sparser
"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."
36224569
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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."
29738527
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"Lastly, S6K1 inhibits IRS-1 activity by phosphorylation at Ser318 XREF_BIBR."
22102801
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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]."
25296981
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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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sparser
"On the other hand, the mTORC1 substrate RPS6KB1 phosphorylates and inhibits IRS1 [ xref , xref ]."
33544134
signor
"Turnover of the active fraction of irs1 involves raptor-mtor- and s6k1-dependent serine phosphorylation in cell culture models of tuberous sclerosiss6k1 phosphorylates irs1 in vitro on multiple residues showing strong preference for rxrxxs/t over s/t,p sites."
9312143
sparser
"mTORC1-activated S6K1 inactivates IRS-1 by phosphorylation on S422 [ xref ], leading to its proteasomal degradation [ xref ]."
34208071
eidos
"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 ."
33684837
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
signor
"Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulates insulin."
15306821
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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."
25969542
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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."
23054135
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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]."
25450580
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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."
20507574
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"S6K1 can phosphorylate and inactivate IRS1, thereby allowing a feedback regulation of the IRS1/PI3K/AKT pathway [ xref , xref , xref ]."
26999118
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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."
15249583
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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."
24416418
signor
"Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin."
15306821
sparser
"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."
18797463
sparser
"S6K1 also phosphorylates and inactivates IRS1, thereby providing a negative feedback loop [ xref ]."
24352740
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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."
18797463
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"The ribosomal protein S6 kinase 1 (S6K1), a component of insulin signaling transduction, negatively regulates insulin receptor substrate 1 (IRS1)."
33364490
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"When mTOR is inhibited S6K1 does not inhibit IRS-1."
24244833
sparser
"Whereby S6K1 inhibits IRS-1 and prevents ERK1/EKR2 activation, ERK2 inhibition results in S6K1 downregulation ( xref )."
36133808
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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."
25969542
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"In addition, BNIP3L can inhibit insulin signaling through activation of MTOR-RPS6KB and p70S6 kinase inhibition of IRS1, which is contingent on phosphatidic acids and RHEB."
33044904
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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."
29077858
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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."
11342583
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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]."
32054043
signor
"Turnover of the active fraction of irs1 involves raptor-mtor- and s6k1-dependent serine phosphorylation in cell culture models of tuberous sclerosiss6k1 phosphorylates irs1 in vitro on multiple residues showing strong preference for rxrxxs/t over s/t,p sites."
16914728
sparser
"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 )."
21216931
sparser
"mTORC1 activates S6K1, which inhibits IRS-1 through phosphorylation in serine 302 xref ."
19098454
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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]."
23599172
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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]."
28324268
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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."
26116835
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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."
20507574
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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)."
15249583
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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]"
20932932
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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."
23673367