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TSC2 inhibits RPS6KB1. 33 / 36
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"These data demonstrate that tuberin negatively regulates the activity of S6 and p70S6K specifically, and suggest a potential mechanism for abnormal cell growth in LAM."
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"Interestingly, ERK1/2 can phosphorylate TSC2 on S644, inactivating the TSC complex, and the autoinhibitory domain (T421/S424) on S6K1, promoting mTORC1 signaling activation [4] ."
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"For example, loss of either TSC1 or TSC2 expression caused constitutive activation of S6K1 that was not reversed upon nutrient withdrawal [49] ."
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"First, Rheb is genetically epistatic to TSC2 : loss of Rheb blocks the increased cell growth and increased S6K1 activity caused by loss of TSC2 (Saucedo et al., 2003; Stocker et al., 2003)."
14536067
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"Moreover, in mammalian cells in culture, co-overexpression of TSC1 and TSC2 prevents amino acid dependent activation of S6K1 [XREF_BIBR]."
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"14-3-3 mediates mTOR signaling by regulating the product of tuberous sclerosis complex (TSC) 2 tumor suppressor gene, tuberin that inhibits the downstream target of mTOR, p70 ribosomal S6 kinase [96] [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70S6 kinase by the hamartin-tuberin complex."
14551205
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"Here we review recent findings demonstrating that the TSC1 and TSC2 inhibitory complex normally acts on Rheb to mediate mTOR and S6K1 signalling."
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"It will be of great interest to determine the molecular nature of S6K1 inhibition by the tuberin-hamartin complex in the absence of mitogenic stimuli."
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"In HT29 colon tumoral cells XREF_BIBR, AMPK activation by synthetic molecules or polyphenolic compounds was shown to activate TSC2, which in turn inhibits TORC1 and mTOR and p70S6K."
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"The tuberin S939A and T1462A mutant but not wild-type tuberin also significantly reduces S6K1 activity from cells growing in full serum."
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"This suggests that these phosphorylation sites are normally required for the PI3K-Akt pathway to relieve tuberin mediated inhibition of S6K1 (see Discussion)."
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"Additionally, it should be examined whether phosphomimetic mutations in TSC2, like depletion of TSC2 by RNAi, abrogate the ability of amino acid starvation to inhibit S6K1."
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"Moreover, S6K1 activation by either TSC2 depletion or constitutively active S6K1 mutants induces ESC differentiation, therefore demonstrating that mTOR repression is required to maintain ESC pluripotency."
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"Their studies all suggest that the onset of epilepsy is related to the time point of PTEN depletion.Some study found that the encoded products of TSC2 and TSC1 inhibit mTOR-mediated signaling of ribos[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Phosphorylation of TSC2 and Raptor subsequently decreases phosphorylation of S6 Kinase 1 (S6K1) resulting in decreased protein and lipid synthesis [21]."
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"Incubation of RMCs with 1,25 (OH) 2 D 3 for 48 h increased VDR expression (p < 0.05), restored the expression of TSC1 and TSC2 and 4E-BP1, and blocked the aberrant upregulation of Rheb, mTOR and p70S6K."
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"Our study demonstrates that IFNbeta dependent activation of STATs and p38 MAPK is not sufficient to fully inhibit proliferation of cells with TSC2 dysfunction and that TSC2 dependent inhibition of mTOR and S6K1 cooperates with IFNbeta in inhibiting human LAM and TSC2-null ELT3 cell proliferation."
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"The results showed that high significantly expression of TSC2 dramatically suppressed mRNA expression of mTOR , p70S6K and myogenic genes, including MyoD , MyoG and MyHC ( Fig. 7 A), which was consist[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Furthermore, overexpression of Hamartin and Tuberin blocked S6K1 activation upon the readdition of amino acids to nutrient starved cells [18, 19]."
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"The loss of TSC2, which is upstream of mTOR, activates S6K1, promotes cell growth and survival, activates mTOR kinase activities, inhibits mTORC1 and mTORC2 via mTOR inhibitors, and suppresses S6K1 and Akt."
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"Over-expression of TSC1 and TSC2 also markedly inhibited S6K1, positioning TSC1 and TSC2 upstream of S6K1."
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"In this case, previous studies have demonstrated that TSC2 inhibits small G protein Rheb by its own GAP activity and inhibits the activation of downstream mTOR , and thus inhibits the downstream targe[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"In TSC2-/- MEF and TSC2-/- rat cells, loss of tuberin resulted in the constitutive activation of S6K1 leading to the hyperphosphorylation of ribosomal protein S6 [71,72]."
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"The ability of WISP1 to limit TSC2 (Ser 1387) phosphorylation appears to allow WISP1 to increase the activity of p70S6K, since gene silencing of TSC2 further enhances WISP1 phosphorylation of p70S6K."
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"In HEK293 cells, overexpression of tuberin and hamartin attenuated basal, insulin-and Ras stimulated S6K1 activation [37,86]."
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"Finally, we analyzed whether Rheb mediated activation of S6K1 is affected by a pathologic mutation in human TSC2, which fails to inhibit S6K1 activation.If the effects of TSC1/2 loss of function mutat[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"In cancer, there is an increase in the activity of PI3K-AKT axis, and TSC1 and TSC2 is inhibited by AKT, allowing mTORC1 activation and subsequently activation of P70S6K1 and EIF4e."
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"While investigators concluded that tuberin and hamartin inhibit insulin induced activation of the overexpressed wild-type S6K1, conflicting data exist concerning the effect of tuberin and hamartin on [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"In response to PI3K activation, tuberin is directly phosphorylated by Akt at Thr1462 and Ser939, and a tuberin lacking PI3K-dependent phosphorylation sites can block the activation of S6K1."
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"Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70S6 kinase by the hamartin-tuberin complex."
14551205
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"The ability of WISP1 to limit TSC2 (Ser 1387) phosphorylation appears to allow WISP1 to increase the activity of p70S6K."
23244622
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"Under the condition of starvation, AMPK phosphorylates tuberous sclerosis 2 (TSC2), which inhibits mTOR and S6K1 pathway [XREF_BIBR] : phosphorylation of TSC2 by AMPK is critical in the process of mRNA translation and cell size regulation during energy deficiency (XREF_FIG)."
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