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RHEB activates RPS6KB1. 56 / 60
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"Overexpression of Rheb was sufficient to enhance S6K1 activity in the absence of nutrients, indicating that Rheb may be a component of the nutrient sensing machinery of mTOR."
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"Overexpression of Rab5CA was still able to inhibit amino acid stimulated mTORC1 and S6K1 in TSC2-/- MEFs, whereas cooverexpression of Myc-Rheb with Rab5CA in TSC2-/- MEFs blocked the inhibition of mTORC1 and S6K1 signaling (XREF_FIG, C and D)."
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"In contrast, Rheb overexpression drastically increased S6K1 activity when assayed in parallel."
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"We reveal that Rheb specifically activates mTOR mediated signaling rather than cell signaling through MEK and ERK and PI3K, as shown by Rheb mediated activation of S6K1 but not Akt or RSK1."
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"In many cell types, activation of mTORC1 by Rheb activates S6K1, which in turn suppresses the PI3K-Akt signaling pathway by phosphorylation and inhibition of IRS [XREF_BIBR]."
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"Amino acid withdrawal will decrease phosphorylation of the p70S6 kinase, a key mTORC1 target, but overexpression of Rheb rescues p70S6K activation (31), drawing a clear connection between mTORC1 activity and Rheb."
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"These data are consistent with the report by Garami et al, which shows that a loss-of-function mutant in TSC2 GAP domain failed to block RheB activation of S6K1 [ xref ]."
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"Moreover, Rheb does not activate a S6K1 mutant that is unresponsive to mTOR-mediated signals, confirming that Rheb functions upstream of mTOR."
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"Rheb activation of mTOR and S6K1 signaling."
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"Overexpression of the Tuberin and Hamartin heterodimer inhibits Rheb mediated S6K1 activation, suggesting that Tuberin functions as a Rheb GTPase activating protein (GAP)."
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"Co-expression of a human TSC2 harboring a disease associated point mutation in the GAP domain, failed to stimulate Rheb GTPase activity or block Rheb activation of S6K1 [XREF_BIBR, XREF_BIBR]."
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"Finally, coexpression of a human TSC2 cDNA harboring a disease-associated point mutation in the GAP domain, failed to stimulate Rheb GTPase activity or block Rheb activation of S6K1."
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"These data are consistent with the report by Garami et al, which shows that a loss-of-function mutant in TSC2 GAP domain failed to block RheB activation of S6K1 [XREF_BIBR]."
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"In contrast, Rheb potently activated S6K1 by 11-fold when assayed in parallel."
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"These findings suggest that Rheb does not function upstream of either PI3K and Akt or ERK and RSK1 signaling pathways.Because Rheb enhanced the activity of S6K1, a downstream component of mTOR, we inv[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"BFA completely abolished Rheb dependent activation of p70S6K."
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"During conditions of amino acid withdrawal, Rheb overexpression potently activated S6K1, which was completely blocked by rapamycin but only partially inhibited by wortmannin."
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"However, the farnesylation deficient Rheb was still able to activate S6K1 to a lesser degree than the wild-type when it was expressed at higher levels."
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"If the effects of wortmannin and rapamycin on the TSC2 loss-of-function phenotype are mediated by Rheb, similar effects of the two inhibitors would be expected on Rheb induced S6K1 activation."
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"Furthermore, we show that Tuberin when associated with Hamartin functions as a GAP toward Rheb.To examine whether Rheb overexpression could modulate S6K1 activity, we coexpressed S6K1 with Rheb at two[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Together, our results show that constitutively active Rheb promotes the survival of retinal ganglion cells and axon regeneration through modulating S6K1 and 4E-BP1 activity."
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"These findings strongly suggest that Rheb induces S6K1 activation via a signaling input that is upstream of mTOR but not PI3K.Previous work revealed that overexpression of wild-type Rheb led to a sign[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Even in the absence of the nutrients, overexpression of Rheb is able to promote S6K1 activity and cell growth (Garami et al., 2003; Stocker et al., 2003; Zhang et al., 2003)."
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"Importantly, the Rheb-inhibitory function of Tuberin-Hamartin heterodimers depends on an intact Tuberin GAP domain; patient derived point mutations within the GAP domain of TSC2 prevented the Tuberin [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Overexpression of Rheb, But Not Increased Activation of Endogenous Rheb, Rescues mTORC1 and S6K1 Signaling in Cells Expressing Rab5CA."
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"Rheb also activates S6K1 during amino acid insufficiency via a rapamycin sensitive mechanism, suggesting that Rheb participates in nutrient signaling through mTOR."
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"Higher levels of Rheb expression enhanced the basal and insulin stimulated activity of S6K1 by 5.6- and 1.7-fold, respectively, and this activity level was more potent than the S6K1 activity observed [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Consistent with the inhibitory effects of 2-deoxyglucose (2-DG) on mTOR being attributed to its lowering of intracellular ATP levels , which act directly on mTOR, 2-DG almost totally abolishes Rheb-in[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"If the effects of wortmannin and rapamycin on the TSC2 loss-of-function phenotype are mediated by Rheb, similar effects of the two inhibitors would be expected on Rheb-induced S6K1 activation."
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"Overexpression of Rheb potently activated wild-type S6K1 basally (by 11-fold; Figure 4, lane 5) and during insulin stimulation (by 17-fold; Figure 4, lane 5) but did not enhance the activity of the S6[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"In contrast, the three TSC2 GAP domain point mutants were unable to repress Rheb induced S6K1 activation, revealing that the GAP domain of Tuberin is critical for Tuberin 's ability to repress Rheb me[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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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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"Finally, coexpression of a human TSC2 cDNA harboring a disease associated point mutation in the GAP domain, failed to stimulate Rheb GTPase activity or block Rheb activation of S6K1."
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"However, mutation of these sites significantly inhibits Rheb-induced S6K1 activation through decreased Rheb-GTP loading, suggesting that AKT regulates tuberin function by causing tuberin translocation to the cytosol, rather than by directly inhibiting its intrinsic GAP activity toward Rheb."
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"Moreover, the Rheb associated kinase activity directed specifically toward p70S6K Thr412 is increased by coexpression with wild-type HA-mTOR to an even greater extent than is the overall Rheb catalyze[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Meanwhile treatment with AFC, an inhibitor of farnesylcysteine methyl transferase, had no effect on Rheb mediated p70S6K activation."
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"Coexpression of Rheb alone induced S6K1 activation to a higher extent than that achieved by insulin stimulation, as determined by increased S6K1-T389 phosphorylation."
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"Once mTORC1 is recruited to the lysosome, the TOR serine threonine kinase is activated by Rheb [XREF_BIBR] and phosphorylates its canonical substrates S6K1, 4EBP1, ULK1 and TFEB."
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"As a test result, overexpression of Rheb in HEK293E cells activated S6K1 but not Akt and RSK1, and TSC2 inhibited Rheb activity in HEK293E cells [87]."
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"The results of this experiment reveal that wortmannin has little effect on Rheb-induced S6K1 activation, whereas it totally abolishes the insulin response ."
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"We show that the Tuberin and Hamartin heterodimer inhibits Rheb induced S6K1 activation during conditions of amino acid withdrawal."
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"Consistent with these findings, amino acid withdrawal has no negative impact on Rheb-induced S6K1 activation; indeed, it consistently leads to a slight stimulation, whereas insulin-induced activation [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"However, mutation of these sites significantly inhibits Rheb induced S6K1 activation through decreased Rheb-GTP loading, suggesting that AKT regulates tuberin function by causing tuberin translocation to the cytosol, rather than by directly inhibiting its intrinsic GAP activity toward Rheb."
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"Rheb also activates S6K1 during amino acid insufficiency via a rapamycin-sensitive mechanism, suggesting that Rheb participates in nutrient signaling through mTOR."
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"To address this possibility, we investigated whether Rheb promotes S6K1 activation in the absence of amino acids."
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"In parallel, we tested whether ectopic expression of Rheb induces S6K1 activation and whether insulin induced S6K1 stimulation is dependent on Rheb."
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"We show that Rheb overexpression potently enhances the activity of S6K1 during conditions of nutrient withdrawal."
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"Likewise, coexpression of the wild-type TSC2, but not the TSC2 GAP mutant, blocked Rheb induced S6K1 activation."
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"Under serum starved conditions, Rheb potently activated S6K1, which was fully blocked by coexpression of wild-type Tuberin with Hamartin."
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"Consistent with the inhibitory effects of 2-deoxyglucose (2-DG) on mTOR being attributed to its lowering of intracellular ATP levels (Dennis et al., 2001), which act directly on mTOR, 2-DG almost tota[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"The results of this experiment reveal that wortmannin has little effect on Rheb induced S6K1 activation, whereas it totally abolishes the insulin response."
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"Overexpression of Rheb activates 40S ribosomal protein S6 kinase 1 (S6K1) but not p90 ribosomal S6 kinase 1 (RSK1) or Akt."
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"The increase in cell size caused by Rheb overexpression is abrogated by mutation of TOR, and the increase in S6K1 activity caused by Rheb overexpression remains sensitive to rapamycin (Garami et al., [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"To indirectly measure Rheb activity, we analyzed Rheb induced S6K1 activation within nutrient deprived HEK293E cells."
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"We observed that coexpression of Hamartin and Tuberin completely blocked Rheb 's ability to activate S6K1, implying that Tuberin may function as a RhebGAP.If the GAP domain of Tuberin is essential for[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"We show that transient expression of the wild type Rheb1 or Rheb2 causes activation of p70S6K, while expression of Rheb1D60K mutant results in inhibition of basal level activity of p70S6K."
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