mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin

Kang, Seong A.; Pacold, Michael E.; Cervantes, Christopher L.; Lim, Daniel; Lou, Hua; Ottina, Kathleen; Gray, Nathanael S.; Turk, Benjamin E.; Yaffe, Michael B.; Sabatini, David M.

doi:10.1126/science.1236566

Cited by 403 publications

(432 citation statements)

References 50 publications

(77 reference statements)

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“…In contrast to the effective suppression of T-ALL progression by rapamycin, the cytostatic effect of rapamycin was not sufficient for the total eradication of T-ALL cells. The presence of rapamycin-insensitive mTORC1 substrates, like 4E-BP1, may account for this incomplete effect (13). Alternatively, the cytostatic effect of rapamycin on T-ALL may be mediated by mTORC2 inhibition because it was reported that Rictor deficiency significantly, but not completely, suppresses Notchdriven T-ALL (34), which is similar to the effect of rapamycin observed in our study.…”

Section: Inactivation Of Mtorc1 Prevents Oncogenic Kras-induced T-allsupporting

confidence: 78%

“…However, a study of conditional deletion of Rheb, which encodes an mTORC1 activator, or of mTOR with a Cd4-Cre transgene showed that mTORC1 inactivation does not result in apparent thymic phenotypes under steady-state conditions (12), leading to the possibility that rapamycin may affect T-cell development in an mTORC1-independent manner. In addition, it has been reported that 4E-BP1 is a rapamycininsensitive mTORC1 substrate, suggesting that rapamycin treatment does not necessarily represent mTORC1 inactivation (13).…”

mentioning

confidence: 99%

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Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells

Hoshii

Kasada

Hatakeyama

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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mTOR is an evolutionarily conserved kinase that plays a critical role in sensing and responding to environmental determinants. Recent studies have shown that fine-tuning of the activity of mTOR complexes contributes to organogenesis and tumorigenesis. Although rapamycin, an allosteric mTOR inhibitor, is an effective immunosuppressant, the precise roles of mTOR complexes in early T-cell development remain unclear. Here we show that mTORC1 plays a critical role in the development of both early T-cell progenitors and leukemia. Deletion of Raptor, an essential component of mTORC1, produced defects in the earliest development of T-cell progenitors in vivo and in vitro. Deficiency of Raptor resulted in cell cycle abnormalities in early T-cell progenitors that were associated with instability of the Cyclin D2/D3-CDK6 complexes; deficiency of Rictor, an mTORC2 component, did not have the same effect, indicating that mTORC1 and -2 control T-cell development in different ways. In a model of myeloproliferative neoplasm and T-cell acute lymphoblastic leukemia (T-ALL) evoked by Kras activation, Raptor deficiency dramatically inhibited the cell cycle in oncogenic Kras-expressing T-cell progenitors, but not myeloid progenitors, and specifically prevented the development of T-ALL. Although rapamycin treatment significantly prolonged the survival of recipient mice bearing T-ALL cells, rapamycin-insensitive leukemia cells continued to propagate in vivo. In contrast, Raptor deficiency in the T-ALL model resulted in cell cycle arrest and efficient eradication of leukemia. Thus, understanding the cell-contextdependent role of mTORC1 illustrates the potential importance of mTOR signals as therapeutic targets.

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Section: Inactivation Of Mtorc1 Prevents Oncogenic Kras-induced T-allsupporting

confidence: 78%

mentioning

confidence: 99%

Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells

Hoshii

Kasada

Hatakeyama

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Interestingly, 2 studies aiming to characterize the mTOR phosphoproteome repertoire have identified LARP1 as a potential mTORC1 phosphorylation substrate. 74,75 This finding was recently corroborated using both in vitro and in vivo phosphorylation assays, 76 confirming LARP1 as a bona fide mTORC1 substrate. 77 Consistent with this, LARP1 was found to interact with the mTORC1-specific component Raptor, suggesting that LARP1 is an mTORC1-specific cell growth effector.…”

Section: Translational Control Of Top Mrnasmentioning

confidence: 49%

Regulation of global and specific mRNA translation by the mTOR signaling pathway

2015

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“…According to the gene ontology analysis, there are about 30 predicted amino acid permeases in the fission yeast genome. Half of these (49) are affected by ⌬isp7, either positively (3) or negatively (50) (see Tables S2 and S3 in the supplemental material). Interestingly, the amino acid permease aap1 ϩ , which we found as a multicopy suppressor of the sensitivity to rapamycin in tsc mutant cells, is downregulated in ⌬isp7 cells.…”

Section: Resultsmentioning

confidence: 99%

Isp7 Is a Novel Regulator of Amino Acid Uptake in the TOR Signaling Pathway

Laor

Cohen

Pasmanik‐Chor

et al. 2014

Molecular and Cellular Biology

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c TOR proteins reside in two distinct complexes, TOR complexes 1 and 2 (TORC1 and TORC2), that are central for the regulation of cellular growth, proliferation, and survival. TOR is also the target for the immunosuppressive and anticancer drug rapamycin. In Schizosaccharomyces pombe, disruption of the TSC complex, mutations in which can lead to the tuberous sclerosis syndrome in humans, results in a rapamycin-sensitive phenotype under poor nitrogen conditions. We show here that the sensitivity to rapamycin is mediated via inhibition of TORC1 and suppressed by overexpression of isp7 ؉ , a member of the family of 2-oxoglutarate-Fe(II)-dependent oxygenase genes. The transcript level of isp7 ؉ is negatively regulated by TORC1 but positively regulated by TORC2. Yet we find extensive similarity between the transcriptome of cells disrupted for isp7؉ and cells mutated in the catalytic subunit of TORC1. Moreover, Isp7 regulates amino acid permease expression in a fashion similar to that of TORC1 and opposite that of TORC2. Overexpression of isp7 ؉ induces TORC1-dependent phosphorylation of ribosomal protein Rps6 while inhibiting TORC2-dependent phosphorylation and activation of the AGC-like kinase Gad8. Taken together, our findings suggest a central role for Isp7 in amino acid homeostasis and the presence of isp7 ؉ -dependent regulatory loops that affect both TORC1 and TORC2.

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mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin

Cited by 403 publications

References 50 publications

Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells

Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells

Regulation of global and specific mRNA translation by the mTOR signaling pathway

Isp7 Is a Novel Regulator of Amino Acid Uptake in the TOR Signaling Pathway

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