mTORC1 induces eukaryotic translation initiation factor 4E interaction with TOS-S6 kinase 1 and its activation

Majeed, Sheikh Tahir; Batool, Asiya; Majeed, Rabiya; Bhat, Nadiem Nazir; Zargar, Muhammad Afzal; Andrabi, Khurshid Iqbal

doi:10.1080/15384101.2021.1901038

Cited by 11 publications

(18 citation statements)

References 41 publications

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“…Furthermore, absence of a consensus TOS motif in other mTORC1 substrates question the centrality of TOS in mediating mTORC1 specific substrate phosphorylation. The observation is further endorsed by our recent findings that identify eIF4E as mTORC1 substrate and an intermediate in transducing signals downstream of mTORC1 onto S6K1(28). The data, therein, demonstrates that the role of mTORC1 is restricted to engaging eIF4E with TOS motif of S6K1, required for relieving auto-inhibition and subsequently priming S6K1 for Thr-412 phosphorylation in mTORC1 independent manner (28).…”

Section: Resultssupporting

confidence: 57%

“…Contrarily however, the data demonstrating continued display of HM phosphorylation in S6K1 mutants, which harbour mutations disrupting TOS function, suggest that mTORC1 regulates S6K1 in a manner that is distinct from the one that regulates HM phosphorylation (22,23).These observations are further supported by the recent data that demonstrates raptor is not always involved in S6K1 phosphorylation (24).Furthermore, identification of other mTORC1 substrates without a consensus TOS motif also undermine the centrality of TOS in mediating raptor binding (25)(26)(27). Notably, our recent data identifies eukaryotic translation initiation factor 4E (eIF4E) as an intermediate in transducing signals from mTORC1 onto S6K1 (28). Therein, we demonstrate that the role of mTORC1 is restricted to engaging eIF4E with S6K1-TOS motif for relieving the auto-inhibition due to carboxy terminal auto-inhibitory domain (CAD) and thereby facilitating the consequential HM phosphorylation and activation of S6K1.These observations, being consistent with our earlier data (29,30), highlight the discordance in mTORC1 mediated HM phosphorylation and therefore suggest an alternative mechanism for the regulation of HM phosphorylation of S6K1.…”

Section: Introductionsupporting

confidence: 59%

“…The proposal that mTORC1 is HM kinase of S6K1 while mTORC2 mediated HM phosphorylation (Thr-412) is only a non-physiological/random event determined by the structure of S6K1, does not satisfactorily reconcile with the data that demonstrate T412 phosphorylation in TOS deficient S6K1 mutants (22, 23, 28). The findings contest the preposition that interaction between raptor and S6K1-TOS motif is the basis for mTORC1 mediated T412 phosphorylation.…”

Section: Resultsmentioning

confidence: 87%

“…To determine whether TOS motif is indispensable for mediating Thr-412 phosphorylation of S6K1 and whether relieving –NH2 and –COOH termini renders S6K1 active and independent of-the-regulation by mTORC1, we used previously described HEK293 cells stably expressing Flag-tagged wild type S6K1 (28). In addition, we created lines of HEK293 cells stably expressing Flag-tagged S6K1 truncation mutant ΔNHΔCT to observe their state of Thr-412 phosphorylation in response to mTORC1 inhibition.…”

Section: Resultsmentioning

confidence: 99%

“…HEK293, HEK293T cells and NIH3T3 cells, described previously (28), and MEFs were maintained in Dulbecco's modified Eagles medium (DMEM) supplemented with 10% (v/v) foetal bovine serum (Invitrogen), 50 μg/ml penicillin and 100 μg/ml streptomycin (Sigma-Aldrich) at 37°C with 5% CO2.…”

Section: Cell Lines and Culture Conditionsmentioning

confidence: 99%

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MTORC2 is a physiological hydrophobic motif kinase of S6 Kinase 1

Majeed

Zargar

et al. 2021

Preprint

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Ribosomal protein S6 kinase (S6K1), a major downstream effector molecule of mTORC1, regulates cell growth and proliferation via modulating protein translation and ribosomal biogenesis. We have previously identified eIF4E as an intermediate in transducing signals from mTORC1 to S6K1 and further demonstrated that the role of mTORC1 is restricted to relieving S6K1 auto-inhibition to allow hydrophobic motif (HM) phosphorylation of the enzyme for activation. These observations rule out the role of mTORC1 as an HM kinase of S6K1 and point towards the involvement of mTORC1 independent kinase in mediating HM phosphorylation. Here, we report mTORC2 as an in-vivo HM kinase of S6K1. We show that S6K1 truncation mutant, incapacitated to respond to mTORC1 signals, continues to display HM phosphorylation which remains sensitive towards mTOR kinase inhibitor-torin 1. Furthermore, we identify a highly conserved amino acid stretch in S6K1 responsible for mediating HM phosphorylation. We show that deletion of this stretch leads to HM dephosphorylation and subsequent in activation of the enzyme. We, therefore, propose a novel mechanism for S6K1 regulation where mTOR complex 1 and 2 act in tandem to activate the enzyme.

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Section: Resultssupporting

confidence: 57%

Section: Introductionsupporting

confidence: 59%

Section: Resultsmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Cell Lines and Culture Conditionsmentioning

confidence: 99%

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MTORC2 is a physiological hydrophobic motif kinase of S6 Kinase 1

Majeed

Zargar

et al. 2021

Preprint

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Curcumin and its anti‐colorectal cancer potential: From mechanisms of action to autophagy

Brockmueller,

Ruiz de Porras,

Shakibaei

2024

Phytotherapy Research

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Colorectal cancer (CRC) development and progression, one of the most common cancers globally, is supported by specific mechanisms to escape cell death despite chemotherapy, including cellular autophagy. Autophagy is an evolutionarily highly conserved degradation pathway involved in a variety of cellular processes, such as the maintenance of cellular homeostasis and clearance of foreign bodies, and its imbalance is associated with many diseases. However, the role of autophagy in CRC progression remains controversial, as it has a dual function, affecting either cell death or survival, and is associated with cellular senescence in tumor therapy. Indeed, numerous data have been presented that autophagy in cancers serves as an alternative to cell apoptosis when the latter is ineffective or in apoptosis‐resistant cells, which is why it is also referred to as programmed cell death type II. Curcumin, one of the active constituents of Curcuma longa, has great potential to combat CRC by influencing various cellular signaling pathways and epigenetic regulation in a safe and cost‐effective approach. This review discusses the efficacy of curcumin against CRC in vitro and in vivo, particularly its modulation of autophagy and apoptosis in various cellular pathways. While clinical studies have assessed the potential of curcumin in cancer prevention and treatment, none have specifically examined its role in autophagy. Nonetheless, we offer an overview of potential correlations to support the use of this polyphenol as a prophylactic or co‐therapeutic agent in CRC.

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Recent Advances in the Pharmacological Properties and Molecular Mechanisms of Carvacrol

Ali

Majeed

et al. 2023

Rev. Bras. Farmacogn.

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mTORC1 induces eukaryotic translation initiation factor 4E interaction with TOS-S6 kinase 1 and its activation

Cited by 11 publications

References 41 publications

MTORC2 is a physiological hydrophobic motif kinase of S6 Kinase 1

MTORC2 is a physiological hydrophobic motif kinase of S6 Kinase 1

Curcumin and its anti‐colorectal cancer potential: From mechanisms of action to autophagy

Recent Advances in the Pharmacological Properties and Molecular Mechanisms of Carvacrol

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