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MTORC2 is a physiological hydrophobic motif kinase of S6 Kinase 1

Ribosomal protein S6 kinase 1 (S6K1), a major downstream effector molecule of mTORC1, regulates cell growth and proliferation by modulating protein translation and ribosome biogenesis. We have recently identified eIF4E as an intermediate in transducing signals from mTORC1 to S6K1 and further demonstrated that the role of mTORC1 is restricted to inducing eIF4E phosphorylation and interaction with S6K1. This interaction relieves S6K1 auto-inhibition and facilitates its hydrophobic motif (HM) phosphorylation and activation as a consequence. These observations underscore a possible involvement of mTORC1 independent kinase in mediating HM phosphorylation. Here, we report mTORC2 as an in-vivo/physiological HM kinase of S6K1. We show that rapamycin-resistant S6K1 truncation mutant ∆NH∆CT continues to display HM phosphorylation with selective sensitivity toward Torin-1. We also show that HM phosphorylation of wildtype S6K1and ∆NH∆CT depends on the presence of mTORC2 regulatory subunit-rictor. Furthermore, truncation mutagenesis and molecular docking analysis reveal the involvement of a conserved 19 amino acid stretch of S6K1 in mediating interaction with rictor. We finally show that deletion of the 19 amino acid region from wildtype S6K1 results in loss of interaction with rictor, with a resultant loss of HM phosphorylation regardless of the presence of functional TOS motif. Our data demonstrate that mTORC2 acts as a physiological HM kinase that can activate S6K1 after its auto-inhibition is overcome by mTORC1. We, therefore, propose a novel mechanism for S6K1 regulation where mTOR complexes 1 and 2 act in tandem to activate the enzyme.

 

Comments：

Based on the information provided, it appears that the study has identified mTORC2 as a physiological hydrophobic motif (HM) kinase of S6K1. The researchers have demonstrated that mTORC1 induces eIF4E phosphorylation and interaction with S6K1, which relieves S6K1 auto-inhibition and facilitates its HM phosphorylation and activation by mTORC2. The researchers have also shown that the presence of mTORC2 regulatory subunit-rictor is required for HM phosphorylation of S6K1.

Furthermore, the researchers have identified a conserved 19 amino acid stretch of S6K1 that mediates its interaction with rictor. Deletion of this region results in the loss of interaction with rictor and the loss of HM phosphorylation, regardless of the presence of a functional TOS motif.

Overall, this study proposes a novel mechanism for S6K1 regulation where mTORC1 and mTORC2 act in tandem to activate the enzyme. This research provides valuable insights into the complex signaling pathways that regulate cell growth and proliferation, and may have important implications for the development of new therapeutic strategies for diseases such as cancer.

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S2817 Torin 2 Torin 2 is a potent and selective mTOR inhibitor with IC50 of 0.25 nM in p53−/− MEFs cell line; 800-fold greater selectivity for mTOR than PI3K and improved pharmacokinetic properties. Inhibition of ATM/ATR/DNA-PK with EC50 of 28 nM/35 nM/118 nM,in PC3 cell lines respectively. Torin 2 decreases cell viability and induces autophagy and apoptosis.

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