Abstract
Eukaryotic translation initiation factor 4E was recently shown to be a substrate of mTORC1, suggesting it may be a mediator of mTORC1 signaling. Here, we present evidence that eIF4E phosphorylated at S209 interacts with TOS motif of S6 Kinase1 (S6K1). We also show that this interaction is sufficient to overcome rapamycin sensitivity and mTORC1 dependence of S6K1. Furthermore, we show that eIF4E-TOS interaction relieves S6K1 from auto-inhibition due to carboxy terminal domain (CTD) and primes it for hydrophobic motif (HM) phosphorylation and activation in mTORC1 independent manner. We conclude that the role of mTORC1 is restricted to engaging eIF4E with S6K1-TOS motif to influence its state of HM phosphorylation and inducing its activation.
Keywords:
S6 Kinase 1; eIF4E; mTOR.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Motifs
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Animals
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Cell Line, Tumor
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Enzyme Activation / drug effects
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Eukaryotic Initiation Factor-4E / metabolism*
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HEK293 Cells
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Humans
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Intracellular Signaling Peptides and Proteins / metabolism
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Mechanistic Target of Rapamycin Complex 1 / metabolism*
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Mice
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Models, Biological
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NIH 3T3 Cells
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Phosphorylation / drug effects
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Protein Binding / drug effects
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Protein Serine-Threonine Kinases / metabolism
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Ribosomal Protein S6 Kinases / chemistry*
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Ribosomal Protein S6 Kinases / metabolism*
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Sirolimus / pharmacology
Substances
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Eukaryotic Initiation Factor-4E
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Intracellular Signaling Peptides and Proteins
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MKNK1 protein, human
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Mechanistic Target of Rapamycin Complex 1
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Protein Serine-Threonine Kinases
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Ribosomal Protein S6 Kinases
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Sirolimus
Grants and funding
This work was supported by the Department of Biotechnology, Ministry of Science and Technology, Government of India [BT/PR5867/BRB/10/1107/2012]; University Grants Commission [201920-BL/18-19/0544]; SERB-Department of Science and Technology, Governemet of India [EMR/2016/000803]and University Grants Commission [2-5/2016(NS/PE)].