Dataset Information

MTORC1 and CK2 coordinate ternary and eIF4F complex assembly.

ABSTRACT: Ternary complex (TC) and eIF4F complex assembly are the two major rate-limiting steps in translation initiation regulated by eIF2? phosphorylation and the mTOR/4E-BP pathway, respectively. How TC and eIF4F assembly are coordinated, however, remains largely unknown. We show that mTOR suppresses translation of mRNAs activated under short-term stress wherein TC recycling is attenuated by eIF2? phosphorylation. During acute nutrient or growth factor stimulation, mTORC1 induces eIF2? phosphorylation and recruitment of NCK1 to eIF2, decreases eIF2? phosphorylation and bolsters TC recycling. Accordingly, eIF2? mediates the effect of mTORC1 on protein synthesis and proliferation. In addition, we demonstrate a formerly undocumented role for CK2 in regulation of translation initiation, whereby CK2 stimulates phosphorylation of eIF2? and simultaneously bolsters eIF4F complex assembly via the mTORC1/4E-BP pathway. These findings imply a previously unrecognized mode of translation regulation, whereby mTORC1 and CK2 coordinate TC and eIF4F complex assembly to stimulate cell proliferation.

SUBMITTER: Gandin V

PROVIDER: S-EPMC4822005 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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mTORC1 and CK2 coordinate ternary and eIF4F complex assembly.

Gandin Valentina V Masvidal Laia L Cargnello Marie M Gyenis Laszlo L McLaughlan Shannon S Cai Yutian Y Tenkerian Clara C Morita Masahiro M Balanathan Preetika P Jean-Jean Olivier O Stambolic Vuk V Trost Matthias M Furic Luc L Larose Louise L Koromilas Antonis E AE Asano Katsura K Litchfield David D Larsson Ola O Topisirovic Ivan I

Nature communications 20160404

Ternary complex (TC) and eIF4F complex assembly are the two major rate-limiting steps in translation initiation regulated by eIF2α phosphorylation and the mTOR/4E-BP pathway, respectively. How TC and eIF4F assembly are coordinated, however, remains largely unknown. We show that mTOR suppresses translation of mRNAs activated under short-term stress wherein TC recycling is attenuated by eIF2α phosphorylation. During acute nutrient or growth factor stimulation, mTORC1 induces eIF2β phosphorylation ...[more]

PMID: 27040916

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Project description:BackgroundThe most commonly occurring cancer mutations, including oncogenes such as MYC, Ras and PIK3C, are found in signal transductions pathways feeding into the translational machinery. A broad range of translation initiation factors are also commonly found to be either amplified or mis-regulated in tumours, including eIF4E (elongation initiation factor 4E). eIF4E is a subunit of the eIF4F protein initiation complex and required for its recruitment. Here we measure the formation of the eIF4F complex through interactions of eIF4E and eIF4G subunits, and the effect of oncogenic signalling pathways on complex formation.ResultsWe developed a protein fragment complementation (PCA) assay that can accurately measure the status of the eIF4E-eIF4G interaction in cells and quantify the signalling flux through the RAS/ERK and PI3K/AKT pathways regulating eIF4F assembly. Complex disruption induced by inhibition of either pathway was shown to be a function of the phosphorylation status of 4EBP1, a key mediator of eIF4F assembly that interacts directly with eIF4E, confirming 4EBP1's ability to integrate multiple signals affecting cap-dependent translation. Maximal measured disruption of the eIF4F complex occurred under combined mTORC1 and mTORC2 inhibition, whilst combined inhibition of both RAS/ERK and PI3K/AKT pathways in parallel resulted in greater inhibition of eIF4F formation than individually. v-Myc-mediated resistance to dual mTORC/PI3K inhibition was also principally demonstrated to depend on the lack of competent 4EBP1 available in the cell to bind eIF4E.ConclusionsWe show that 4EBP1 is a critical regulator of the mitogen responsive RAS/ERK and PI3K/AKT pathways and a key transducer of resistance mechanisms that affect small molecule inhibition of these pathways, principally by attenuating their effects on cap-dependent translation. These findings highlight the importance of highly efficacious direct inhibitors of eIF4E and eIF4F assembly, which could potentially target a wide spectrum of tumours containing differing mutations that effect these pathways and which confer chemo-resistance.

Dataset Information

MTORC1 and CK2 coordinate ternary and eIF4F complex assembly.

Publications

mTORC1 and CK2 coordinate ternary and eIF4F complex assembly.

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