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Nat Commun. 2016 Apr 4;7:11127. doi: 10.1038/ncomms11127.

mTORC1 and CK2 coordinate ternary and eIF4F complex assembly.

Author information

1
Lady Davis Institute, SMBD JGH, McGill University, Montreal, Quebec, Canada H3T 1E2.
2
Department of Oncology, McGill University, Montreal, Quebec, Canada H3T 1E2.
3
Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3T 1E2.
4
Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada H3T 1E2.
5
Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm 171 76, Sweden.
6
Departments of Biochemistry and Oncology, Schulich School of Medicine &Dentistry, Western University, London, Ontario, Canada N6A 4L6.
7
Cancer Program, Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Victoria 3168, Australia.
8
UPMC Univ Paris 06, CNRS-UMR8256, Paris 75005, France.
9
Princess Margaret Cancer Centre, University Health Network, and the Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
10
MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Scotland DD1 5EH, UK.
11
Department of Medicine, Polypeptide Laboratory, McGill University and The Research Institute of McGill University Health Centre, Montreal, Quebec, Canada H3A 2B2.
12
Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, Kansas 66506, USA.

Abstract

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 and recruitment of NCK1 to eIF2, decreases eIF2α phosphorylation and bolsters TC recycling. Accordingly, eIF2β 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 eIF2β 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.

PMID:
27040916
PMCID:
PMC4822005
DOI:
10.1038/ncomms11127
[Indexed for MEDLINE]
Free PMC Article

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