mTORC1 and CK2 coordinate ternary and eIF4F complex assembly

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Casein Kinase II / genetics
  • Casein Kinase II / metabolism
  • Casein Kinase II / physiology*
  • Eukaryotic Initiation Factor-2 / metabolism
  • Eukaryotic Initiation Factor-2 / physiology
  • Eukaryotic Initiation Factor-4F / metabolism*
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • MCF-7 Cells
  • Mechanistic Target of Rapamycin Complex 1
  • Models, Genetic
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Multiprotein Complexes / physiology*
  • Oncogene Proteins / metabolism
  • Peptide Chain Initiation, Translational
  • Phosphorylation
  • Signal Transduction
  • Stress, Physiological
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • TOR Serine-Threonine Kinases / physiology*
  • Ternary Complex Factors / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Eukaryotic Initiation Factor-2
  • Eukaryotic Initiation Factor-4F
  • Multiprotein Complexes
  • Nck protein
  • Oncogene Proteins
  • Ternary Complex Factors
  • TOR Serine-Threonine Kinases
  • Casein Kinase II
  • Mechanistic Target of Rapamycin Complex 1