Journal Article

mTORC1 and CK2 coordinate ternary and eIF4F complex assembly

Gandin, Valentina, Masvidal, Laia, Trost, Matthias, Litchfield, David, Balanathan, Preetika, Morita, Masahiro, Jean-Jean, Olivier, Cargnello, Marie, Tenkerian, Clara, Furic, Luc, Topisirovic, Ivan, Stambolic, Vuk, Larsson, Ola, Asano, Katsura, Gyenis, Laszlo, McLaughlan, Shannon, Cai, Yutian, Koromilas, Antonis E., Larose, Louise

2016

Overview

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. Ternary complex (TC) and eIF4F complex assembly are rate-limiting steps in translation initiation that are regulated by eIF2α phosphorylation and the mTOR/4E-BP pathway. Here the authors show that the protein kinases mTORC1 and CK2 coordinate TC and eIF4F complex assembly through eIF2β to stimulate cell proliferation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/106 / 13/109 / 13/89 / 13/95 / 38/39 / 38/77 / 631/45/607/275 / 631/45/612/1230 / 631/80/458/1733 / 631/80/83/2359 / Adaptor Proteins, Signal Transducing - metabolism / Biochemistry, Molecular Biology / 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 / Humanities and Social Sciences / Humans / Life Sciences / MCF-7 Cells / Mechanistic Target of Rapamycin Complex 1 / Models, Genetic / multidisciplinary / Multiprotein Complexes - genetics / Multiprotein Complexes - metabolism / Multiprotein Complexes - physiology / Oncogene Proteins - metabolism / Peptide Chain Initiation, Translational / Phosphorylation / Protein synthesis / Science / Science (multidisciplinary) / Signal Transduction / Stress, Physiological / Ternary Complex Factors - metabolism / TOR Serine-Threonine Kinases - genetics / TOR Serine-Threonine Kinases - metabolism / TOR Serine-Threonine Kinases - physiology