TY - JOUR
T1 - MTORC1 and CK2 coordinate ternary and eIF4F complex assembly
AU - Gandin, Valentina
AU - Masvidal, Laia
AU - Cargnello, Marie
AU - Gyenis, Laszlo
AU - McLaughlan, Shannon
AU - Cai, Yutian
AU - Tenkerian, Clara
AU - Morita, Masahiro
AU - Balanathan, Preetika
AU - Jean-Jean, Olivier
AU - Stambolic, Vuk
AU - Trost, Matthias
AU - Furic, Luc
AU - Larose, Louise
AU - Koromilas, Antonis E.
AU - Asano, Katsura
AU - Litchfield, David
AU - Larsson, Ola
AU - Topisirovic, Ivan
N1 - Funding Information:
This research was supported by the Swedish Research Council, the Swedish Childhood Cancer Foundation, the Swedish Cancer Society, the Cancer Society in Stockholm, the Wallenberg Academy Fellows Program and STRATCAN grants (O.L.), and grants from the Canadian Institutes of Health Research (MOP-115195 to I.T., MOP-38160 to A.E.K. and MOP-37854 to D.L.) and Cancer Research Society to I.T. (01713). O.L., L.F. and I.T. are supported by the Swedish foundation for international cooperation in research and higher education (STINT). I.T. is a recipient of CIHR New Investigator Salary Award and recipient of La subvention d'etablissement de jeune chercheur-Junior 1 from Fonds de recherche du Quebec-Sante (FRQ-S). L.M. is supported by a postdoctoral fellowship from the Swedish Childhood Cancer Foundation. Y.C. and M.C. are supported by The McGill Integrated Cancer Research Training Program fellowship (MICRTP; M.C. and Y.C.) and internal McGill Faculty of Medicine Award (Y.C.). I.T. is indebted to Professor Roderick R. McInnes for allowing him to focus on science and not nonsense.
PY - 2016/4/4
Y1 - 2016/4/4
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84962707047
UR - https://www.scopus.com/pages/publications/84962707047#tab=citedBy
U2 - 10.1038/ncomms11127
DO - 10.1038/ncomms11127
M3 - Article
C2 - 27040916
AN - SCOPUS:84962707047
SN - 2041-1723
VL - 7
JO - Nature communications
JF - Nature communications
M1 - 11127
ER -