title: 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 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.
authors.affiliation: Lady Davis Institute, SMBD JGH, McGill University, Montreal, Quebec, Canada H3T 1E2.|Department of Oncology, McGill University, Montreal, Quebec, Canada H3T 1E2.|Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3T 1E2.|Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada H3T 1E2.
authors.forename: Valentina
authors.initials: V
authors.lastname: Gandin
authors.affiliation: Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm 171 76, Sweden.
authors.forename: Laia
authors.initials: L
authors.lastname: Masvidal
authors.affiliation: Lady Davis Institute, SMBD JGH, McGill University, Montreal, Quebec, Canada H3T 1E2.|Department of Oncology, McGill University, Montreal, Quebec, Canada H3T 1E2.|Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3T 1E2.|Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada H3T 1E2.
authors.forename: Marie
authors.initials: M
authors.lastname: Cargnello
authors.affiliation: Departments of Biochemistry and Oncology, Schulich School of Medicine &Dentistry, Western University, London, Ontario, Canada N6A 4L6.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Gyenis
authors.affiliation: Lady Davis Institute, SMBD JGH, McGill University, Montreal, Quebec, Canada H3T 1E2.|Department of Oncology, McGill University, Montreal, Quebec, Canada H3T 1E2.|Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3T 1E2.|Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada H3T 1E2.
authors.forename: Shannon
authors.initials: S
authors.lastname: McLaughlan
authors.affiliation: Lady Davis Institute, SMBD JGH, McGill University, Montreal, Quebec, Canada H3T 1E2.|Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3T 1E2.
authors.forename: Yutian
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Lady Davis Institute, SMBD JGH, McGill University, Montreal, Quebec, Canada H3T 1E2.|Departments of Biochemistry and Oncology, Schulich School of Medicine &Dentistry, Western University, London, Ontario, Canada N6A 4L6.
authors.forename: Clara
authors.initials: C
authors.lastname: Tenkerian
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3T 1E2.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Morita
authors.affiliation: Cancer Program, Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Victoria 3168, Australia.
authors.forename: Preetika
authors.initials: P
authors.lastname: Balanathan
authors.affiliation: UPMC Univ Paris 06, CNRS-UMR8256, Paris 75005, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Jean-Jean
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, and the Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Vuk
authors.initials: V
authors.lastname: Stambolic
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Scotland DD1 5EH, UK.
authors.forename: Matthias
authors.identifier: http://orcid.org/0000-0002-5732-700X
authors.initials: M
authors.lastname: Trost
authors.affiliation: Cancer Program, Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Victoria 3168, Australia.
authors.forename: Luc
authors.initials: L
authors.lastname: Furic
authors.affiliation: Department of Medicine, Polypeptide Laboratory, McGill University and The Research Institute of McGill University Health Centre, Montreal, Quebec, Canada H3A 2B2.
authors.forename: Louise
authors.initials: L
authors.lastname: Larose
authors.affiliation: Lady Davis Institute, SMBD JGH, McGill University, Montreal, Quebec, Canada H3T 1E2.|Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada H3T 1E2.|Departments of Biochemistry and Oncology, Schulich School of Medicine &Dentistry, Western University, London, Ontario, Canada N6A 4L6.
authors.forename: Antonis E
authors.initials: AE
authors.lastname: Koromilas
authors.affiliation: Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, Kansas 66506, USA.
authors.forename: Katsura
authors.initials: K
authors.lastname: Asano
authors.affiliation: Departments of Biochemistry and Oncology, Schulich School of Medicine &Dentistry, Western University, London, Ontario, Canada N6A 4L6.
authors.forename: David
authors.initials: D
authors.lastname: Litchfield
authors.affiliation: Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm 171 76, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Larsson
authors.affiliation: Lady Davis Institute, SMBD JGH, McGill University, Montreal, Quebec, Canada H3T 1E2.|Department of Oncology, McGill University, Montreal, Quebec, Canada H3T 1E2.|Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3T 1E2.|Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada H3T 1E2.
authors.forename: Ivan
authors.identifier: http://orcid.org/0000-0002-5510-9762
authors.initials: I
authors.lastname: Topisirovic
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism / Q000502:physiology; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D008957:Models, Genetic; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015513:Oncogene Proteins / Q000378:metabolism; D010442:Peptide Chain Initiation, Translational; D010766:Phosphorylation; D015398:Signal Transduction; D013312:Stress, Physiological; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050801:Ternary Complex Factors / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015852:Eukaryotic Initiation Factor-2; D039562:Eukaryotic Initiation Factor-4F; D046912:Multiprotein Complexes; C078332:Nck protein; D015513:Oncogene Proteins; D050801:Ternary Complex Factors; D047390:Casein Kinase II; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases