title: Phosphorylation of eukaryotic elongation factor 2 (eEF2) by cyclin A-cyclin-dependent kinase 2 regulates its inhibition by eEF2 kinase.
abstract: Protein synthesis is highly regulated via both initiation and elongation. One mechanism that inhibits elongation is phosphorylation of eukaryotic elongation factor 2 (eEF2) on threonine 56 (T56) by eEF2 kinase (eEF2K). T56 phosphorylation inactivates eEF2 and is the only known normal eEF2 functional modification. In contrast, eEF2K undergoes extensive regulatory phosphorylations that allow diverse pathways to impact elongation. We describe a new mode of eEF2 regulation and show that its phosphorylation by cyclin A-cyclin-dependent kinase 2 (CDK2) on a novel site, serine 595 (S595), directly regulates T56 phosphorylation by eEF2K. S595 phosphorylation varies during the cell cycle and is required for efficient T56 phosphorylation in vivo. Importantly, S595 phosphorylation by cyclin A-CDK2 directly stimulates eEF2 T56 phosphorylation by eEF2K in vitro, and we suggest that S595 phosphorylation facilitates T56 phosphorylation by recruiting eEF2K to eEF2. S595 phosphorylation is thus the first known eEF2 modification that regulates its inhibition by eEF2K and provides a novel mechanism linking the cell cycle machinery to translational control. Because all known eEF2 regulation is exerted via eEF2K, S595 phosphorylation may globally couple the cell cycle machinery to regulatory pathways that impact eEF2K activity.
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Asli A
authors.initials: AA
authors.lastname: Hizli
authors.forename: Yong
authors.initials: Y
authors.lastname: Chi
authors.forename: Jherek
authors.initials: J
authors.lastname: Swanger
authors.forename: John H
authors.initials: JH
authors.lastname: Carter
authors.forename: Yi
authors.initials: Y
authors.lastname: Liao
authors.forename: Markus
authors.initials: M
authors.lastname: Welcker
authors.forename: Alexey G
authors.initials: AG
authors.lastname: Ryazanov
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Clurman
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D019925:Cyclin A / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D054736:Elongation Factor 2 Kinase / Q000378:metabolism*; D006801:Humans; D008938:Mitosis; D008969:Molecular Sequence Data; D020652:Peptide Elongation Factor 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017354:Point Mutation; D012694:Serine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013912:Threonine / Q000737:chemistry / Q000378:metabolism
chemical_list: D019925:Cyclin A; D020652:Peptide Elongation Factor 2; D013912:Threonine; D012694:Serine; D054736:Elongation Factor 2 Kinase; D051357:Cyclin-Dependent Kinase 2