title: Characterization of a new family of cyclin-dependent kinase activators.
abstract: Progression through the cell cycle is regulated by CDKs (cyclin-dependent kinases), which associate with activating partners, named cyclins, to efficiently phosphorylate substrates. We previously reported the identification of RINGO, a Xenopus protein that can activate CDK1 and CDK2 despite lack of sequence similarity to cyclins, which plays a role in the regulation of the meiotic cell cycle in oocytes. In the present study we report the characterization of four mammalian RINGO proteins, which are 53-68% identical with Xenopus RINGO in a central core of about 75 residues. We show that all RINGO family members can bind to and activate CDK1 and CDK2, albeit with different efficiencies, but they do not bind to CDK4 or CDK6. The core RINGO sequences are critical for CDK activation. We also identified key residues in CDK2 that are required for RINGO binding. All RINGO proteins can also bind the CDK inhibitor p27Kip1, but with an inverse efficiency of their ability to bind to CDK1. Our results identify a new family of mammalian proteins that can activate CDKs and therefore potentially function as cell cycle regulators. The ability of RINGO proteins to activate CDK1 and CDK2 suggest also cyclin-independent roles for these kinases.
authors.affiliation: European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Dinarina
authors.forename: Laurent H
authors.initials: LH
authors.lastname: Perez
authors.forename: Amparo
authors.initials: A
authors.lastname: Davila
authors.forename: Markus
authors.initials: M
authors.lastname: Schwab
authors.forename: Tim
authors.initials: T
authors.lastname: Hunt
authors.forename: Angel R
authors.initials: AR
authors.lastname: Nebreda
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D042846:CDC2-CDC28 Kinases / Q000737:chemistry / Q000378:metabolism; D003001:Cloning, Molecular; D019295:Computational Biology / Q000379:methods; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D020536:Enzyme Activators / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009865:Oocytes / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D025941:Protein Interaction Mapping / Q000379:methods; D016415:Sequence Alignment / Q000379:methods; D017386:Sequence Homology, Amino Acid; D029867:Xenopus Proteins / Q000737:chemistry / Q000502:physiology
chemical_list: D020536:Enzyme Activators; D010446:Peptide Fragments; D029867:Xenopus Proteins; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases