title: Hrr25/CK1δ-directed release of Ltv1 from pre-40S ribosomes is necessary for ribosome assembly and cell growth.
abstract: Casein kinase 1δ/ε (CK1δ/ε) and their yeast homologue Hrr25 are essential for cell growth. Further, CK1δ is overexpressed in several malignancies, and CK1δ inhibitors have shown promise in several preclinical animal studies. However, the substrates of Hrr25 and CK1δ/ε that are necessary for cell growth and survival are unknown. We show that Hrr25 is essential for ribosome assembly, where it phosphorylates the assembly factor Ltv1, which causes its release from nascent 40S subunits and allows subunit maturation. Hrr25 inactivation or expression of a nonphosphorylatable Ltv1 variant blocked Ltv1 release in vitro and in vivo, and prevented entry into the translation-like quality control cycle. Conversely, phosphomimetic Ltv1 variants rescued viability after Hrr25 depletion. Finally, Ltv1 knockdown in human breast cancer cells impaired apoptosis induced by CK1δ/ε inhibitors, establishing that the antiproliferative activity of these inhibitors is due, at least in part, to disruption of ribosome assembly. These findings validate the ribosome assembly pathway as a novel target for the development of anticancer therapeutics.
authors.affiliation: Department of Cancer Biology and Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458.
authors.forename: Homa
authors.initials: H
authors.lastname: Ghalei
authors.affiliation: Department of Cancer Biology and Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458 Department of Tumor Biology, Moffitt Cancer and Research Institute, Tampa, FL 33612.
authors.forename: Franz X
authors.initials: FX
authors.lastname: Schaub
authors.affiliation: Department of Cancer Biology and Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458.
authors.forename: Joanne R
authors.initials: JR
authors.lastname: Doherty
authors.affiliation: Department of Cancer Biology and Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Noguchi
authors.affiliation: Department of Cancer Biology and Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458.
authors.forename: William R
authors.initials: WR
authors.lastname: Roush
authors.affiliation: Department of Cancer Biology and Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458 Department of Tumor Biology, Moffitt Cancer and Research Institute, Tampa, FL 33612.
authors.forename: John L
authors.initials: JL
authors.lastname: Cleveland
authors.affiliation: Department of Biological Science and Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306 Department of Biological Science and Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306.
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Stroupe
authors.affiliation: Department of Cancer Biology and Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458 kkarbst@scripps.edu.
authors.forename: Katrin
authors.initials: K
authors.lastname: Karbstein
mesh_terms: D047389:Casein Kinase I / Q000502:physiology*; D048148:Casein Kinase Idelta / Q000502:physiology*; D045744:Cell Line, Tumor; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D012269:Ribosomal Proteins / Q000378:metabolism; D054682:Ribosome Subunits, Small, Eukaryotic / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism* / Q000502:physiology*
chemical_list: C104527:ENP1 protein, S cerevisiae; C501335:LTV1 protein, S cerevisiae; D009687:Nuclear Proteins; C501334:RPS3 protein, S cerevisiae; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; D047389:Casein Kinase I; D048148:Casein Kinase Idelta; C070775:HRR25 protein, S cerevisiae