Role for Slimb in the degradation of Drosophila Period protein phosphorylated by Doubletime

@article{Ko2002RoleFS,
  title={Role for Slimb in the degradation of Drosophila Period protein phosphorylated by Doubletime},
  author={Hyuk Wan Ko and Jin Jiang and Isaac Edery},
  journal={Nature},
  year={2002},
  volume={420},
  pages={673-678}
}
Protein phosphorylation has a key role in modulating the stabilities of circadian clock proteins in a manner specific to the time of day. A conserved feature of animal clocks is that Period (Per) proteins undergo daily rhythms in phosphorylation and levels, events that are crucial for normal clock progression. Casein kinase Iε (CKIε) has a prominent role in regulating the phosphorylation and abundance of Per proteins in animals. This was first shown in Drosophila with the characterization of… 
The DOUBLETIME protein kinase regulates phosphorylation of the Drosophila PDP1ε
TLDR
Evidence is presented that Par Domain Protein 1ε (PDP1ε), a transcription factor and mediator of clock output in Drosophila, is phosphorylated in vivo and in cultured cells by DBT activity and that DBT regulates phosphorylation, stability and localization of PDP1ε, and that it has multiple targets in the Drosophile circadian system.
Balance between DBT/CKIepsilon kinase and protein phosphatase activities regulate phosphorylation and stability of Drosophila CLOCK protein.
  • E. Y. Kim, I. Edery
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2006
TLDR
It is shown that DBT activity is required for the phase-specific hyperphosphorylation of CLK in vivo, an event that correlates with times of maximal repression in per RNA levels, and support a conserved role for dynamic regulation of reversible phosphorylation in directly modulating the activities of circadian transcription factors.
A DOUBLETIME Kinase Binding Domain on the Drosophila PERIOD Protein Is Essential for Its Hyperphosphorylation, Transcriptional Repression, and Circadian Clock Function
TLDR
These findings indicate that the binding of dPER to CLK is not sufficient for transcriptional inhibition, implicating a more indirect mode of action whereby dPER acts as a molecular bridge to “deliver” DBT and/or other factors that directly repress CLK-dependent gene expression.
Activating PER Repressor through a DBT-Directed Phosphorylation Switch
TLDR
This study examines the role of the protein kinase Doubletime (DBT), a Drosophila ortholog of human casein kinase I (CKI)ɛ/δ, and shows that several DBT-directed phosphorylations regulate PER activity in an integrated fashion.
Ribosomal S6 Kinase Cooperates with Casein Kinase 2 to Modulate the Drosophila Circadian Molecular Oscillator
TLDR
It is proposed that the two kinases cooperate within clock neurons to fine-tune circadian period, improving the precision of the clock mechanism.
The phospho-occupancy of an atypical SLIMB-binding site on PERIOD that is phosphorylated by DOUBLETIME controls the pace of the clock.
TLDR
It is proposed that the gradual DBT-mediated phosphorylation of a nonconsensus SLIMB-binding site establishes a temporal threshold for when in a daily cycle the majority of PER proteins are tagged for rapid degradation.
Control of Mammalian Circadian Rhythm by CKIε-Regulated Proteasome-Mediated PER2 Degradation
TLDR
A cell-based model of PER2 degradation provides a biochemical mechanism and functional relevance for the observed phosphorylation-degradation cycle of mammalian PER2, and supports the idea that CKIε inhibition causes a significant lengthening of circadian period in synchronized Rat-1 cells.
Kinetics of Doubletime Kinase-dependent Degradation of the Drosophila Period Protein*
TLDR
The study provides a simple model in which the changes in Drosophila behavioral rhythms can be explained solely by changes in the rate of PER degradation, which resembles that with wild-type DBT.
The proteasome-dependent degradation of CKB4 is regulated by the Arabidopsis biological clock.
TLDR
It is demonstrated that the nuclear-localized CKB4 protein exists in vivo as different isoforms, resulting from phosphorylation on serine residues, and that the phosphorylated isoforms are the preferred substrate for ubiquitination and degradation by the proteasome pathway.
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