Regulation of BMAL1 Protein Stability and Circadian Function by GSK3β-Mediated Phosphorylation

Background Circadian rhythms govern a large array of physiological and metabolic functions. To achieve plasticity in circadian regulation, proteins constituting the molecular clock machinery undergo various post-translational modifications (PTMs), which influence their activity and intracellular loc...

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Bibliographic Details
Published in:PloS one 2010-01, Vol.5 (1), p.e8561
Main Authors: Sahar, Saurabh, Zocchi, Loredana, Kinoshita, Chisato, Borrelli, Emiliana, Sassone-Corsi, Paolo
Format: Article
Language:English
Subjects:
AKT protein
Biomedical materials
BMAL1 protein
Cell Biology
Cell Biology/Gene Expression
Cell cycle
Circadian rhythm
Circadian rhythms
CLOCK protein
Control
Control stability
Dopamine
Dopamine D2 receptors
Epigenetics
Gene expression
Glucose
Homeostasis
Kinases
Localization
Machinery
Mammals
Molecular Biology
Neostriatum
Pharmacology
Phosphorylation
Physiology
Plasmids
Post-translation
Proteins
Proteomics
Signal transduction
Signaling
Sleep
Surgical implants
Ubiquitin
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Summary:Background Circadian rhythms govern a large array of physiological and metabolic functions. To achieve plasticity in circadian regulation, proteins constituting the molecular clock machinery undergo various post-translational modifications (PTMs), which influence their activity and intracellular localization. The core clock protein BMAL1 undergoes several PTMs. Here we report that the Akt-GSK3β signaling pathway regulates BMAL1 protein stability and activity. Principal Findings GSK3β phosphorylates BMAL1 specifically on Ser 17 and Thr 21 and primes it for ubiquitylation. In the absence of GSK3β-mediated phosphorylation, BMAL1 becomes stabilized and BMAL1 dependent circadian gene expression is dampened. Dopamine D2 receptor mediated signaling, known to control the Akt-GSK3β pathway, influences BMAL1 stability and in vivo circadian gene expression in striatal neurons. Conclusions These findings uncover a previously unknown mechanism of circadian clock control. The GSK3β kinase phosphorylates BMAL1, an event that controls the stability of the protein and the amplitude of circadian oscillation. BMAL1 phosphorylation appears to be an important regulatory step in maintaining the robustness of the circadian clock.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0008561