title: The CK2 kinase stabilizes CLOCK and represses its activity in the Drosophila circadian oscillator.
abstract: Phosphorylation is a pivotal regulatory mechanism for protein stability and activity in circadian clocks regardless of their evolutionary origin. It determines the speed and strength of molecular oscillations by acting on transcriptional activators and their repressors, which form negative feedback loops. In Drosophila, the CK2 kinase phosphorylates and destabilizes the PERIOD (PER) and TIMELESS (TIM) proteins, which inhibit CLOCK (CLK) transcriptional activity. Here we show that CK2 also targets the CLK activator directly. Downregulating the activity of the catalytic α subunit of CK2 induces CLK degradation, even in the absence of PER and TIM. Unexpectedly, the regulatory β subunit of the CK2 holoenzyme is not required for the regulation of CLK stability. In addition, downregulation of CK2α activity decreases CLK phosphorylation and increases per and tim transcription. These results indicate that CK2 inhibits CLK degradation while reducing its activity. Since the CK1 kinase promotes CLK degradation, we suggest that CLK stability and transcriptional activity result from counteracting effects of CK1 and CK2.
authors.affiliation: Institut de Neurobiologie Alfred Fessard, Centre National de la Recherche Scientifique Unité Propre de Recherche 3294, Gif-sur-Yvette, France ; Département de Biologie, Université Paris Sud, Orsay, France.
authors.forename: Aron
authors.initials: A
authors.lastname: Szabó
authors.forename: Christian
authors.initials: C
authors.lastname: Papin
authors.forename: Daniela
authors.initials: D
authors.lastname: Zorn
authors.forename: Prishila
authors.initials: P
authors.lastname: Ponien
authors.forename: Frank
authors.initials: F
authors.lastname: Weber
authors.forename: Thomas
authors.initials: T
authors.lastname: Raabe
authors.forename: François
authors.initials: F
authors.lastname: Rouyer
mesh_terms: D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation
chemical_list: D029721:Drosophila Proteins; C096445:tim protein, Drosophila; D056926:CLOCK Proteins