A role for casein kinase 2α in the Drosophila circadian clock

Lin, Jul Ming; Kilman, Valerie L.; Keegan, Kevin P.; Paddock, Brie; Emery-Le, Myai; Rosbash, Michael; Allada, Ravi

doi:10.1038/nature01235

Cited by 324 publications

(399 citation statements)

References 28 publications

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“…The roles of CKI and CKII appear to be conserved in various eukaryotic circadian systems Price et al 1998;Sugano et al 1999;Lowrey et al 2000;Gorl et al 2001;Lin et al 2002;Yang et al 2002Yang et al , 2003Akten et al 2003). Recent evidence in Drosophila and Neurospora further demonstrated that the proteasomemediated degradation of the phosphorylated clock proteins are both mediated by a conserved F-box/WD40-repeat-containing protein (Grima et al 2002;Ko et al 2002;He et al 2003).…”

Section: Genes and Developmentmentioning

confidence: 99%

“…Furthermore, it has been shown that PP2A can form complexes with CKII or a calciumcalmodulin-dependent kinase (Heriche et al 1997;Westphal et al 1998), suggesting that phosphorylation and dephosphorylation of cellular proteins are tightly coupled. Interestingly, both CKII and a calciumcalmodulin-dependent kinase were shown to be FRQ kinases in Neurospora (Yang et al 2001, raising the possibility that the functions of CKII and CAMK-1 in FRQ phosphorylation are regulated by PP2A.The roles of CKI and CKII appear to be conserved in various eukaryotic circadian systems Price et al 1998;Sugano et al 1999;Lowrey et al 2000;Gorl et al 2001;Lin et al 2002;Yang et al 2002Yang et al , 2003Akten et al 2003). Recent evidence in Drosophila and Neurospora further demonstrated that the proteasomemediated degradation of the phosphorylated clock proteins are both mediated by a conserved F-box/WD40-repeat-containing protein (Grima et al 2002;Ko et al 2002;He et al 2003).…”

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confidence: 99%

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Distinct roles for PP1 and PP2A in the Neurospora circadian clock

Yang¹,

He²,

Cheng³

et al. 2004

Genes Dev.

111

116

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Phosphorylation of the Neurospora circadian clock protein FREQUENCY by several kinases promotes its degradation and is important for the function of the circadian feedback loop. Here, we show that FRQ is less stable in a ppp-1 (catalytic subunit of PP1) mutant, resulting in its advanced phase and short period. In contrast, FRQ stability is not altered in a rgb-1 (a regulatory subunit of PP2A) mutant, but levels of frq protein and mRNA are low, resulting in a low-amplitude and longperiod oscillation of the clock. Furthermore, PP1 and PP2A expressed in Neurospora can dephosphorylate the endogenous FRQ in vitro, suggesting that these two phosphatases may differentially regulate FRQ and, consequently, the behavior of the circadian clock.Supplemental material is available at http://www.genesdev.org.Received September 15, 2003; revised version accepted December 15, 2003. Reversible phosphorylation is an important regulatory mechanism for many biological processes in eukaryotic organisms. The phosphorylation state of a protein is controlled dynamically by protein kinases and phosphatases. Previous studies have demonstrated that phosphorylation of circadian clock proteins is an essential posttranscriptional mechanism in the regulation of circadian clocks (Dunlap 1999;Young and Kay 2001). Several kinases, including casein kinase I (CKI) and CKII, have been shown to phosphorylate and regulate the key clock components in eukaryotic systems Sugano et al. 1999;Lowrey et al. 2000;Gorl et al. 2001;Yang et al. 2002).FREQUENCY (FRQ), WHITE COLLAR-1 (WC-1), and WC-2 proteins are three key components in the Neurospora frq-wc-based circadian oscillator . In addition to being the circadian blue light photoreceptor (Froehlich et al. 2002;He et al. 2002), in the dark, WC-1 forms a heterodimeric complex with WC-2 through their PAS domains and activate frq transcription by binding its promoter (Crosthwaite et al. 1997;Talora et al. 1999;Cheng et al. 2001bCheng et al. , 2002Cheng et al. , 2003Froehlich et al. 2003). FRQ, the negative element of the feedback loop, inhibits its own transcription through interactions with the WC complex (Aronson et al. 1994;Cheng et al. 2001a;Denault et al. 2001;Froehlich et al. 2003). FRQ protein is immediately phosphorylated after its synthesis and becomes extensively phosphorylated prior to its degradation by the ubiquitin/proteasome pathway Liu et al. 2000;He et al. 2003). In constant darkness, FRQ is not only robustly rhythmic in its cellular concentration, but also in its phosphorylation states, so that the level and the phosphorylation status of FRQ define the time of the clock during a circadian cycle .Phoshorylation of FRQ is mediated by CKI, CKII, and a calcium/calmodulin-dependent kinase (Gorl et al. 2001;Yang et al. 2001Yang et al. , 2002Yang et al. , 2003. Molecular, genetic, and biochemical experiments have shown that phosphorylation of FRQ has several functions. Mutations of the FRQ phosphorylation sites lead to the stabilization of the FRQ protein and long period rhythms of the clock (Li...

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Section: Genes and Developmentmentioning

confidence: 99%

mentioning

confidence: 99%

Distinct roles for PP1 and PP2A in the Neurospora circadian clock

Yang¹,

He²,

Cheng³

et al. 2004

Genes Dev.

111

116

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“…In addition, Drosophila casein kinase 2 (dCK2) was shown to phosphorylate dPER. This phosphorylation predominantly functions in the regulation of the subcellular localization of dPER by promoting its nuclear entry and accumulation, whereas its effects on dPER stability are rather weak (Lin et al 2002(Lin et al , 2005Akten et al 2003). Moreover, Shaggy-the Drosophila homolog of mammalian glycogen synthase kinase 3β (GSK3β)-phosphorylates dTIM, the essential binding partner of dPER, thereby promoting the nuclear entry of the PER/TIM heterodimer (Martinek et al 2001).…”

Section: Kinases and Phosphatasesmentioning

confidence: 99%

Role of Phosphorylation in the Mammalian Circadian Clock

Vanselow¹,

Kramer²

2007

Cold Spring Harbor Symposia on Quantitative Biology

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Circadian clocks regulate a wide variety of processes ranging from gene expression to behavior. At the molecular level, circadian rhythms are thought to be produced by a set of clock genes and proteins interconnected to form transcriptional-translational feedback loops. Rhythmic gene expression was formerly regarded as the major drive for rhythms in clock protein abundance, but recent findings underline the crucial importance of posttranslational mechanisms for both the generation and dynamics of circadian rhythms. In particular, the reversible phosphorylation of PER proteins-essential components within the negative feedback loop in Drosophila and mammals-seems to have a key role for the correct timing of nuclear repression. To understand how PER protein phosphorylation regulates the dynamics of the circadian oscillator, we have mapped endogenous phosphorylation sites in mPER2. Detailed investigation of the functional role of one particular phosphorylation site (Ser-659, which is mutated in the familial advanced sleep phase syndrome [FASPS]) led us propose a model of functionally different phosphorylation sites in PER2. This concept explains not only the FASPS phenotype, but also the effect of the tau mutation in hamster.

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“…SGG overexpression leads to hyperphosphorylated TIM and the PER/TIM heterodimer translocates into the nucleus ∼4 h early, shortening the period as CLK/CYC activity is inhibited prematurely [30]. Many other factors contribute to this loop, including DOUBLE-TIME (DBT), a Casein Kinase Iɛ homologue [23], Casein Kinase II [31,32], Protein Phosphatase 2A (PP2A) [33], the F-box protein SLIMB [34,35], and the blue light photoreceptor CRYPTOCHROME (CRY), that also doubles as a transcriptional repressor in some clock cells [26,36,37]. Attention has largely focussed on how these proteins regulate the stability of PER and TIM, although DBT and PP2A also regulate CLK activity [38], with hypophosphorylated CLK associated with maximal per transcription [29,38].…”

Section: The Drosophila Molecular Clockmentioning

confidence: 99%

Even a stopped clock tells the right time twice a day: circadian timekeeping in Drosophila

Collins

Blau

2007

Pflugers Arch - Eur J Physiol

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"Even a stopped clock tells the right time twice a day, and for once I'm inclined to believe Withnail is right. We are indeed drifting into the arena of the unwell... What we need is harmony. Fresh air. Stuff like that." Bruce Robinson (1986, ref. 1). Although a stopped Drosophila clock probably does not tell the right time even once a day, recent findings have demonstrated that accurate circadian time-keeping is dependent on harmony between groups of clock neurons within the brain. Furthermore, when harmony between the environment and the endogenous clock is lost, as during jet lag, we definitely feel unwell. In this review, we provide an overview of the current understanding of circadian rhythms in Drosophila, focussing on recent discoveries that demonstrate how approximately 100 neurons within the Drosophila brain control the behaviour of the whole fly, and how these rhythms respond to the environment.

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A role for casein kinase 2α in the Drosophila circadian clock

Cited by 324 publications

References 28 publications

Distinct roles for PP1 and PP2A in the Neurospora circadian clock

Distinct roles for PP1 and PP2A in the Neurospora circadian clock

Role of Phosphorylation in the Mammalian Circadian Clock

Even a stopped clock tells the right time twice a day: circadian timekeeping in Drosophila

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