Distinct roles for PP1 and PP2A in the <i>Neurospora</i> circadian clock

Yang, Yuhong; He, Qun; Cheng, Ping; Wrage, Philip C.; Yarden, Oded; Liu, Yi

doi:10.1101/gad.1152604

Cited by 111 publications

(122 citation statements)

References 41 publications

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“…A strain lacking functional RGB-1 (rgb-1 RIP ), a regulatory subunit of PP2A, is severely compromised in cell growth and displays irregular conidiation patterns with >24-h rhythms. Although FRQ stability is not altered, overall levels of frq RNA and FRQ protein are reduced in the rgb-1 RIP strain (Yang et al 2004). The low expression of frq RNA reflects a function of PP2A in activating WCC, the transcriptional activator of frq .…”

Section: Physical Properties Of Frqmentioning

confidence: 97%

“…FRQ is dephosphorylated by PP1 and PP2A in vitro, and both phosphatases regulate FRQ and the circadian clock in vivo in a specific manner (Yang et al 2004). It is not known whether these phosphatases are expressed in rhythmic fashion.…”

Section: Physical Properties Of Frqmentioning

confidence: 99%

“…Furthermore, protein kinases and phosphatases have been identified, which phosphorylate and dephosphorylate FRQ in vitro and affect FRQ phosphorylation status and clock function in vivo (Liu et al 2000;Görl et al 2001;Yang et al 2001Yang et al , 2002Yang et al , 2003Yang et al , 2004Schafmeier et al 2006). When putative phosphorylation sites are mutated or when the function of a particular kinase or phosphatase is compromised, the overall kinetics of FRQ turnover and/or clock function is affected.…”

Section: Physical Properties Of Frqmentioning

confidence: 99%

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Transcriptional and post-transcriptional regulation of the circadian clock of cyanobacteria and Neurospora

Brunner¹,

Schafmeier²

2006

Genes Dev.

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Circadian clocks are self-sustained oscillators modulating rhythmic transcription of large numbers of genes. Clock-controlled gene expression manifests in circadian rhythmicity of many physiological and behavioral functions. In eukaryotes, expression of core clock components is organized in a network of interconnected positive and negative feedback loops. This network is thought to constitute the pacemaker that generates circadian rhythmicity. The network of interconnected loops is embedded in a supra-net via a large number of interacting factors that affect expression and function of core clock components on transcriptional and post-transcriptional levels. In particular, phosphorylation and dephosphorylation of clock components are critical processes ensuring robust self-sustained circadian rhythmicity and entrainment of clocks to external cues. In cyanobacteria, three clock proteins have the capacity to generate a self-sustained circadian rhythm of autophosphorylation and dephosphorylation independent of transcription and translation. This phosphorylation rhythm regulates the function of these clock components, which then facilitate rhythmic gene transcription, including negative feedback on their own genes. In this article, we briefly present the mechanism of clock function in cyanobacteria. We then discuss in detail the contribution of transcriptional feedback and protein phosphorylation to various functional aspects of the circadian clock of Neurospora crassa.Circadian rhythms are found in numerous light-perceiving organisms including cyanobacteria, algae, fungi, plants, insects, and vertebrates. The rhythms are supported by cell-autonomous circadian clocks, which regulate expression of a large number of genes on the level of transcription (for review, see Transcriptional/translational feedback loops are hallmarks of circadian clocks in all organisms. In eukaryotes, expression of core clock components is organized in a complex network of interconnected positive and negative feedback loops (for review, see Dunlap and Loros 2004;Gachon et al. 2004;Hardin 2005). This network of gene expression is assumed to generate circadian rhythmicity. Elimination of key components of these interconnected loops disrupts many, if not all, rhythmic outputs, depending on the organism. Expression, subcellular localization, assembly, function, and turnover of clock components are crucial for circadian rhythmicity, and thus, the core clock is embedded in a supra-net of cellular machinery regulating various aspects of clock function. Protein phosphorylation and dephosphorylation are important regulatory mechanisms that are critical for self-sustained circadian rhythmicity and entrainment of clocks to external cues. It is unclear to what extent reversible phosphorylations are mechanistically instrumental for generation of rhythmicity in eukaryotic clocks.Recent findings have shown that clock proteins in cyanobacteria generate a self-sustained circadian rhythm of autophosphorylation and dephosphorylation, which is independent of tra...

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Section: Physical Properties Of Frqmentioning

confidence: 97%

Section: Physical Properties Of Frqmentioning

confidence: 99%

Section: Physical Properties Of Frqmentioning

confidence: 99%

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Transcriptional and post-transcriptional regulation of the circadian clock of cyanobacteria and Neurospora

Brunner¹,

Schafmeier²

2006

Genes Dev.

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“…We estimate that ∼40%-50% of WC-1 is degraded through this process. Phosphorylation-dependent protein degradation has been demonstrated for FRQ in Neurospora, a critical process regulating the circadian clock (Liu et al 2000;Gorl et al 2001;Yang et al 2002Yang et al , 2004He et al 2003).…”

Section: Photoadaptation In Neurosporamentioning

confidence: 99%

Molecular mechanism of light responses in Neurospora: from light-induced transcription to photoadaptation

He¹,

Liu²

2005

Genes Dev.

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“…Under normal physiological conditions, FRQ is phosphorylated by CK-1a, CKII, and PKA (21,22,(25)(26)(27)(28). On the other hand, FRQ is also dephosphorylated and stabilized by protein phosphatases PP1 and PP4 (20,29). In the ck-1a, cka, and ckb-1 mutants, FRQ is hypophosphorylated and more stable than in the wild-type strain, leading to arrhythmic or long period conidiation rhythms in constant darkness (22,26,27).…”

mentioning

confidence: 99%

Regulation of the Activity and Cellular Localization of the Circadian Clock Protein FRQ

Cha

Yuan

Liu

2011

Journal of Biological Chemistry

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Eukaryotic circadian clocks employ autoregulatory negative feedback loops to control daily rhythms. In the filamentous fungus Neurospora, FRQ, FRH, WC-1, and WC-2 are the core components of the circadian negative feedback loop. To close the transcription-based negative feedback loop, the FRQ-FRH complex inhibits the activity of the WC complex in the nucleus by promoting the casein kinases-mediated WC phosphorylation. Despite its essential role in the nucleus, most FRQ is found in the cytoplasm. In this study, we mapped the FRQ regions that are important for its cellular localization. We show that the C-terminal part of FRQ, particularly the FRQ-FRH interaction domain, plays a major role in controlling FRQ localization. Both the mutation of the FRQ-FRH interaction domain and the down-regulation of FRH result in the nuclear enrichment of FRQ, suggesting that FRH regulates FRQ localization via a physical interaction. To study the role of FRQ phosphorylation, we examined the FRQ localization in wild-type as well as an array of FRQ kinase, FRQ phosphatase, and FRQ phosphorylation site mutants. Collectively, our results suggest that FRQ phosphorylation does not play a significant role in regulating its cellular localization. Instead, we find that phosphorylation of FRQ inhibits its transcriptional repressor activity in the circadian negative feedback loop. Such an effect is achieved by inhibiting the ability of FRQ to interact with WCC and casein kinase 1a. Our results indicate that the rhythmic FRQ phosphorylation profile observed is an important part of the negative feedback mechanism that drives robust circadian gene expression.The eukaryotic circadian oscillators are comprised of autoregulatory negative feedback loops (1-5). Despite the evolutionary distance between the filamentous fungus Neurospora crassa and higher eukaryotes, their circadian oscillator mechanisms share remarkable similarities (6 -8). In N. crassa, two PAS (PER-ARNT-SIM) domain-containing transcription factors, WC-1 and WC-2, form a complex (WCC) 2 that activates the transcription of the frq gene by binding to its promoter (9 -13). FRQ protein binds FRH to form the FRQ-FRH complex (FFC), which acts as the negative element in the circadian negative feedback loop (14 -17). To close the circadian negative feedback loop, FFC decreases frq mRNA-levels by promoting frq mRNA degradation and by inhibiting frq transcription. To repress frq transcription, FFC inhibits WCC activity by recruiting casein kinase 1a (CK-1a) and CKII to phosphorylate the WC proteins, resulting in a decrease of WCC DNA binding activity and an increase of WCC nuclear export (9, 10, 14 -24). Like the animal PER proteins, FRQ is progressively phosphorylated upon its synthesis and becomes extensively phosphorylated before its disappearance, resulting in robust oscillations of its level and phosphorylation profile (25). Under normal physiological conditions, FRQ is phosphorylated by CK-1a, CKII, and PKA (21,22,(25)(26)(27)(28). On the other hand, FRQ is also dephosphorylated and st...

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Distinct roles for PP1 and PP2A in the Neurospora circadian clock

Cited by 111 publications

References 41 publications

Transcriptional and post-transcriptional regulation of the circadian clock of cyanobacteria and Neurospora

Transcriptional and post-transcriptional regulation of the circadian clock of cyanobacteria and Neurospora

Molecular mechanism of light responses in Neurospora: from light-induced transcription to photoadaptation

Regulation of the Activity and Cellular Localization of the Circadian Clock Protein FRQ

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