GRK2 Fine-Tunes Circadian Clock Speed and Entrainment via Transcriptional and Post-translational Control of PERIOD Proteins

Mehta, Neel; Cheng, Arthur H.; Chiang, Cheng‐Kang; Mendoza-Viveros, Lucía; Ling, Harrod H.; Patel, Abhilasha; Xu, Bo; Figeys, Daniel; Cheng, Hai-Ying Mary

doi:10.1016/j.celrep.2015.07.037

Cited by 17 publications

(15 citation statements)

References 33 publications

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“…The purpose of this study, therefore, was to extend our understanding of the functions of PER1/2 proteins by determining the localization of their expression within the SCN. In WT mice, PER1/2 protein abundance exhibits robust rhythms that peak in the early subjective night (Field et al, 2000;Mehta et al, 2015). We sought to determine whether at their peak both PER1/2 expression occurs in all SCN neurons and regions, and if not, whether expression of each of these proteins is locally clustered or dispersed within the SCN.…”

Section: Introductionmentioning

confidence: 99%

Differential localization of PER1 and PER2 in the brain master circadian clock

Riddle

Mezias

Foley

et al. 2016

Eur J of Neuroscience

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The hypothalamic suprachiasmatic nucleus (SCN), locus of the master circadian clock, bears many neuronal types. At the cellular-molecular level, the clock is comprised of feedback loops involving “clock” genes including Period1 and Period2, and their protein products, PERIOD1 and PERIOD2 (PER1/2). In the canonical model of circadian oscillation, the PER1/2 proteins oscillate together. While their rhythmic expression in the SCN as a whole has been described, the possibility of regional differences is unknown. To explore these clock proteins in distinct SCN regions, we assessed their expression through the rostro-caudal extent of the SCN in sagittal sections. We developed an automated method for tracking three fluorophores in digital images of sections triply labelled for PER1, PER2, and gastrin releasing peptide (used to locate the core). In the SCN as a whole, neurons expressing high levels of PER2 were concentrated in the rostral, rostrodorsal and caudal portions of the nucleus, and those expressing high levels of PER1 lay in a broad central area. Within these overall patterns, adjacent cells differed in expression levels of the two proteins. The results demonstrate spatially distinct localization of high PER1 vs. PER2 expression, raising the possibility that their distribution is functionally significant in encoding and communicating temporal information. The findings provoke the question of whether there are fundamental differences in PER1/2 levels among SCN neurons and/or whether topographical differences in protein expression are a product of SCN network organization rather than intrinsic differences among neurons.

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Section: Introductionmentioning

confidence: 99%

Differential localization of PER1 and PER2 in the brain master circadian clock

Riddle

Mezias

Foley

et al. 2016

Eur J of Neuroscience

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“…Further studies have identified Ser661 and Ser663 of mouse PER1 as being important CKIε-dependent nuclear localization 44 . For PER2, PKCα and G-protein-coupled receptor kinase 2 (GRK2) promote phosphorylation and cytosolic retention, both of which are important for the lightinduced phase shifts of mouse behavioral rhythms 45,46 .…”

Section: Nuclear Entry Of Per Regulated By Phosphorylation and Proteimentioning

confidence: 99%

The intricate dance of post-translational modifications in the rhythm of life

Hirano

Ptáček

2016

Nat Struct Mol Biol

149

135

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“…CK2 phosphorylates PER2 at Ser53 and promotes PER2 proteasomal degradation in both CK1δ/ε-dependent and-independent pathways [42]. PKCα [43] and GRK2 [44] regulate the nuclear entry of PER2 and might affect the stability of PER2. In this study, we showed that PER2-S478A mutation attenuated CK1δ/ε-mediated degradation of PER2 protein and lengthened the circadian period.…”

Section: Discussionmentioning

confidence: 99%

Mutation of a PER2 phosphodegron perturbs the circadian phosphoswitch

Masuda

Narasimamurthy

Yoshitane

et al. 2019

Preprint

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AbstractCasein kinase 1 (CK1) plays a central role in regulating the period of the circadian clock. In mammals, PER2 protein abundance is regulated by CK1-mediated phosphorylation and proteasomal degradation. On the other hand, recent studies have questioned whether the degradation of the core circadian machinery is a critical step in clock regulation. Prior cell-based studies found that CK1 phosphorylation of PER2 at Ser478 recruits the ubiquitin E3 ligase β-TrCP, leading to PER2 degradation. Creation of this phosphodegron is regulated by a phosphoswitch that is also implicated in temperature compensation. However, in vivo evidence that this phosphodegron influences circadian period is lacking. Here, we generated and analyzed PER2-Ser478Ala knock-in mice. The mice showed longer circadian period in behavioral analysis. Molecularly, mutant PER2 protein accumulated in both the nucleus and cytoplasm of the mouse liver, while Per2 mRNA levels were minimally affected. Nuclear PER1, CRY1 and CRY2 proteins also increased, probably due to stabilization of PER2-containing complexes. In mouse embryonic fibroblasts derived from PER2-Ser478Ala::LUC mice, three-phase decay and temperature compensation of the circadian period was perturbed. These data provide direct in vivo evidence for the importance of phosphorylation-regulated PER2 stability in the circadian clock and validate the phosphoswitch in a mouse model.

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GRK2 Fine-Tunes Circadian Clock Speed and Entrainment via Transcriptional and Post-translational Control of PERIOD Proteins

Cited by 17 publications

References 33 publications

Differential localization of PER1 and PER2 in the brain master circadian clock

Differential localization of PER1 and PER2 in the brain master circadian clock

The intricate dance of post-translational modifications in the rhythm of life

Mutation of a PER2 phosphodegron perturbs the circadian phosphoswitch

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