Cyclin-dependent Kinase 5 (Cdk5) Regulates the Function of CLOCK Protein by Direct Phosphorylation

Kwak, Yongdo; Jeong, Jong Ju; Lee, Saebom; Park, Young Un; Lee, Seol Ae; Han, Dong Hee; Kim, Joung Hun; Ohshima, Toshio; Mikoshiba, Katsuhiko; Suh, Yoo‐Hun; Cho, Sehyung; Park, Sang Ki

doi:10.1074/jbc.m113.494856

Cited by 37 publications

(46 citation statements)

References 58 publications

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“…S4) for being strongly circadian regulated. The average phase difference (±SEM) between circadian alignment and misalignment of these 30 strongly circadian-regulated proteins is 2.2 h ± 0.2 h. Of these 30 circadian-regulated proteins, 23 have not previously been identified as being circadian regulated (Dataset S1), and previous findings suggest two of the circadian-regulated proteins, Lamin-B1 (43) and cyclindependent kinase-5 (44), interact with the molecular circadian clock and more specifically that cyclin-dependent kinase-5 can phosphorylate the CLOCK protein (44). When circadian aligned, 20 of these 30 circadian-regulated proteins peaked between 1400 h and 1900 h (relative clock hour), and, similarly, when circadian misaligned, 19 of these 30 circadian-regulated proteins peaked between 1400 h and 2100 h ( Fig.…”

Section: Proteins With 24-h Time-of-day Patterns and With Alterationsmentioning

confidence: 95%

Mistimed food intake and sleep alters 24-hour time-of-day patterns of the human plasma proteome

Depner

Melanson

McHill

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Proteomics holds great promise for understanding human physiology, developing health biomarkers, and precision medicine. However, how much the plasma proteome varies with time of day and is regulated by the master circadian suprachiasmatic nucleus brain clock, assessed here by the melatonin rhythm, is largely unknown. Here, we assessed 24-h time-of-day patterns of human plasma proteins in six healthy men during daytime food intake and nighttime sleep in phase with the endogenous circadian clock (i.e., circadian alignment) versus daytime sleep and nighttime food intake out of phase with the endogenous circadian clock (i.e., circadian misalignment induced by simulated nightshift work). We identified 24-h time-of-day patterns in 573 of 1,129 proteins analyzed, with 30 proteins showing strong regulation by the circadian cycle. Relative to circadian alignment, the average abundance and/or 24-h time-of-day patterns of 127 proteins were altered during circadian misalignment. Altered proteins were associated with biological pathways involved in immune function, metabolism, and cancer. Of the 30 circadian-regulated proteins, the majority peaked between 1400 hours and 2100 hours, and these 30 proteins were associated with basic pathways involved in extracellular matrix organization, tyrosine kinase signaling, and signaling by receptor tyrosine-protein kinase erbB-2. Furthermore, circadian misalignment altered multiple proteins known to regulate glucose homeostasis and/or energy metabolism, with implications for altered metabolic physiology. Our findings demonstrate the circadian clock, the behavioral wake-sleep/food intake-fasting cycle, and interactions between these processes regulate 24-h time-of-day patterns of human plasma proteins and help identify mechanisms of circadian misalignment that may contribute to metabolic dysregulation.

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Section: Proteins With 24-h Time-of-day Patterns and With Alterationsmentioning

confidence: 95%

Mistimed food intake and sleep alters 24-hour time-of-day patterns of the human plasma proteome

Depner

Melanson

McHill

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…Phosphorylation-deficient forms of CLOCK and BMAL1 exhibit less transcriptional activity and greater stability than the wild-type proteins, in agreement with a model in which unstable CLOCK and BMAL1 have higher activity 87,88 . Similarly, Thr451 and Thr461 in CLOCK are phosphorylated by cyclin-dependent kinase 5 (Cdk5) and consequently degraded 89 , thus resulting in increased CLOCK-mediated transactivation. In the peripheral clock, knockout Q13 Q13 P P P P P P P P P P P P P P P P P P P P P P P P P P P Debbie Maizels/Nature Publishing Group Figure 4 Temporal regulation of CLOCK-BMAL1 activity.…”

Section: Q12 Q12mentioning

confidence: 99%

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

Hirano

Ptáček

2016

Nat Struct Mol Biol

155

141

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“…Phosphorylation decreases the stability of CLOCK and BMAL1 but promotes their activity 85 , 86 . Cyclin-dependent kinase 5 (CDK5) phosphorylates CLOCK at Thr451 and Thr461 87 . GSK-3 phosphorylates CLOCK at Ser427 and BMAL1 at Ser17 85 , 86 .…”

Section: Regulatory Mechanisms Of the Ttflsmentioning

confidence: 99%

Extracellular Vesicles: Potential Participants in Circadian Rhythm Synchronization

Tao¹,

Guo²

2018

Int. J. Biol. Sci.

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The circadian rhythm (CR) is a set of autonomous endogenous oscillators. Exposure to the 24-hour day-night cycle synchronizes our CR system, maintaining homeostasis and human health. Several mechanisms for the CR system have been proposed, including those underlying the function (transcriptional-translational negative-feedback loops, or TTFLs), mechanisms regulating the TTFLs, and the mechanism by which the “server clock” is synchronized to environmental time. Several pathways downstream of the “server clock” perform well-characterized biological functions. However, the synchronization between the “server clock” (the endogenous master clock seated in the suprachiasmatic nucleus within the hypothalamus) and the “client clock” (imbedded in nearly every cell in the form of interlocking TTFLs) is difficult to explain with current theories. Extracellular vesicles (EVs), which are involved in intercellular communication and have recently been found to participate in regulation of the “client clock”, might be the answer to this question. In this review, we summarize the current knowledge of CRs, TTFLs, and EVs, examine research findings about the functions of EVs in the CR system, and discuss the issues requiring attention in future research.

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Cyclin-dependent Kinase 5 (Cdk5) Regulates the Function of CLOCK Protein by Direct Phosphorylation

Cited by 37 publications

References 58 publications

Mistimed food intake and sleep alters 24-hour time-of-day patterns of the human plasma proteome

Mistimed food intake and sleep alters 24-hour time-of-day patterns of the human plasma proteome

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

Extracellular Vesicles: Potential Participants in Circadian Rhythm Synchronization

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