Abstract
Circadian rhythms are intrinsic ~24 hour cycles that regulate diverse aspects of physiology, and in turn are regulated by interactions with the external environment. Casein kinase 1 delta (CK1δ, CSNK1D) is a key regulator of the clock, phosphorylating both stabilizing and destabilizing sites on the PER2 protein, in a mechanism known as the phosphoswitch. CK1δ can itself be regulated by phosphorylation on its regulatory domain, but the specific sites involved, and the role this plays in control of circadian rhythms as well as other CK1-dependent processes is not well understood. Using a sensitized PER2::LUC reporter assay, we identified a specific phosphorylation site, T347, on CK1δ, that regulates CK1δ activity towards PER2. A mutant CK1δ T347A was more active in promoting PER2 degradation. This CK1δ regulatory site is phosphorylated in cells in trans by dinaciclib- and staurosporine-sensitive kinases, consistent with their potential regulation by cyclin dependent and other proline-directed kinases. The regulation of CK1δ by site-specific phosphorylation via the cell cycle and other signaling pathways provides a mechanism to couple external stimuli to regulation of CK1δ-dependent pathways including the circadian clock.
Highlights
Circadian rhythms are intrinsic ~24 hour cycles of behavioral, neural, hormonal and biochemical processes occurring in most organisms exposed to daily changes in light and dark
These rhythms are controlled by a master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus, which in turn can be reset by external light cues via input from ganglion cells in the retina
Mutation of S659 to alanine (S659A) in the Familial Advanced Sleep Phase (FASP) region on mouse PER2 prevents phosphorylation of the FASP region and exposes the β-TrCP site to CK1, leading to a short half-life mutant PER2 that is sensitive to CK1 activity
Summary
Circadian rhythms are intrinsic ~24 hour cycles of behavioral, neural, hormonal and biochemical processes occurring in most organisms exposed to daily changes in light and dark. These rhythms are controlled by a master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus, which in turn can be reset by external light cues via input from ganglion cells in the retina. Circadian rhythms in diverse tissues coordinate tissue specific functions such as digestion, sleep, and motor activity. Disruption of circadian rhythms, for example by shift work, jet lag, or sleep deprivation increases the risk of multiple diseases including diabetes, heart disease, mood disorders, and cancer [3,4,5,6,7].
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