Regulation of Casein Kinase I ε and Casein Kinase I δ by anin Vivo Futile Phosphorylation Cycle

Rivers, Ann M.; Gietzen, Kimberly Fish; Vielhaber, Erica; Virshup, David M.

doi:10.1074/jbc.273.26.15980

Cited by 108 publications

(120 citation statements)

References 25 publications

Supporting

Mentioning

115

Contrasting

Order By: Relevance

“…We first used just the catalytic domain of wild-type CKI , lacking the C-terminal regulatory domain [⌬CKI (wt)] to prevent potential confusion that could result from the autophosphorylation of this regulatory domain and the subsequent repression of CKI kinase activity. This use of the catalytic domain was also justified by evidence that CKI is kept in a dephosphorylated, active state in vivo (35).…”

Section: Resultsmentioning

confidence: 99%

CKIε/δ-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock

Isojima

Nakajima

Ukai

et al. 2009

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

239

271

View full text Add to dashboard Cite

T he circadian clock is a molecular mechanism underlying endogenous, self-sustained oscillations with a period of Ϸ24 h, manifested in diverse physiological and metabolic processes (1-3). The most striking feature of circadian clock is its flexible yet robust response to various environmental conditions. For example, circadian periodicity varies with light intensity (4-6) while remaining robust over a wide range of temperatures (''temperature compensation'') (1, 3, 7-9). This flexible-yetrobust characteristic is evolutionarily conserved in organisms ranging from photosynthetic bacteria to warm-blooded mammals (3, 10-12), and has interested researchers from a broad range of disciplines. However, despite many genetic and molecular studies (13-22), the detailed biochemical mechanism underlying this characteristic remains poorly elucidated (3).The simplest explanation for this flexible-yet-robust property is that the key period-determining reactions are insensitive to temperature but responsive to other environmental conditions. Indeed, Pittendrigh proposed the existence of a temperatureinsensitive component in the clock system in 1954 (7), and in 1968, he and his colleagues demonstrated that both the wave form and the period of circadian oscillations are invariant with temperature (23). However, the idea of a temperatureinsensitive biochemical reaction is counterintuitive, as elementary chemical processes are highly temperature-sensitive. One exception is the cyanobacterial clock, in which temperatureinsensitive enzymatic reactions are observed (24,25). However, the cyanobacterial clock is quite distinct from other clock systems, and this biochemical mechanism has not been demonstrated in other clocks.Recently, a chemical-biological approach was proposed to help elucidate the basic processes underlying circadian clocks (26), and high-throughput screening of a large chemical compound library was performed (27). In this report, to analyze systematically the fundamental processes involved in determining the period length of mammalian clocks, we tested 1,260 pharmacologically active compounds for their effect on period length in mouse and human clock cell lines, and found 10 compounds that most markedly lengthened the period of both clock cell lines affected both the central and peripheral circadian clocks. Most compounds inhibited CKI or CKI␦ activity, suggesting that CKI /␦-dependent phosphorylation is an important period-determining process in the mammalian circadian clock. Surprisingly, the degradation rate of endogenous PER2, which is regulated by CKI -dependent phosphorylation (28) and probably by CKI␦-dependent phosphorylation, was temperatureinsensitive in the living clock cells, and the temperatureinsensitivity was preserved even for the in vitro CKI /␦-dependent phosphorylation of a synthetic peptide derived from PER2. These results suggest that this period-determining process is flexible in response to chemical perturbation yet robust in the face of temperature perturbations. Based on these findings, we prop...

show abstract

Section: Resultsmentioning

confidence: 99%

CKIε/δ-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock

Isojima

Nakajima

Ukai

et al. 2009

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

239

271

View full text Add to dashboard Cite

show abstract

“…The C-terminal 125 amino acids of CK1␦ is ϳ50% identical to the corresponding domain of CK1⑀. In addition, several in vitro studies have found that the activity of CK1␦, like CK1⑀, is regulated by autophosphorylation (16,26). In vitro studies have also indicated that all three CK1␥ isoforms can be autophosphorylated (16), raising the possibility that these isoforms are regulated as well.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Regulation of Casein Kinase I Activity by Group I Metabotropic Glutamate Receptors

Liu¹,

Virshup²,

Nairn³

et al. 2002

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Previously, we reported that (S)-3,5-dihydroxypenylglycine (DHPG), an agonist for group I metabotropic glutamate receptors (mGluRs), stimulates CK1 and Cdk5 kinase activities in neostriatal neurons, leading to enhanced phosphorylation, respectively, of Ser-137 and Thr-75 of DARPP-32 (dopamine and cAMP-regulated phosphoprotein, 32 kDa). We have now investigated the signaling pathway that leads from mGluRs to casein kinase 1 (CK1) activation. In mouse neostriatal slices, the effect of DHPG on phosphorylation of Ser-137 or Thr-75 of DARPP-32 was blocked by the phospholipase C␤ inhibitor U73122, the Ca 2؉ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid (BAPTA/ AM), and the calcineurin inhibitor cyclosporin A. In neuroblastoma N2a cells, the effect of DHPG on the activity of transfected HA-tagged CK1⑀ was blocked by BAPTA/AM and cyclosporin A. In neostriatal slices, the effect of DHPG on Cdk5 activity was also abolished by BAPTA/AM and cyclosporin A, presumably through blocking activation of CK1. Metabolic labeling studies and phosphopeptide mapping revealed that a set of C-terminal sites in HA-CK1⑀ were transiently dephosphorylated in N2a cells upon treatment with DHPG, and this was blocked by cyclosporin A. A mutant CK1⑀ with a nonphosphorylatable C-terminal domain was not activated by DHPG. Together, these studies suggest that DHPG activates CK1⑀ via Ca 2؉ -dependent stimulation of calcineurin and subsequent dephosphorylation of inhibitory C-terminal autophosphorylation sites. Casein kinase 1 (CK1)1 was one of the first serine/threonine protein kinases to be isolated and characterized. There are at least seven mammalian CK1 isoforms (␣, ␤, ␥1, ␥2, ␥3, ␦, and ⑀ (1, 2)), and distinct CK1 family members are likely to have a variety of roles in eukaryotic cells. An increasing number of potential physiologic substrates for CK1 isoforms have been identified. CK1␣ phosphorylates M1 and M3 muscarinic receptors and rhodopsin in an agonist-dependent manner (3, 4). CK1⑀ and CK1␦ phosphorylate N-terminal residues of p53 in vitro and in vivo, and DNA-damaging drugs enhance this activity (4 -6). CKI⑀ is an important regulator of ␤-catenin in the Wnt pathway; CKI⑀ mimicked Wnt in inducing a secondary axis in Xenopus, stabilizing ␤-catenin, and stimulating ␤-catenin-dependent gene transcription (7-11). In Drosophila, the double-time gene product, a CK1⑀ homolog, has been found to interact with dPER and regulate circadian cycle length (12). CK1␦ and CK1⑀ have also both been implicated in the regulation of the circadian clock in mammals (13-15).CK1 family members contain a highly related, central kinase domain that is flanked by N-and C-terminal extensions of variable length. The amino acid sequences of the C-terminal extensions are in general not highly related. However, the 124-amino acid C-terminal domain of mammalian CK1⑀ is 50% identical to that of CK1␦. Notably, several in vitro studies have shown that the activities of CK1␦ and CK1⑀ are regulated by autophosphorylation of their respective C-terminal domains (...

show abstract

“…The hemagglutinin (HA)-tagged CKI was cloned in pCEP4 (Invitrogen) as previously described (39,40). Myc epitope-tagged PER1 and PER2, myc-CKI␦, and ␤TrCP(⌬Fbox) were subcloned into pCS2ϩMT as described (14,19).…”

Section: Methodsmentioning

confidence: 99%

An opposite role for tau in circadian rhythms revealed by mathematical modeling

Gallego

Eide

Woolf

et al. 2006

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

Self Cite

166

160

View full text Add to dashboard Cite

Biological clocks with a period of Ϸ24 h (circadian) exist in most organisms and time a variety of functions, including sleep-wake cycles, hormone release, bioluminescence, and core body temperature fluctuations. Much of our understanding of the clock mechanism comes from the identification of specific mutations that affect circadian behavior. A widely studied mutation in casein kinase I (CKI), the CKI tau mutant, has been shown to cause a loss of kinase function in vitro, but it has been difficult to reconcile this loss of function with the current model of circadian clock function. Here we show that mathematical modeling predicts the opposite, that the kinase mutant CKI tau increases kinase activity, and we verify this prediction experimentally. CKI tau is a highly specific gain-of-function mutation that increases the in vivo phosphorylation and degradation of the circadian regulators PER1 and PER2. These findings experimentally validate a mathematical modeling approach to a complex biological function, clarify the role of CKI in the clock, and demonstrate that a specific mutation can be both a gain and a loss of function depending on the substrate.kinase ͉ systems biology ͉ phosphorylation ͉ PER ͉ degradation C ircadian rhythms govern key physiologic processes including sleep-wake cycles; glucose, lipid, and drug metabolism; heart rate; stress and growth hormones; and immunity, as well as basic cellular processes such as timing of the cell division cycle (1-6). The disruption of circadian rhythm causes significant physiologic stress, is frequently experienced in jet lag and night-shift work, and has been linked to bipolar disorder (7). Thus, circadian regulation of physiology has important consequences for health. A detailed quantitative model that makes clear, testable, and accurate predictions about the clock and how we may manipulate it can therefore have benefits for human health.Much of our understanding of clock components and their interactions began with the identification of mutations that affect circadian behavior (8, 9). In mammals, the original and most extensively studied circadian rhythm mutation is the semidominant tau, first described in 1988. Hamsters with this mutation show phase-advanced activity and have a circadian period of 20 h when homozygous mutant animals are isolated from time cues (9). This tau mutation has been identified as a missense mutation within the substrate recognition site of casein kinase I (denoted CKI tau ) (10). CKI and the closely related CKI␦ are widely expressed serine-threonine protein kinases implicated in development, circadian rhythms, and DNA metabolism (11). When tested in vitro on multiple substrates, CKI tau was shown to have a much reduced overall catalytic activity (10,12,13). This partial loss-of-function mutation and its phenotype have been difficult to reconcile with our current understanding of the molecular feedback loop that governs timing in mammalian cells (13) and recent empirical observations on clock function (14-16). For example, Dey et al. (1...

show abstract

Regulation of Casein Kinase I ε and Casein Kinase I δ by anin Vivo Futile Phosphorylation Cycle

Cited by 108 publications

References 25 publications

CKIε/δ-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock

CKIε/δ-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock

Mechanism of Regulation of Casein Kinase I Activity by Group I Metabotropic Glutamate Receptors

An opposite role for tau in circadian rhythms revealed by mathematical modeling

Contact Info

Product

Resources

About