casein kinase iepsilon


Summary: A casein kinase I isoenzyme with specificity for proteins involved the regulation of the CIRCADIAN RHYTHM.

Top Publications

  1. Um J, Yang S, Yamazaki S, Kang H, Viollet B, Foretz M, et al. Activation of 5'-AMP-activated kinase with diabetes drug metformin induces casein kinase Iepsilon (CKIepsilon)-dependent degradation of clock protein mPer2. J Biol Chem. 2007;282:20794-8 pubmed
    ..One of the regulators of the period length is casein kinase Iepsilon (CKIepsilon), which by phosphorylating and inducing the degradation of the circadian clock component, ..
  2. Tsai I, Amack J, Gao Z, Band V, Yost H, Virshup D. A Wnt-CKIvarepsilon-Rap1 pathway regulates gastrulation by modulating SIPA1L1, a Rap GTPase activating protein. Dev Cell. 2007;12:335-47 pubmed
    ..Our data demonstrate a role for CKIvarepsilon in noncanonical Wnt signaling and indicate that Wnt regulates morphogenesis in part through CKIvarepsilon-mediated control of Rap1 signaling. ..
  3. Sehadova H, Ichihara N, Iwai S, Mita K, Takeda M. Casein kinases I of the silkworm, Bombyx mori: their possible roles in circadian timing and developmental determination. J Biol Rhythms. 2006;21:335-49 pubmed publisher
    Doubletime (DBT), a homolog of casein kinase Iepsilon (CKIepsilon), is an essential circadian clock component and developmental regulator in Drosophila melanogaster...
  4. Sprouse J, Reynolds L, Swanson T, Engwall M. Inhibition of casein kinase I epsilon/delta produces phase shifts in the circadian rhythms of Cynomolgus monkeys. Psychopharmacology (Berl). 2009;204:735-42 pubmed publisher
    ..clock-related proteins is a function of synthesis and degradation, the latter involving phosphorylation by casein kinase Iepsilon and delta...
  5. Kim E, Edery I. Balance between DBT/CKIepsilon kinase and protein phosphatase activities regulate phosphorylation and stability of Drosophila CLOCK protein. Proc Natl Acad Sci U S A. 2006;103:6178-83 pubmed
  6. Swiatek W, Kang H, Garcia B, Shabanowitz J, Coombs G, Hunt D, et al. Negative regulation of LRP6 function by casein kinase I epsilon phosphorylation. J Biol Chem. 2006;281:12233-41 pubmed
    ..Generation of active CKIepsilon may induce a negative feedback loop by phosphorylation of sites on LRP5/6 that modulate axin binding and hence beta-catenin degradation. ..
  7. Schwarz Romond T, Metcalfe C, Bienz M. Dynamic recruitment of axin by Dishevelled protein assemblies. J Cell Sci. 2007;120:2402-12 pubmed
    ..Here, we show that these Dvl2 assemblies recruit axin, and also casein kinase Iepsilon. Using photobleaching experiments of GFP-tagged Dvl2 and axin to study the dynamics of their interaction, ..
  8. Kim E, Ko H, Yu W, Hardin P, Edery I. A DOUBLETIME kinase binding domain on the Drosophila PERIOD protein is essential for its hyperphosphorylation, transcriptional repression, and circadian clock function. Mol Cell Biol. 2007;27:5014-28 pubmed
  9. Yu W, Zheng H, Price J, Hardin P. DOUBLETIME plays a noncatalytic role to mediate CLOCK phosphorylation and repress CLOCK-dependent transcription within the Drosophila circadian clock. Mol Cell Biol. 2009;29:1452-8 pubmed publisher
    ..A similar mechanism likely operates in mammals, given the conserved activities of PER, DBT, and CLK orthologs. ..

More Information


  1. Cyran S, Yiannoulos G, Buchsbaum A, Saez L, Young M, Blau J. The double-time protein kinase regulates the subcellular localization of the Drosophila clock protein period. J Neurosci. 2005;25:5430-7 pubmed
    ..Here, we show that these effects of SGG on PER nuclear accumulation require TIM. We propose a revised clock model that incorporates this tight kinase regulation of PER and TIM nuclear entry. ..
  2. Kloss B, Price J, Saez L, Blau J, Rothenfluh A, Wesley C, et al. The Drosophila clock gene double-time encodes a protein closely related to human casein kinase Iepsilon. Cell. 1998;94:97-107 pubmed
    The cloning of double-time (dbt) is reported. DOUBLETIME protein (DBT) is most closely related to human casein kinase Iepsilon. dbtS and dbtL mutations, which alter period length of Drosophila circadian rhythms, produce single amino acid ..
  3. Long A, Zhao H, Huang X. Structural basis for the interaction between casein kinase 1 delta and a potent and selective inhibitor. J Med Chem. 2012;55:956-60 pubmed publisher
    ..These structures provide a molecular basis for the strong and specific inhibitor interactions and suggest clues for further development of CK1?/? inhibitors. ..
  4. Nawathean P, Rosbash M. The doubletime and CKII kinases collaborate to potentiate Drosophila PER transcriptional repressor activity. Mol Cell. 2004;13:213-23 pubmed
    ..This interpretation suggests further that the circadian regulation of PER nuclear localization in flies reflects changes in PER transcriptional activity rather than in PER nuclear import or export activity. ..
  5. Takano A, Uchiyama M, Kajimura N, Mishima K, Inoue Y, Kamei Y, et al. A missense variation in human casein kinase I epsilon gene that induces functional alteration and shows an inverse association with circadian rhythm sleep disorders. Neuropsychopharmacology. 2004;29:1901-9 pubmed
    ..8-fold more active than wild-type CKIepsilon. These results indicate that the N408 allele in CKIepsilon plays a protective role in the development of DSPS and N-24 through alteration of the enzyme activity. ..
  6. Bao S, Rihel J, Bjes E, Fan J, Price J. The Drosophila double-timeS mutation delays the nuclear accumulation of period protein and affects the feedback regulation of period mRNA. J Neurosci. 2001;21:7117-26 pubmed
    ..These results suggest that dbt can regulate the feedback of per protein on its mRNA by delaying the time at which it is translocated to nuclei and altering the level of nuclear PER during the declining phase of the cycle. ..
  7. Suri V, Hall J, Rosbash M. Two novel doubletime mutants alter circadian properties and eliminate the delay between RNA and protein in Drosophila. J Neurosci. 2000;20:7547-55 pubmed
  8. Rothenfluh A, Abodeely M, Young M. Short-period mutations of per affect a double-time-dependent step in the Drosophila circadian clock. Curr Biol. 2000;10:1399-402 pubmed
    ..We conclude that, in wild-type flies, the previously defined PER'short domain' [7,8] may regulate the activity of DBT on PER. ..
  9. Grozav A, Chikamori K, Kozuki T, Grabowski D, Bukowski R, Willard B, et al. Casein kinase I delta/epsilon phosphorylates topoisomerase IIalpha at serine-1106 and modulates DNA cleavage activity. Nucleic Acids Res. 2009;37:382-92 pubmed publisher
    ..These results provide strong support for an essential role of CKIdelta/epsilon in phosphorylating Ser-1106 in human topo IIalpha and in regulating enzyme function. ..
  10. Bryant C, Graham M, Distler M, Munoz M, Li D, Vezina P, et al. A role for casein kinase 1 epsilon in the locomotor stimulant response to methamphetamine. Psychopharmacology (Berl). 2009;203:703-11 pubmed publisher
  11. Eide E, Virshup D. Casein kinase I: another cog in the circadian clockworks. Chronobiol Int. 2001;18:389-98 pubmed
    ..Phosphorylation may regulate multiple properties of clock proteins, including stability and intracellular localization. ..
  12. Dahlberg C, Nguyen E, Goodlett D, Kimelman D. Interactions between Casein kinase Iepsilon (CKIepsilon) and two substrates from disparate signaling pathways reveal mechanisms for substrate-kinase specificity. PLoS ONE. 2009;4:e4766 pubmed publisher
    ..The biochemical interactions between CKIepsilon and Disheveled, Period, and its own C-terminus lead to models that explain CKIepsilon's specificity and regulation. ..
  13. Strutt H, Price M, Strutt D. Planar polarity is positively regulated by casein kinase Iepsilon in Drosophila. Curr Biol. 2006;16:1329-36 pubmed
    ..Finally, we also find that dco function in polarity is partially redundant with CKIalpha. ..
  14. Chergui K, Svenningsson P, Greengard P. Physiological role for casein kinase 1 in glutamatergic synaptic transmission. J Neurosci. 2005;25:6601-9 pubmed
    ..These results provide the first evidence for a role of CK1 in the regulation of synaptic transmission in the brain. ..
  15. Cong F, Schweizer L, Varmus H. Casein kinase Iepsilon modulates the signaling specificities of dishevelled. Mol Cell Biol. 2004;24:2000-11 pubmed
    ..We also found that casein kinase Iepsilon (CKIepsilon), a previously identified positive regulator of Wnt signaling, stimulated Dvl activity in the ..
  16. Sprouse J, Reynolds L, Kleiman R, Tate B, Swanson T, Pickard G. Chronic treatment with a selective inhibitor of casein kinase I delta/epsilon yields cumulative phase delays in circadian rhythms. Psychopharmacology (Berl). 2010;210:569-76 pubmed publisher
    ..Most importantly, these changes in circadian behavior occurred in the presence of a fixed L:D cycle, confirming the drug to be a robust modulator of circadian phase in the presence of the natural zeitgeber. ..
  17. Kani S, Oishi I, Yamamoto H, Yoda A, Suzuki H, Nomachi A, et al. The receptor tyrosine kinase Ror2 associates with and is activated by casein kinase Iepsilon. J Biol Chem. 2004;279:50102-9 pubmed
    ..We show that when expressed in mammalian cells, Ror2 associates with casein kinase Iepsilon (CKIepsilon), a crucial regulator of Wnt signaling...
  18. Foldynova Trantirkova S, Sekyrova P, Tmejov√° K, Brumovsk√° E, Bernatik O, Blankenfeldt W, et al. Breast cancer-specific mutations in CK1epsilon inhibit Wnt/beta-catenin and activate the Wnt/Rac1/JNK and NFAT pathways to decrease cell adhesion and promote cell migration. Breast Cancer Res. 2010;12:R30 pubmed publisher
  19. Zilian O, Frei E, Burke R, Brentrup D, Gutjahr T, Bryant P, et al. double-time is identical to discs overgrown, which is required for cell survival, proliferation and growth arrest in Drosophila imaginal discs. Development. 1999;126:5409-20 pubmed
  20. Lee H, Chen R, Lee Y, Yoo S, Lee C. Essential roles of CKIdelta and CKIepsilon in the mammalian circadian clock. Proc Natl Acad Sci U S A. 2009;106:21359-64 pubmed publisher
    ..Our results show that an essential role of CKIdelta/epsilon is conserved between Drosophila and mammals, but CKIdelta/epsilon and DBT may have divergent non-catalytic functions in the clockwork as well. ..
  21. Loudon A, Meng Q, Maywood E, Bechtold D, Boot Handford R, Hastings M. The biology of the circadian Ck1epsilon tau mutation in mice and Syrian hamsters: a tale of two species. Cold Spring Harb Symp Quant Biol. 2007;72:261-71 pubmed publisher
    ..tau has consistent effects in both hamsters and mice on the circadian organization of behavior and metabolism, highlighting the global impact of this mutation on mammalian clockwork in brain and periphery. ..
  22. Meng Q, Logunova L, Maywood E, Gallego M, Lebiecki J, Brown T, et al. Setting clock speed in mammals: the CK1 epsilon tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins. Neuron. 2008;58:78-88 pubmed publisher
  23. Sekine T, Yamaguchi T, Hamano K, Young M, Shimoda M, Saez L. Casein kinase I epsilon does not rescue double-time function in Drosophila despite evolutionarily conserved roles in the circadian clock. J Biol Rhythms. 2008;23:3-15 pubmed publisher
    ..Thus, caution should be used in interpreting assays that measure activity of mammalian casein kinase mutants in Drosophila, or that employ vertebrate CKI in studies of dPER phosphorylations. ..
  24. Kloss B, Rothenfluh A, Young M, Saez L. Phosphorylation of period is influenced by cycling physical associations of double-time, period, and timeless in the Drosophila clock. Neuron. 2001;30:699-706 pubmed
    The clock gene double-time (dbt) encodes an ortholog of casein kinase Iepsilon that promotes phosphorylation and turnover of the PERIOD protein...
  25. Ko H, Jiang J, Edery I. Role for Slimb in the degradation of Drosophila Period protein phosphorylated by Doubletime. Nature. 2002;420:673-8 pubmed
    ..b>Casein kinase Iepsilon (CKIepsilon) has a prominent role in regulating the phosphorylation and abundance of Per proteins in ..
  26. Zhang L, Jia J, Wang B, Amanai K, Wharton K, Jiang J. Regulation of wingless signaling by the CKI family in Drosophila limb development. Dev Biol. 2006;299:221-37 pubmed
    ..Finally, we provide evidence that several CKI isoforms including CKIalpha and Gish/CKIgamma can phosphorylate the Wg coreceptor Arrow (Arr), which may account, at least in part, for their positive roles in the Wg pathway. ..
  27. Klimowski L, Garcia B, Shabanowitz J, Hunt D, Virshup D. Site-specific casein kinase 1epsilon-dependent phosphorylation of Dishevelled modulates beta-catenin signaling. FEBS J. 2006;273:4594-602 pubmed
    ..b>Casein kinase Iepsilon is a Wnt-activated positive regulator of this pathway...
  28. Klein T, Jenny A, Djiane A, Mlodzik M. CKIepsilon/discs overgrown promotes both Wnt-Fz/beta-catenin and Fz/PCP signaling in Drosophila. Curr Biol. 2006;16:1337-43 pubmed
    ..Furthermore, we have identified the primary kinase target residue of CKIepsilon on Dsh. Thus, our data suggest that CKIepsilon modulates Wnt/beta-catenin and Fz/PCP signaling pathways via kinase-dependent and -independent mechanisms. ..
  29. Muskus M, Preuss F, Fan J, Bjes E, Price J. Drosophila DBT lacking protein kinase activity produces long-period and arrhythmic circadian behavioral and molecular rhythms. Mol Cell Biol. 2007;27:8049-64 pubmed
    ..This first analysis of adult flies with a virtual lack of DBT activity demonstrates that DBT's kinase activity is necessary for normal circadian rhythms and that a general reduction of DBT kinase activity does not produce short periods. ..
  30. Brockschmidt C, Hirner H, Huber N, Eismann T, Hillenbrand A, Giamas G, et al. Anti-apoptotic and growth-stimulatory functions of CK1 delta and epsilon in ductal adenocarcinoma of the pancreas are inhibited by IC261 in vitro and in vivo. Gut. 2008;57:799-806 pubmed publisher
    ..Targeting CK1 isoforms by IC261 influences both pancreatic tumour cell growth and apoptosis sensitivity in vitro and the growth of induced tumours in vivo, thus providing a promising new strategy for the treatment of pancreatic tumours. ..
  31. Saez L, Meyer P, Young M. A PER/TIM/DBT interval timer for Drosophila's circadian clock. Cold Spring Harb Symp Quant Biol. 2007;72:69-74 pubmed publisher
    ..The cultured cell assay provides a potent system to study interactions among new and known genes involved in the generation of circadian behavior. ..
  32. Meng Q, Maywood E, Bechtold D, Lu W, Li J, Gibbs J, et al. Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes. Proc Natl Acad Sci U S A. 2010;107:15240-5 pubmed publisher
    ..Accordingly, selective pharmacological targeting of the endogenous circadian regulator CK1delta offers an avenue for therapeutic modulation of perturbed circadian behavior. ..
  33. Kim S, Dunn I, Firestein R, Gupta P, Wardwell L, Repich K, et al. CK1epsilon is required for breast cancers dependent on beta-catenin activity. PLoS ONE. 2010;5:e8979 pubmed publisher
  34. Bae K, Edery I. Regulating a circadian clock's period, phase and amplitude by phosphorylation: insights from Drosophila. J Biochem. 2006;140:609-17 pubmed
  35. Etchegaray J, Machida K, Noton E, Constance C, Dallmann R, Di Napoli M, et al. Casein kinase 1 delta regulates the pace of the mammalian circadian clock. Mol Cell Biol. 2009;29:3853-66 pubmed publisher
    ..These results reveal important functional differences between CK1delta and CK1epsilon: CK1delta plays an unexpectedly important role in maintaining the 24-h circadian cycle length. ..
  36. Isojima Y, Nakajima M, Ukai H, Fujishima H, Yamada R, Masumoto K, et al. CKIepsilon/delta-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock. Proc Natl Acad Sci U S A. 2009;106:15744-9 pubmed publisher
    ..Most compounds inhibited casein kinase Iepsilon (CKIepsilon) or CKIdelta phosphorylation of the PER2 protein...
  37. Cheong J, Nguyen T, Wang H, Tan P, Voorhoeve P, Lee S, et al. IC261 induces cell cycle arrest and apoptosis of human cancer cells via CK1?/? and Wnt/?-catenin independent inhibition of mitotic spindle formation. Oncogene. 2011;30:2558-69 pubmed publisher
    ..This activity accounts for many of the diverse biological effects of IC261 and, most importantly, for its selective cancer cell killing. ..
  38. Dolezal T, Kucerova K, Neuhold J, Bryant P. Casein kinase I epsilon somatic mutations found in breast cancer cause overgrowth in Drosophila. Int J Dev Biol. 2010;54:1419-24 pubmed publisher
    ..Our results thus strongly support the conclusion that CKIepsilon mutations play important roles in breast carcinogenesis. ..
  39. Walton K, Fisher K, Rubitski D, Marconi M, Meng Q, Sladek M, et al. Selective inhibition of casein kinase 1 epsilon minimally alters circadian clock period. J Pharmacol Exp Ther. 2009;330:430-9 pubmed publisher
    ..These data indicate that CK1epsilon is not the predominant mediator of circadian timing relative to CK1delta. PF-4800567 should prove useful in probing unique roles between these two kinases in multiple signaling pathways. ..
  40. Yang W, Stockwell B. Inhibition of casein kinase 1-epsilon induces cancer-cell-selective, PERIOD2-dependent growth arrest. Genome Biol. 2008;9:R92 pubmed publisher
    ..These data support the hypothesis that circadian clock genes can control the cell cycle and cell survival signaling, and emphasize a central role of CK1epsilon and PERIOD2 in linking these systems. ..
  41. Virshup D, Eide E, Forger D, Gallego M, Harnish E. Reversible protein phosphorylation regulates circadian rhythms. Cold Spring Harb Symp Quant Biol. 2007;72:413-20 pubmed publisher
    ..The precision of clock timing is controlled by protein kinases and phosphatases. Casein kinase Iepsilon is a protein kinase that regulates the circadian clock by periodic phosphorylation of the proteins PER1 ..
  42. Eide E, Woolf M, Kang H, Woolf P, Hurst W, Camacho F, et al. Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation. Mol Cell Biol. 2005;25:2795-807 pubmed
    ..CKIepsilon (casein kinase Iepsilon) has been postulated to prime PER2 for degradation...
  43. Badura L, Swanson T, Adamowicz W, Adams J, Cianfrogna J, Fisher K, et al. An inhibitor of casein kinase I epsilon induces phase delays in circadian rhythms under free-running and entrained conditions. J Pharmacol Exp Ther. 2007;322:730-8 pubmed
    b>Casein kinase Iepsilon (CKIepsilon) is an essential component of the biological clock, phosphorylating PER proteins, and in doing so regulating their turnover and nuclear entry in oscillator cells of the suprachiasmatic nucleus (SCN)...
  44. Wang H, Ko C, Koletar M, Ralph M, Yeomans J. Casein kinase I epsilon gene transfer into the suprachiasmatic nucleus via electroporation lengthens circadian periods of tau mutant hamsters. Eur J Neurosci. 2007;25:3359-66 pubmed
  45. Lee C. The circadian clock and tumor suppression by mammalian period genes. Methods Enzymol. 2005;393:852-61 pubmed
    ..Genetic studies have demonstrated that many key regulators of cell cycle and growth control are also important circadian clock regulators, confirming the critical role of circadian function in organismal homeostasis. ..
  46. Guan J, Li H, Rogulja A, Axelrod J, Cadigan K. The Drosophila casein kinase Iepsilon/delta Discs overgrown promotes cell survival via activation of DIAP1 expression. Dev Biol. 2007;303:16-28 pubmed
    ..In this report, we demonstrate that the Drosophila casein kinase Iepsilon/delta, known as Discs overgrown (Dco), is required for maintaining this low level of apoptosis...
  47. Etchegaray J, Yu E, Indic P, Dallmann R, Weaver D. Casein kinase 1 delta (CK1delta) regulates period length of the mouse suprachiasmatic circadian clock in vitro. PLoS ONE. 2010;5:e10303 pubmed publisher
    ..The results indicate that CK1delta plays a more prominent role than CK1epsilon in the maintenance of 24-hour rhythms in the master circadian oscillator. ..
  48. Thal D, Del Tredici K, Ludolph A, Hoozemans J, Rozemuller A, Braak H, et al. Stages of granulovacuolar degeneration: their relation to Alzheimer's disease and chronic stress response. Acta Neuropathol. 2011;122:577-89 pubmed publisher
    ..Moreover, the association of the GVD stages with those of AD-related pathology but not with other neurodegenerative disorders points to a possible role of GVD and the response to chronic stress in the pathogenesis of AD. ..
  49. Habas R, He X. Cell signaling: moving to a Wnt-Rap. Curr Biol. 2007;17:R474-7 pubmed
    ..A recent study reveals that casein kinase Iepsilon mediates an additional novel non-canonical Wnt pathway via the activation of the Rap1 GTPase during ..
  50. Bischof J, Leban J, Zaja M, Grothey A, Radunsky B, Othersen O, et al. 2-Benzamido-N-(1H-benzo[d]imidazol-2-yl)thiazole-4-carboxamide derivatives as potent inhibitors of CK1?/?. Amino Acids. 2012;43:1577-91 pubmed
    ..In summary, our optimizations lead to the development of new highly selective CK1? and ? specific inhibitors with biological activity. ..
  51. Huang Y, Li J, Wu L, Jin Q, Zhao X, Li J, et al. Association between a casein kinase 1 ? gene polymorphism and schizophrenia in a Chinese Han population. J Mol Neurosci. 2012;47:470-4 pubmed publisher
    ..0032; OR?=?1.532; 95% CI, 1.153-2.037), suggesting that a genetic variant in the Csnk1? gene significantly enhances the probability of schizophrenia in the Chinese Han population. ..
  52. Perreau Lenz S, Vengeliene V, Noori H, Merlo Pich E, Corsi M, Corti C, et al. Inhibition of the casein-kinase-1-?/?/ prevents relapse-like alcohol drinking. Neuropsychopharmacology. 2012;37:2121-31 pubmed publisher
    ..Our data suggest that CK1 inhibitors may be candidates for drug treatment development for alcoholism. ..
  53. Bryant C, PARKER C, Zhou L, Olker C, Chandrasekaran R, Wager T, et al. Csnk1e is a genetic regulator of sensitivity to psychostimulants and opioids. Neuropsychopharmacology. 2012;37:1026-35 pubmed publisher
    ..Furthermore, gene knockout and selective pharmacological inhibition of Csnk1e define its role as a negative regulator of sensitivity to psychostimulants and opioids. ..