Alternative titles; symbols
HGNC Approved Gene Symbol: CSNK1E
Cytogenetic location: 22q13.1 Genomic coordinates (GRCh38): 22:38,290,691-38,318,084 (from NCBI)
The casein kinase I gene family consists of serine/threonine protein kinases that are monomeric and widely distributed. Fish et al. (1995) cloned a member of the family, which they designated CKI-epsilon, from a human placenta cDNA library. The reading frame predicts a basic protein of 416 amino acids (43.7 kD) which is most closely related to CKI-delta (600864). Northern blots showed a major 2.9-kb transcript in all human cell lines examined. Recombinantly expressed enzyme was shown to phosphorylate known CKI substrates and was inhibited by CKI-7, a CKI-specific inhibitor. The human gene was able to rescue yeast with a slow-growth phenotype caused by deletion of HRR25, a yeast CKI locus.
Kloss et al. (1998) cloned the doubletime (dbt) gene in Drosophila and noted that it is most closely related to human casein kinase I-epsilon (CSNK1E). Drosophila dbtS and dbtL mutations, which alter period length of Drosophila circadian rhythms, produce single amino acid changes in conserved regions of the predicted kinase. The dbt mRNA appears to be expressed in the same cell types as are Drosophila 'per' (602260) and 'tim.' Dbt is capable of binding to per in vitro and in Drosophila cells, suggesting that a physical association of per and dbt regulates per phosphorylation and accumulation in vivo.
Lowrey et al. (2000) proposed that the shortened period length of circadian rhythms in tau hamsters (see ANIMAL MODEL) arises as a result of the repression of the CLOCK-BMAL1 complex (see 601851) occurring earlier in tau animals relative to wildtype animals. This explains both the observed reduction in, and an earlier appearance of, Per1 mRNA in tau homozygotes in vivo as revealed by in situ hybridization. Lowrey et al. (2000) proposed that CSNK1E plays a significant role in delaying the negative feedback signal within the transcription-translation-based autoregulatory loop that composes the core of the circadian mechanism. They suggested that since CSNK1E is an enzyme, it makes an ideal target for pharmaceutical compounds influencing circadian rhythms, sleep, and jet lag, as well as other physiologic and metabolic processes under circadian regulation.
Casein kinase I-epsilon has a prominent role in regulating the phosphorylation and abundance of Per proteins in animals. Using a Drosophila cell culture system, Ko et al. (2002) demonstrated that the doubletime gene, the Drosophila homolog of CKI-epsilon, promotes the progressive phosphorylation of Per, leading to the rapid degradation of hyperphosphorylated isoforms by the ubiquitin-proteasome pathway. Slimb (603482), an F-box/WD40-repeat protein functioning in the ubiquitin-proteasome pathway, interacts preferentially with phosphorylated Per and stimulates its degradation. Overexpression of slimb or expression in clock cells of a dominant-negative version of slimb disrupts normal rhythmic activity in flies. Ko et al. (2002) concluded that hyperphosphorylated Per is targeted to the proteasome by interactions with Slimb.
Using mathematical modeling, Vanselow et al. (2006) predicted that differential PER phosphorylation events could result in opposite period phenotypes, and studies in oscillating fibroblasts confirmed that interference with specific aspects of Per2 (603426) phosphorylation leads to either short or long periods. Vanselow et al. (2006) concluded that this concept explains not only the FASPS phenotype (604348), but also the effect of the tau mutation in hamster and doubletime mutations in Drosophila.
Using Drosophila cells and various Per mutants, Chiu et al. (2011) found that Per was progressively phosphorylated by doubletime and the proline-directed serine kinase Nemo (IKBKG; 300248). Per phosphorylation began at a specific cluster of serines at the beginning of the circadian cycle, with additional phosphorylation of Per by doubletime at more distant sites as the cycle progressed.
Cruciat et al. (2013) identified the DEAD box RNA helicase DDX3 (300160) as a regulator of the Wnt (see 164820)-beta-catenin (116806) network, where it acts as a regulatory subunit of CK1-epsilon: in a Wnt-dependent manner, DDX3 binds CK1-epsilon and directly stimulates its kinase activity, and promotes phosphorylation of the scaffold protein dishevelled (see 601365). DDX3 is required for Wnt-beta-catenin signaling in mammalian cells and during Xenopus and C. elegans development. Cruciat et al. (2013) concluded that their results suggested that the kinase-stimulatory function extends to other DDX and CK1 members.
Fish et al. (1995) mapped the CSNK1E gene to 22q12-q13 by fluorescence in situ hybridization.
The tau mutation is a semidominant autosomal allele that dramatically shortens period length of circadian rhythms in Syrian hamsters. Lowrey et al. (2000) reported the molecular identification of the tau locus using genetically directed representational difference analysis to define a region of conserved synteny in hamsters with both the mouse and human genomes. The tau locus is encoded by CSNK1E, a homolog of the Drosophila circadian gene doubletime (dbt). In vitro expression and functional studies of wildtype and tau mutant CSNK1E enzyme revealed that the mutant enzyme has a markedly reduced maximum velocity and autophosphorylation state. In addition, in vitro CSNK1E can interact with mammalian PERIOD proteins, and the mutant enzyme is deficient in its ability to phosphorylate PERIOD. Lowrey et al. (2000) concluded that tau is an allele of hamster Csnk1e and proposed a mechanism by which the mutation leads to the observed aberrant circadian phenotype in mutant animals.
Meng et al. (2008) generated a mouse model of the Csnk1e tau mutant and observed that the mutation shortened the circadian period of behavior in a dose-dependent manner, but acted as a gain-of-function mutation. Csnk1e-null mice showed a small yet significant lengthening of the circadian period compared to wildtype (24.0 vs 23.6 hours, respectively). Mice heterozygous for the null allele behaved similarly to wildtype. Asymmetric oxygen consumption data suggested that the tau mutation may accelerate the period by specifically compressing the inactive phase of the cycle. Recordings of suprachiasmatic neurons isolated from the various mutants showed a significant correlation between firing rate rhythms and behavior. Cells from the tau mutants showed accelerated firing compared to wildtype, although gene loss did not alter the fundamental electrophysiologic properties of suprachiasmatic neurons. The tau mutation acted by promoting the degradation of Per1 (602260) and Per2 (603426) in the early circadian night. The tau mutation also accelerated the molecular dynamics of circadian time-keeping in peripheral tissues, indicating that it plays a global role in the organism.
Chiu, J. C., Ko, H. W., Edery, I. NEMO/NLK phosphorylates PERIOD to initiate a time-delay phosphorylation circuit that sets circadian clock speed. Cell 145: 357-370, 2011. Note: Erratum: Cell 145: 635 only, 2011. [PubMed: 21514639] [Full Text: https://doi.org/10.1016/j.cell.2011.04.002]
Cruciat, C.- M., Dolde, C., de Groot, R. E. A., Ohkawara, B., Reinhard, C., Korswagen, H. C., Niehrs, C. RNA helicase DDX3 is a regulatory subunit of casein kinase 1 in Wnt-beta-catenin signaling. Science 339: 1436-1441, 2013. [PubMed: 23413191] [Full Text: https://doi.org/10.1126/science.1231499]
Fish, K. J., Cegielska, A., Getman, M. E., Landes, G. M., Virshup, D. M. Isolation and characterization of human casein kinase I-epsilon (CKI), a novel member of the CKI gene family. J. Biol. Chem. 270: 14875-14883, 1995. [PubMed: 7797465] [Full Text: https://doi.org/10.1074/jbc.270.25.14875]
Kloss, B., Price, J. L., Saez, L., Blau, J., Rothenfluh, A., Wesley, C. S., Young, M. W. The Drosophila clock gene double-time encodes a protein closely-related to human casein kinase I-epsilon. Cell 94: 97-107, 1998. [PubMed: 9674431] [Full Text: https://doi.org/10.1016/s0092-8674(00)81225-8]
Ko, H. W., Jiang, J., Edery, I. Role for Slimb in the degradation of Drosophila Period protein phosphorylated by Doubletime. Nature 420: 673-678, 2002. [PubMed: 12442174] [Full Text: https://doi.org/10.1038/nature01272]
Lowrey, P. L., Shimomura, K., Antoch, M. P., Yamazaki, S., Zamenides, P. D., Ralph, M. R., Menaker, M., Takahashi, J. S. Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288: 483-491, 2000. [PubMed: 10775102] [Full Text: https://doi.org/10.1126/science.288.5465.483]
Meng, Q.-J., Logunova, L., Maywood, E. S., Gallego, M., Lebiecki, J., Brown, T. M., Sladek, M., Semikhodskii, A. S., Glossop, N. R. J., Piggins, H. D., Chesham, J. E., Bechtold, D. A., Yoo, S.-H., Takahashi, J. S., Virshup, D. M., Boot-Handford, R. P., Hastings, M. H., Loudon, A. S. I. Setting clock speed in mammals: the CK1-epsilon tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins. Neuron 58: 78-88, 2008. [PubMed: 18400165] [Full Text: https://doi.org/10.1016/j.neuron.2008.01.019]
Vanselow, K., Vanselow, J. T., Westermark, P. O., Reischl, S., Maier, B., Korte, T., Herrmann, A., Herzel, H., Schlosser, A., Kramer, A. Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS). Genes Dev. 20: 2660-2672, 2006. [PubMed: 16983144] [Full Text: https://doi.org/10.1101/gad.397006]