Casein kinase 1 isoform epsilon

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Casein kinase I isoform epsilon or CK1ε, is an enzyme that in humans is encoded by the CSNK1E gene.[1][2] CK1ε is a serine/threonine protein kinase and is very highly conserved; therefore, this kinase is very similar to other members of the casein kinase 1 family.[3] This gene is a major component of the mammalian oscillator which controls cellular circadian rhythms.[3]

Discovery

The human CK1ε was first isolated and cloned in 1995, officially identified as an isoform of the casein kinase 1 family.[4] Three transcript variants encoding the same protein have been found for this gene in rat: CK1ε1, CK1ε2, and CK1ε3; and two have been found in humans.[5][6] In humans, the CSNK1E gene localizes at 22q13.1 and consists of 12 exons.[6]

Function

Enzyme function

The protein encoded by the casein kinase 1 epsilon gene is a serine/threonine protein kinase and a member of the casein kinase I protein family, whose members have been implicated in the control of cytoplasmic and nuclear processes, including DNA replication and repair.[6] Like other casein kinase 1 protein family members, casein kinase 1 epsilon recognizes the Ser(p)XXSer/Thr motif for phosphorylation.[7] It is found in the cytoplasm as a monomer and can phosphorylate a variety of proteins, including itself.[6] This autophosphorylation occurs in the protein's C-Terminal domain, a region believed to behave as a pseudosubstrate, and inhibits kinase activity.[3][8][9]

The Circadian Clock

The Casein kinase 1 epsilon protein is part of the mammalian oscillator, a group of proteins that keep cells on a roughly 24-hour schedule. This oscillator, or "circadian clock," is made up of a transcription-translation negative feedback loop (TTNFL) in which several proteins work in tandem, each regulating the others' expression to generate a roughly 24-hour cycle of both mRNA and protein levels.[10] The TTFNL also generates roughly 24-hour rhythms of outputs such as levels of cellular hormone release. Daily oscillations in protein and mRNA transcription have been observed in many cells, including the mammalian master clock known as the suprachiasmatic nucleus (SCN). However, unlike most circadian rhythm proteins, casein kinase 1 epsilon is constitutively active.[11]

The most important proteins which make up the mammalian TTNFL are the Period (PER), and Cryptochrome (CRY) proteins, BMAL1, CLOCK, and casein kinase 1 epsilon. PER and CRY levels are regulated by negative feedback, meaning that they repress their own transcription. BMAL1 and CLOCK work to increase PER and CRY transcription by binding on the E-box domain upstream from the PER and CRY gene coding sequences. The level of PER and CRY proteins is regulated by casein kinase 1 through phosphorylation, which marks these proteins for degradation by the cell.[6][11] Phosphorylation also hinders PER's ability to enter the nucleus by inducing a conformational change in its nuclear localization sequence.[3][12][13] However, if CRY proteins bind to PER before this phosphorylation can occur, all three proteins stabilize into a complex that can enter the nucleus.[3] Once inside the nucleus, PER and CRY can work to inhibit their own transcription, while casein kinase 1 epsilon works to modulate the activity of BMAL1 and CLOCK through phosphorylation.[3]

As previously stated, the C-Terminal domain of casein kinase 1 epsilon behaves as a pseudosubstrate when phosphorylated, inhibiting kinase activity.[3][8][9] The C-Terminal domain has also been shown to be dephosphorylated by phosphatases such as Protein phosphatase 1 (PP1) in vitro and cell culture, which regulates levels of active casein kinase in vivo.[3][10][14] Current theory of circadian rhythms hypothesizes that this phosphorylation/dephosphorylation cycle of casein kinase 1 epsilon is important in modulation of the period of circadian rhythms in the cell, with increased phosphorylation decreasing casein kinase 1 epsilon activity (and subsequently increasing active CRY and PER) and dephosphorylation of casein kinase 1 epsilon resulting in a more active kinase (and lower levels of active CRY and PER).[10]

In mice, casein kinase 1 epsilon has been shown to phosphorylate both PER1 and PER2, as well as CRY1 and CRY2.[11] Casein kinase 1 results in a cyclic expression of mammalian oscillator proteins, resulting in a timekeeper (mammalian oscillator) for the cell:

Mammalian PER and CRY Protein Levels
Protein Level Immediate Result Delayed Result
12 a.m. (midnight) low PER and CRY protein concentration Per and Cry (gene) actively transcribed and stimulated by transcription factors BMAL1 and CLOCK N/A
12 p.m.

(noon)

high PER and CRY protein concentration high PER and CRY protein levels repress Per and Cry (gene) transcription casein kinase 1 epsilon phosphorylates PER and CRY, marking the protein for degradation: PER and CRY protein concentration decreases

Mutations to circadian function

In hamsters, the CK1ε-tau mutation was first discovered by Michael Menaker and colleagues while studying a laboratory shipment of Syrian hamsters. The prominent phenotype in the mutant hamsters was an unusually short free-running period — 22 hours in heterozygotes, and 20 hours in homozygotes for the mutation—making this allele semidominant. The gene was later mapped and identified by Joseph Takahashi and colleagues, which revealed a single base-pair C-to-T substitutional mutation in the hamster CK1ε gene. This single nucleotide polymorphism (SNP) results in an arginine-to-cysteine substitution in a phosphate recognition domain region of CK1ε, a highly conserved region of the gene across mammals.[15] Presently, it is unclear how exactly the CK1ε-tau mutation results in a shorter free-running period.[16] The CK1ε-tau mutation in hamsters was the first full description of a mammalian circadian mutant.[17]

In humans, mutations affecting the PER2 phosphorylation site of the CK1ε gene results in Familial advanced sleep phase syndrome (FASPS).[18] This mutation, which results in the loss of a single phosphate acceptor site on PER2, prevents CK1ε protein from binding to PER and leads to an unusually short circadian period.[19] Therefore, while the mutation to the human Per2 gene results in a similarly shortened period as in the CK1ε-tau hamsters, the biological mechanisms behind each phenotype are a result of disruptions to different parts of the clock pathway.

Non-mammalian homologs

Two circadian rhythm functional homologs of this mammalian protein can be found in Drosophila melanogaster (fruit fly).[20] Functional homologs refer to proteins sharing a similar function in another animal but that are not necessarily genetically similar.

One gene, coding for the protein Doubletime (abbreviated DBT), serves a similar purpose to casein kinase 1 epsilon in chronobiology, as it plays a role in the phosphorylation of PER. However its gene sequence shows no sequence homology.[3][6][20] In addition, casein kinase 1 epsilon does not completely rescue circadian rhythms in fruit fly doubletime knockouts (dbt -/-), suggesting that these enzymes serve similar, but not identical, functions.[21]

Another functional homolog, the Drosophila gene for glycogen synthase kinase 3 (GSK3), called shaggy and abbreviated sgg, codes for a protein which phosphorylates Timeless (TIM), the fruit fly CRY functional homolog.[22] Like dbt, shaggy is not a sequence homolog to casein kinase 1 epsilon.[22] Conversely, Gsk3 is also found in mammals, and mutants have been implicated in circadian rhythm abnormalities in patients suffering with bipolar disorder.[3]

The Drosophila melanogaster genome contains other casein kinase 1 family enzymes, which are believed to serve no circadian function. However, a different casein kinase family enzyme, casein kinase 2 alpha, has been implicated in providing the initial phosphorylation of a serine residue that is recognized by both DBT and Shaggy for sequential PER and TIM phosphorylation.

Other functions

Canonical Wnt pathway

The canonical Wnt Pathway involves the accumulation of β-catenin in the cytoplasm, which activates transcription factors.[23] Casein kinase 1 epsilon, and related casein kinase 1 delta, is dephosphorylated in this pathway. Dephosphorylation of casein kinase 1 epsilon is likely achieved by Protein Phosphatase 2 (PP2A), which increases both the enzymes' kinase activity in vivo.[3] Casein kinase 1 epsilon and casein kinase 1 delta have been implicated in increasing β-catenin's stability in the cytoplasm, although studies of the mechanism for this stabilization are inconclusive. The current theory for how casein kinase 1 epsilon and/or casein kinase 1 delta function in this pathway is that both casein kinases either directly stabilize β-catenin though positive regulation, or that they indirectly stabilizes β-catenin through negative regulation of the β-catenin degradation complex (protease).[3]

Cancer

Casein kinase 1 epsilon and delta are known to phosphorylate a tumor suppressor protein, p53 in vivo in both humans and murine, or old world rats.[3][24][25][26] Casein kinase 1 epsilon is also implicated as indirectly causing cancer through its regulation of Yes-associated protein (YAP), an oncogene and regulator of organ size. After priming through phosphorylation by the serine/threonine kinase LATS, both casein kinase 1 epsilon and casein kinase 1 delta have been shown to phosphorylate YAP and marking it for ubiquitination and degradation.[27]

Interactions

Casein kinase 1 epsilon has been shown to interact with PER1,[28] PER2, CRY1, CRY2, BMAL1, CLOCK, NPAS2, and AXIN1.[3][29]

Inhibitors

The use of these inhibitors has allowed for further study of the function of casein kinase 1 epsilon in a variety of processes including its regulation of circadian rhythms.

Selective
Non-selective
  • PF-670462 (also inhibits CK1-δ)

See also

References

  1. ↑ Fish KJ, Cegielska A, Getman ME, Landes GM, Virshup DM (Jun 1995). "Isolation and characterization of human casein kinase I epsilon (CKI), a novel member of the CKI gene family". The Journal of Biological Chemistry. 270 (25): 14875–83. doi:10.1074/jbc.270.25.14875. PMID 7797465.
  2. ↑ Sakanaka C, Leong P, Xu L, Harrison SD, Williams LT (Oct 1999). "Casein kinase iepsilon in the wnt pathway: regulation of beta-catenin function". Proceedings of the National Academy of Sciences of the United States of America. 96 (22): 12548–52. doi:10.1073/pnas.96.22.12548. PMC 22983. PMID 10535959.
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 Knippschild; et al. "The casein kinase I family: participation in multiple cellular processes in eukaryotes". Cell Signaling. Retrieved 2015-04-04.
  4. ↑ Rodriguez, Noah; Yang, Junzheng; Hasselblatt, Kathleen; Liu, Shubai; Zhou, Yilan; Rauh-Hain, Jose; Berkowitz, Ross; Ng, Shu-Wing (2012). "Casein kinase I epsilon interacts with mitochondrial proteins for the growth and survival of human ovarian cancer cells" (PDF). EMBO Molecular Medicine. 4: 952–963. doi:10.1002/emmm.201101094. Retrieved 23 April 2015.
  5. ↑ Albrecht, Urs (2010-01-23). The Circadian Clock. Springer Science & Business Media. ISBN 9781441912626. Retrieved 2015-04-04.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "Entrez Gene: CSNK1E casein kinase 1, epsilon".
  7. ↑ Niefind K, Guerra B, Pinna LA, Issinger OG, Schomburg D (May 1998). "Crystal structure of the catalytic subunit of protein kinase CK2 from Zea mays at 2.1 A resolution". The EMBO Journal. 17 (9): 2451–2462. doi:10.1093/emboj/17.9.2451. PMC 1170587. PMID 9564028.
  8. ↑ 8.0 8.1 Graves PR, Roach PJ (Sep 1995). "Role of COOH-terminal phosphorylation in the regulation of casein kinase I delta". The Journal of Biological Chemistry. 270 (37): 21689–21694. doi:10.1074/jbc.270.37.21689. PMID 7665585.
  9. ↑ 9.0 9.1 Klimczak LJ, Farini D, Lin C, Ponti D, Cashmore AR, Giuliano G (Oct 1995). "Multiple isoforms of Arabidopsis casein kinase I combine conserved catalytic domains with variable carboxyl-terminal extensions". Plant Physiology. 109 (2): 687–696. doi:10.1104/pp.109.2.687. PMC 157637. PMID 7480353.
  10. ↑ 10.0 10.1 10.2 Richards, Jacob; Gumz, Michelle L. (2012-09-01). "Advances in understanding the peripheral circadian clocks". The FASEB Journal. 26 (9): 3602–3613. doi:10.1096/fj.12-203554. ISSN 0892-6638. PMC 3425819. PMID 22661008. Retrieved 2015-04-18.
  11. ↑ 11.0 11.1 11.2 Ko CH, Takahashi JS (Oct 2006). "Molecular components of the mammalian circadian clock". Human Molecular Genetics. 15 Spec No 2 (suppl 2): R271–R277. doi:10.1093/hmg/ddl207. PMC 3762864. PMID 16987893.
  12. ↑ Akashi M, Tsuchiya Y, Yoshino T, Nishida E (Mar 2002). "Control of intracellular dynamics of mammalian period proteins by casein kinase I epsilon (CKIepsilon) and CKIdelta in cultured cells". Molecular and Cellular Biology. 22 (6): 1693–1703. doi:10.1128/MCB.22.6.1693-1703.2002. PMC 135601. PMID 11865049.
  13. ↑ Vielhaber E, Eide E, Rivers A, Gao ZH, Virshup DM (Jul 2000). "Nuclear entry of the circadian regulator mPER1 is controlled by mammalian casein kinase I epsilon". Molecular and Cellular Biology. 20 (13): 4888–4899. doi:10.1128/MCB.20.13.4888-4899.2000. PMC 85940. PMID 10848614.
  14. ↑ Gietzen KF, Virshup DM (Nov 1999). "Identification of inhibitory autophosphorylation sites in casein kinase I epsilon". The Journal of Biological Chemistry. 274 (45): 32063–32070. doi:10.1074/jbc.274.45.32063. PMID 10542239.
  15. ↑ Loudon, A.S.I. (2007). "The Biology of the Circadian Ck1ε tau Mutation in Mice and Syrian Hamsters: A Tale of Two Species". Cold Spring Harbor Symposia on Quantitative Biology. 72: 261–271. doi:10.1101/sqb.2007.72.073.
  16. ↑ Meng, Qing-Jun; Logunova, Larisa; Maywood, Elizabeth; Gallego, Monica; Chesham, Johanna E.; Yoo, Seung-Hee; Sládek, Martin; Takahashi, Joseph; Virshup, David M.; Hastings, Michael H.; Loudon, Andrew S.I. (10 April 2008). "Setting clock speed in mammals: the CK1ε tau mutation in mice accelerates the circadian pacemaker by selectively destabilizing PERIOD proteins". Neuron. 58 (1): 78–88. doi:10.1016/j.neuron.2008.01.019. PMC 3756141. PMID 18400165.
  17. ↑ Golombek, Diego A.; Rosenstein, Ruth E. (1 July 2010). "Physiology of Circadian Entrainment". Physiological Reviews. 90 (3): 1063–1102. doi:10.1152/physrev.00009.2009.
  18. ↑ Xu, Ying; Padiath, Quasar S.; Shapiro, Robert E.; Jones, Christopher R.; Wu, Susan C.; Saigoh, Noriko; Saigoh, Kazumasa; Ptáček, Louis J.; Fu, Ying-Hui (4 February 2005). "Functional consequences of a CK1δ mutation causing familial advanced sleep phase syndrome". Nature. 434: 640–644. doi:10.1038/nature03453. PMID 15800623.
  19. ↑ Partch, Carrie; Green, Carla; Takahashi, Joseph (Feb 2014). "Molecular architecture of the mammalian circadian clock". Trends in Cell Biology. 24 (2): 90–99. doi:10.1016/j.tcb.2013.07.002. PMC 3946763. Retrieved 23 April 2015.
  20. ↑ 20.0 20.1 Yu W, Zheng H, Price JL, Hardin PE (Mar 2009). "DOUBLETIME plays a noncatalytic role to mediate CLOCK phosphorylation and repress CLOCK-dependent transcription within the Drosophila circadian clock". Molecular and Cellular Biology. 29 (6): 1452–1458. doi:10.1128/MCB.01777-08. PMC 2648245. PMID 19139270.
  21. ↑ Fan, JY; Agyekum, B; Venkatesan, A; Hall, DR; Keightley, A; Bjes, ES; Bouyain, S; Price, JL. "Noncanonical FK506-Binding Protein BDBT Binds DBT to Enhance Its Circadian Function and Forms Foci at Night". Neuron. 80: 984–996. doi:10.1016/j.neuron.2013.08.004. PMC 3869642. PMID 24210908. Retrieved 2015-04-05.
  22. ↑ 22.0 22.1 Harms E, Young MW, Saez L (2003). "CK1 and GSK3 in the Drosophila and mammalian circadian clock". Novartis Foundation Symposium. 253: 267–277, discussion 102-109, 277–284. PMID 14712927.
  23. ↑ Minde; et al. "Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer?" (PDF). Molecular Cancer. Retrieved 2015-04-05.
  24. ↑ Knippschild U, Milne DM, Campbell LE, DeMaggio AJ, Christenson E, Hoekstra MF, Meek DW (Oct 1997). "p53 is phosphorylated in vitro and in vivo by the delta and epsilon isoforms of casein kinase 1 and enhances the level of casein kinase 1 delta in response to topoisomerase-directed drugs". Oncogene. 15 (14): 1727–1736. doi:10.1038/sj.onc.1201541. PMID 9349507.
  25. ↑ Shieh SY, Ikeda M, Taya Y, Prives C (Oct 1997). "DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2". Cell. 91 (3): 325–334. doi:10.1016/s0092-8674(00)80416-x. PMID 9363941.
  26. ↑ Sakaguchi K, Saito S, Higashimoto Y, Roy S, Anderson CW, Appella E (Mar 2000). "Damage-mediated phosphorylation of human p53 threonine 18 through a cascade mediated by a casein 1-like kinase. Effect on Mdm2 binding". The Journal of Biological Chemistry. 275 (13): 9278–9283. doi:10.1074/jbc.275.13.9278. PMID 10734067.
  27. ↑ Zhou, Qi; Li, Li; Zhao, Bin; Guan, Kun-Liang (Apr 10, 2015). "The Hippo Pathway in Heart Development, Regeneration, and Diseases". Circulation Research. 116 (8): 1431–1447. doi:10.1161/CIRCRESAHA.116.303311. ISSN 1524-4571. PMC 4394208. PMID 25858067.
  28. ↑ Vielhaber E, Eide E, Rivers A, Gao ZH, Virshup DM (Jul 2000). "Nuclear entry of the circadian regulator mPER1 is controlled by mammalian casein kinase I epsilon". Molecular and Cellular Biology. 20 (13): 4888–99. doi:10.1128/MCB.20.13.4888-4899.2000. PMC 85940. PMID 10848614.
  29. ↑ Zhang Y, Qiu WJ, Chan SC, Han J, He X, Lin SC (May 2002). "Casein kinase I and casein kinase II differentially regulate axin function in Wnt and JNK pathways". The Journal of Biological Chemistry. 277 (20): 17706–12. doi:10.1074/jbc.M111982200. PMID 11884395.
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