View source for Casein kinase 1

{{Short description|Family of protein kinases}}
The '''Casein kinase 1''' family ({{EC number|2.7.11.1}}) of [[protein kinase]]s are [[serine]]/[[threonine]]-selective enzymes that function as regulators of [[signal transduction]] pathways in most eukaryotic cell types. CK1 isoforms are involved in [[Wnt signaling pathway|Wnt signaling]], circadian rhythms, nucleo-cytoplasmic shuttling of transcription factors, DNA repair, and DNA transcription.<ref name="Eide"/>

==Discovery==
By the early 1950s it was known from metabolic labeling studies using radioactive [[phosphate]] that phosphate groups attached to [[phosphoprotein]]s inside cells can sometimes undergo rapid exchange of new phosphate for old. In order to perform experiments that would allow isolation and characterization of the [[enzyme]]s involved in attaching and removing phosphate from proteins, there was a need for convenient [[Substrate (biochemistry)|substrates]] for [[protein kinase]]s and [[phosphatase|protein phosphatases]]. [[Casein]] has been used as a substrate since the earliest days of research on protein [[phosphorylation]].<ref>{{cite journal | vauthors = Burnett G, Kennedy EP | title = The enzymatic phosphorylation of proteins | journal = The Journal of Biological Chemistry | volume = 211 | issue = 2 | pages = 969–80 | date = December 1954 | doi = 10.1016/S0021-9258(18)71184-8 | pmid = 13221602 | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=13221602 | doi-access = free }}</ref> By the late 1960s, [[CAMP-dependent protein kinase|cyclic AMP-dependent protein kinase]] had been purified, and most attention was centered on kinases and phosphatases that could regulate the activity of important enzymes. Casein kinase activity associated with the [[endoplasmic reticulum]] of mammary glands was first characterized in 1974, and its activity was shown to not depend on [[Cyclic adenosine monophosphate|cyclic AMP]].<ref>{{cite journal | vauthors = Bingham EW, Farrel HM | title = Casein kinase from the Golgi apparatus of lactating mammary gland | journal = The Journal of Biological Chemistry | volume = 249 | issue = 11 | pages = 3647–51 | date = June 1974 | doi = 10.1016/S0021-9258(19)42622-7 | pmid = 4364664 | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=4364664 | doi-access = free }}</ref>

==CK1 family==
{{Infobox protein
| Name       = casein kinase 1, alpha 1
| Symbol     = CSNK1A1
| EntrezGene = 1452
| OMIM       = 600505
<!--1
| HGNCeG1id = 2451 | RefSeq = NM_001892 | UniProt = P48729
| ECnumber = 2.7.11.1 | Chromosome = 5 | Arm = q | Band = 32 
| LocusSupplementaryData = 
-->| image      = Human casein kinase 1 alpha PDB 6GZD.png
| caption    = Human casein kinase 1 alpha bound to inhibitor (black). {{PDB|6GZD}}
| UniProt    = P48729
}}

The CK1 family of monomeric serine–threonine protein kinases is found in eukaryotic organisms from [[yeast]] to [[humans]]. Mammals have seven family members (sometimes referred to as [[isoforms]], but encoded by distinct genes): alpha, beta 1, gamma 1, gamma 2, gamma 3, delta, and epsilon. Isoforms range from 22 to 55 [[Dalton (unit)|kDa]] and have been identified in the membranes, nucleus, and cytoplasm of eukaryotes and additionally in the mitotic spindle in mammalian cells.<ref name="ReferenceA">{{cite journal | vauthors = Fish KJ, Cegielska A, Getman ME, Landes GM, Virshup DM | title = Isolation and characterization of human casein kinase I epsilon (CKI), a novel member of the CKI gene family | journal = The Journal of Biological Chemistry | volume = 270 | issue = 25 | pages = 14875–83 | date = June 1995 | pmid = 7797465 | doi = 10.1074/jbc.270.25.14875 | doi-access = free }}</ref> The family members have the highest homology in their kinase domains (53%–98% identical) and differ from most other protein kinases by the presence of the sequence S-I-N instead of A-P-E in kinase domain VIII.<ref>{{cite journal | vauthors = Hanks SK, Hunter T | title = Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification | journal = FASEB Journal | volume = 9 | issue = 8 | pages = 576–96 | date = May 1995 | pmid = 7768349 | doi = 10.1096/fasebj.9.8.7768349 | doi-access = free | s2cid = 21377422 }}</ref> The family members appear to have similar substrate specificity ''in vitro'',<ref name=Pulgar99>{{cite journal | vauthors = Pulgar V, Marin O, Meggio F, Allende CC, Allende JE, Pinna LA | title = Optimal sequences for non-phosphate-directed phosphorylation by protein kinase CK1 (casein kinase-1)--a re-evaluation | journal = European Journal of Biochemistry | volume = 260 | issue = 2 | pages = 520–6 | date = March 1999 | pmid = 10095790 | doi = 10.1046/j.1432-1327.1999.00195.x | doi-access = free }}</ref> and substrate selection is thought to be regulated in vivo via subcellular localization and docking sites in specific substrates. One consensus phosphorylation site is S/Tp-X-X-S/T, where S/Tp refers to a phospho-serine or phospho-threonine, X refers to any amino acid, and the underlined residues refer to the target site.<ref>{{cite journal | vauthors = Flotow H, Roach PJ | title = Synergistic phosphorylation of rabbit muscle glycogen synthase by cyclic AMP-dependent protein kinase and casein kinase I. Implications for hormonal regulation of glycogen synthase | journal = The Journal of Biological Chemistry | volume = 264 | issue = 16 | pages = 9126–8 | date = June 1989 | doi = 10.1016/S0021-9258(18)60501-0 | pmid = 2498326 | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=2498326 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Flotow H, Graves PR, Wang AQ, Fiol CJ, Roeske RW, Roach PJ | title = Phosphate groups as substrate determinants for casein kinase I action | journal = The Journal of Biological Chemistry | volume = 265 | issue = 24 | pages = 14264–9 | date = August 1990 | doi = 10.1016/S0021-9258(18)77295-5 | pmid = 2117608 | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=2117608 | doi-access = free }}</ref> Thus, this CKI consensus site requires priming by another kinase. CKI also phosphorylates a related unprimed site, which optimally contains a cluster of acidic amino acids N-terminal to the target S/T including an acidic residue at n − 3 and a hydrophobic region C-terminal to the target S/T.<ref name=Pulgar99/><ref>{{cite journal | vauthors = Flotow H, Roach PJ | title = Role of acidic residues as substrate determinants for casein kinase I | journal = The Journal of Biological Chemistry | volume = 266 | issue = 6 | pages = 3724–7 | date = February 1991 | doi = 10.1016/S0021-9258(19)67854-3 | pmid = 1995625 | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=1995625 | doi-access = free }}</ref> A single acidic residue in the n − 3 position is not sufficient for CKI phosphorylation. In contrast, in several important targets, NF-AT<ref>{{cite journal | vauthors = Zhu J, Shibasaki F, Price R, Guillemot JC, Yano T, Dötsch V, Wagner G, Ferrara P, McKeon F | title = Intramolecular masking of nuclear import signal on NF-AT4 by casein kinase I and MEKK1 | journal = Cell | volume = 93 | issue = 5 | pages = 851–61 | date = May 1998 | pmid = 9630228 | doi = 10.1016/S0092-8674(00)81445-2 | doi-access = free }}</ref> and beta-catenin,<ref>{{cite journal | vauthors = Amit S, Hatzubai A, Birman Y, Andersen JS, Ben-Shushan E, Mann M, Ben-Neriah Y, Alkalay I | title = Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway | journal = Genes & Development | volume = 16 | issue = 9 | pages = 1066–76 | date = May 2002 | pmid = 12000790 | pmc = 186245 | doi = 10.1101/gad.230302 }}</ref><ref>{{cite journal | vauthors = Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X, He X | title = Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism | journal = Cell | volume = 108 | issue = 6 | pages = 837–47 | date = March 2002 | pmid = 11955436 | doi = 10.1016/S0092-8674(02)00685-2 | doi-access = free }}</ref> CKI does not require n − 3 priming but, instead, phosphorylates the first serine in the sequence S-L-S, which is followed by a cluster of acidic residues, albeit less efficiently than the optimal sites.<ref>{{cite journal | vauthors = Marin O, Bustos VH, Cesaro L, Meggio F, Pagano MA, Antonelli M, Allende CC, Pinna LA, Allende JE | title = A noncanonical sequence phosphorylated by casein kinase 1 in beta-catenin may play a role in casein kinase 1 targeting of important signaling proteins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 18 | pages = 10193–200 | date = September 2003 | pmid = 12925738 | pmc = 193538 | doi = 10.1073/pnas.1733909100 | bibcode = 2003PNAS..10010193M | doi-access = free }}</ref>

==Roles==
{{Infobox protein
| Name       = casein kinase 1, gamma 1
| Symbol     = CSNK1G1
| EntrezGene = 53944
| OMIM       = 606274
<!--
| HGNCid = 2454 | RefSeq = NM_022048 | UniProt = Q9HCP0| ECnumber = 2.7.11.1 
| Chromosome = 15 | Arm = q | Band = 22.1-22.31 
| LocusSupplementaryData = 
-->| caption    = Human casein kinase 1 gamma 1 bound to inhibitor (black). {{PDB|2CMW}}
| image      = Human casein kinase 1 gamma 1 PDB 2CMW.png
| UniProt    = Q9HCP0
}}
{{Infobox protein
| Name       = casein kinase 1, gamma 2
| Symbol     = CSNK1G2
| EntrezGene = 1455
| OMIM       = 602214 
<!--
| HGNCid = 2455 | RefSeq = NM_001319 | UniProt = P78368 | ECnumber = 2.7.11.1 
| Chromosome = 19 | Arm = p | Band = 13.3 
| LocusSupplementaryData = 
-->| image      = Human casein kinase 1 gamma 2 PDB 2C47.png
| caption    = Human casein kinase 1 gamma 2 bound to 5-iodotubercidin. {{PDB|2C47}}
| UniProt    = P78368
}}
{{Infobox protein
| Name       = casein kinase 1, gamma 3
| Symbol     = CSNK1G3
| EntrezGene = 1456
| OMIM       = 604253 
<!--
| HGNCid = 2456 | RefSeq = NM_004384 | UniProt = Q9Y6M4 | ECnumber = 2.7.11.1 
| Chromosome = 5 | Arm = q | Band = 23 
| LocusSupplementaryData =
-->| image      = Human casein kinase 1 gamma 3 PDB 2CHL.png
| caption    = Human casein kinase 1 gamma 3 bound to inhibitor (black). {{PDB|2CHL}}
| UniProt    = Q9Y6M4
}}
{{Infobox protein
| Name       = casein kinase 1, delta
| Symbol     = CSNK1D
| AltSymbols = HCKID; CSNK1D
| EntrezGene = 1453
| OMIM       = 600864 
<!--
| HGNCid = 2452| UniProt = P8730 | HPRD=02920 
| Chromosome = 17 | Arm = q | Band = 25 
| LocusSupplementaryData = 
-->| image      = Human casein kinase 1 delta PDB 4TWC.png
| caption    = Human casein kinase 1 delta bound to inhibitor (black). {{PDB|4TWC}}
| UniProt    = P8730
}}
{{Infobox protein
| Name       = casein kinase 1, epsilon
| Symbol     = CSNK1E
| AltSymbols = HCKIE
| EntrezGene = 1454
| OMIM       = 600863 
<!--
| HGNCid = 2453 | RefSeq = NM_001894 | UniProt = P49674
| Chromosome = 22 | Arm = q | Band = 13.1 | LocusSupplementaryData = 
-->| image      = Human casein kinase 1 epsilon PDB 4HNI.png
| caption    = Human casein kinase 1 epsilon bound to inhibitor [[PF-4800567]] (black). {{PDB|4HNI}}
| UniProt    = P49674
}}

Casein kinase activity was found to be present in most cell types and to be associated with multiple enzymes. The type 1 casein kinase family of related gene products are now given designations such as "casein kinase 1 alpha" and "casein kinase 1 epsilon".

===Wnt signaling pathway===
[[Casein kinase 1 isoform epsilon|Casein kinase 1 epsilon]] has been suggested to play a role in phosphorylation of Disheveled in the [[Wnt signaling pathway]].<ref>{{cite journal | vauthors = Takada R, Hijikata H, Kondoh H, Takada S | title = Analysis of combinatorial effects of Wnts and Frizzleds on beta-catenin/armadillo stabilization and Dishevelled phosphorylation | journal = Genes to Cells | volume = 10 | issue = 9 | pages = 919–28 | date = September 2005 | pmid = 16115200 | doi = 10.1111/j.1365-2443.2005.00889.x | doi-access = free }}</ref> Casein kinase 1 alpha (CK1α) binds to and phosphorylates β‑catenin<ref>{{cite journal | vauthors = Zeng X, Tamai K, Doble B, Li S, Huang H, Habas R, Okamura H, Woodgett J, He X | title = A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation | journal = Nature | volume = 438 | issue = 7069 | pages = 873–7 | date = December 2005 | pmid = 16341017 | pmc = 2100418 | doi = 10.1038/nature04185 | bibcode = 2005Natur.438..873Z }}</ref>

In plants the phosphorylation of protein Jade-1 is regulated by casein kinase 1.<ref>{{cite journal | vauthors = Borgal L, Rinschen MM, Dafinger C, Hoff S, Reinert MJ, Lamkemeyer T, Lienkamp SS, Benzing T, Schermer B | title = Casein kinase 1 α phosphorylates the Wnt regulator Jade-1 and modulates its activity | journal = The Journal of Biological Chemistry | volume = 289 | issue = 38 | pages = 26344–56 | date = September 2014 | pmid = 25100726 | pmc = 4176241 | doi = 10.1074/jbc.M114.562165 | doi-access = free }}</ref> In humans there are three casein kinase 1 gamma enzymes.

''[[Xenopus laevis|Xenopus]]'' casein kinase 1 gamma (CK1gamma) is associated with the cell membrane and binds to LRP. CK1gamma was found to be needed for Wnt signaling through LRP, and is both necessary and sufficient to transduce LRP6 signaling in [[vertebrates]] and ''[[Drosophila melanogaster|Drosophila]]'' cells. Wnt binding to LRP causes a rapid increase in phosphorylation of the cytoplasmic domain of LRP by CK1gamma. Phosphorylation of LRP6 by CK1gamma promotes binding of axin to LRP and activation of the Wnt signaling pathway.<ref name="Davidson_2005">{{cite journal | vauthors = Davidson G, Wu W, Shen J, Bilic J, Fenger U, Stannek P, Glinka A, Niehrs C | title = Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction | journal = Nature | volume = 438 | issue = 7069 | pages = 867–72 | date = December 2005 | pmid = 16341016 | doi = 10.1038/nature04170 | bibcode = 2005Natur.438..867D | s2cid = 4322672 }}</ref>

=== Circadian rhythm ===

[[Casein kinase 1 isoform epsilon|CK1ε]] and [[CSNK1D|CK1δ]] are essential in the genetic transcription-translation (and post-translation) feedback loops that generate [[circadian rhythm]] in mammals.<ref>{{cite journal | vauthors = Lee H, Chen R, Lee Y, Yoo S, Lee C | title = Essential roles of CKIdelta and CKIepsilon in the mammalian circadian clock | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 50 | pages = 21359–64 | date = December 2009 | pmid = 19948962 | pmc = 2795500 | doi = 10.1073/pnas.0906651106 | doi-access = free }}</ref>

The previously-characterized CK1ε isoform was first implicated as a clock gene when its ''Drosophila'' homolog, double-time ([[Doubletime (gene)]]), was discovered in 1998.<ref name="ReferenceA"/><ref>{{cite journal | vauthors = Price JL, Blau J, Rothenfluh A, Abodeely M, Kloss B, Young MW | title = double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation | journal = Cell | volume = 94 | issue = 1 | pages = 83–95 | date = July 1998 | pmid = 9674430 | doi = 10.1016/S0092-8674(00)81224-6 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Kloss B, Price JL, Saez L, Blau J, Rothenfluh A, Wesley CS, Young MW | title = The Drosophila clock gene double-time encodes a protein closely related to human casein kinase Iepsilon | journal = Cell | volume = 94 | issue = 1 | pages = 97–107 | date = July 1998 | pmid = 9674431 | doi = 10.1016/s0092-8674(00)81225-8 | doi-access = free }}</ref> Double-time is 86% identical to human CK1ε.<ref name="Eide">{{cite journal | vauthors = Eide EJ, Virshup DM | title = Casein kinase I: another cog in the circadian clockworks | journal = Chronobiology International | volume = 18 | issue = 3 | pages = 389–98 | date = May 2001 | pmid = 11475410 | doi = 10.1081/CBI-100103963 | s2cid = 8581064 }}</ref> Kloss ''et al'' and Price ''et al'' showed that mutations in double-time altered circadian rhythm.  They found two DBT mutants that had abnormal free-running periods and one that was pupal-lethal but resulted in accumulations of hypophosphorylated [[Period (gene)|PER]] protein.  Since then,  double-time's protein product DBT has been well characterized for its role in phosphorylating PER, the protein product of clock gene [[period (gene)|period]] in Drosophila.

The role of CK1 in mammalian circadian rhythms was first identified through a spontaneous mutation in hamsters.<ref>{{Cite journal |last1=Ralph |first1=Martin R. |last2=Menaker |first2=Michael |date=1988-09-02 |title=A Mutation of the Circadian System in Golden Hamsters |url=https://www.science.org/doi/10.1126/science.3413487 |journal=Science |language=en |volume=241 |issue=4870 |pages=1225–1227 |doi=10.1126/science.3413487 |pmid=3413487 |bibcode=1988Sci...241.1225R |issn=0036-8075|url-access=subscription }}</ref> Homologs were subsequently identified in mice,<ref>{{Cite journal |last1=Meng |first1=Qing-Jun |last2=Logunova |first2=Larisa |last3=Maywood |first3=Elizabeth S. |last4=Gallego |first4=Monica |last5=Lebiecki |first5=Jake |last6=Brown |first6=Timothy M. |last7=Sládek |first7=Martin |last8=Semikhodskii |first8=Andrei S. |last9=Glossop |first9=Nicholas R.J. |last10=Piggins |first10=Hugh D. |last11=Chesham |first11=Johanna E. |last12=Bechtold |first12=David A. |last13=Yoo |first13=Seung-Hee |last14=Takahashi |first14=Joseph S. |last15=Virshup |first15=David M. |date=April 2008 |title=Setting Clock Speed in Mammals: The CK1ɛ tau Mutation in Mice Accelerates Circadian Pacemakers by Selectively Destabilizing PERIOD Proteins |url=https://doi.org/10.1016/j.neuron.2008.01.019 |journal=Neuron |volume=58 |issue=1 |pages=78–88 |doi=10.1016/j.neuron.2008.01.019 |issn=0896-6273 |pmc=3756141 |pmid=18400165}}</ref> and characterisation shows it plays a similar role to that proposed for Drosophila.<ref>{{cite journal | vauthors = Nawathean P, Rosbash M | title = The doubletime and CKII kinases collaborate to potentiate Drosophila PER transcriptional repressor activity | journal = Molecular Cell | volume = 13 | issue = 2 | pages = 213–23 | date = January 2004 | pmid = 14759367 | doi = 10.1016/S1097-2765(03)00503-3 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Takano A, Shimizu K, Kani S, Buijs RM, Okada M, Nagai K | title = Cloning and characterization of rat casein kinase 1epsilon | journal = FEBS Letters | volume = 477 | issue = 1–2 | pages = 106–12 | date = July 2000 | pmid = 10899319 | doi = 10.1016/s0014-5793(00)01755-5 | s2cid = 84666478 }}</ref>

In 2021, scientists reported the development of a light-responsive days-lasting modulator of circadian rhythms of tissues via Ck1 inhibition. Such modulators may be useful for [[chronobiology]] research and repair of organs that are "out of sync".<ref>{{cite news |title=Resetting the biological clock by flipping a switch |url=https://phys.org/news/2021-05-resetting-biological-clock-flipping.html |access-date=14 June 2021 |work=phys.org |language=en}}</ref><ref>{{cite journal | vauthors = Kolarski D, Miró-Vinyals C, Sugiyama A, Srivastava A, Ono D, Nagai Y, Iida M, Itami K, Tama F, Szymanski W, Hirota T, Feringa BL | display-authors = 6 | title = Reversible modulation of circadian time with chronophotopharmacology | journal = Nature Communications | volume = 12 | issue = 1 | pages = 3164 | date = May 2021 | pmid = 34039965 | pmc = 8155176 | doi = 10.1038/s41467-021-23301-x | bibcode = 2021NatCo..12.3164K }} [[File:CC-BY icon.svg|50px]] Available under [https://creativecommons.org/licenses/by/4.0/ CC BY 4.0].</ref>

==== Interactions ====

DBT has been shown to physically interact with PER in vitro and in vivo, and to create a stable complex with PER throughout the circadian cycle.<ref name="DBT">{{cite journal | vauthors = Kivimäe S, Saez L, Young MW | title = Activating PER repressor through a DBT-directed phosphorylation switch | journal = PLOS Biology | volume = 6 | issue = 7 | pages = e183 | date = July 2008 | pmid = 18666831 | pmc = 2486307 | doi = 10.1371/journal.pbio.0060183 | editor1-last = Schibler | editor1-first = Ueli | doi-access = free }}</ref> PER that has been phosphorylated by DBT is recognized by the Slimb protein. Slimb is a component of the Skp1/Cullin/F-box protein (SCF) ubiquitin ligase complex, which marks proteins for proteosomal degradation in a phosphorylation-dependent manner.<ref name="DBT"/> Enhanced PER degradation in the cytoplasm is predicted to delay nuclear translocation of both PER and TIM, and to thus affect the period of circadian rhythms.

The mutation dbtS, associated with a [[proline]] to serine substitution at residue 47 [P47S], shortens period length by about 6 h. dbtL contains an amino acid substitution of [[isoleucine]] for [[methionine]] at residue 80 (M80I) and lengthens period to 29 h.<ref name="DBT"/> A third mutation, dbtAR, is associated with a change from [[histidine]] 126 to [[tyrosine]] and causes arrhythmia. PER protein in this mutant is hypophosphorylated.<ref name="DBT"/> Each of these mutations maps to the kinase domain of DBT gene. The short- and long-period alleles of DBT enhance or attenuate, respectively, PER degradation in the nucleus, further demonstrating the importance of timely PER degradation as a critical determinant in establishing 24-h rhythmicity. In addition to influencing protein degradation, DBT affects the timing of nuclear accumulation of PER. The short-period mutant dbtS delays PER nuclear accumulation, which is independent of PER protein stability, and arrhythmic alleles of dbt cause nuclear accumulation of PER in clock-containing cells of larval and adult ''Drosophila''.<ref name="DBT"/>

Both mammalian CK1δ and CK1ε contain closely related 123-amino-acid carboxy-terminal domains that can auto-regulate kinase activity. CK1δ and CK1ε are 53% identical.<ref name="Eide"/> These domains are not related to the carboxy-terminal domain of double-time, suggesting a split in the evolution of the mammalian and fly homologs.<ref name="Knippschild"/>
A similar function for [[casein kinase 2]] has been reported in ''[[Arabidopsis thaliana]]'', [[Drosophila melanogaster|''Drosophila'']], and ''[[Neurospora]]''.<ref>{{cite journal | vauthors = Lin JM, Kilman VL, Keegan K, Paddock B, Emery-Le M, Rosbash M, Allada R | title = A role for casein kinase 2alpha in the Drosophila circadian clock | journal = Nature | volume = 420 | issue = 6917 | pages = 816–20 | year = 2002 | pmid = 12447397 | doi = 10.1038/nature01235 | bibcode = 2002Natur.420..816L | s2cid = 4392513 }}</ref><ref>{{cite journal | vauthors = Ochoa J, Marotte L | title = The nature of the nerve lesion caused by chronic entrapment in the guinea-pig | journal = Journal of the Neurological Sciences | volume = 19 | issue = 4 | pages = 491–5 | date = August 1973 | pmid = 4724822 | doi = 10.1016/0022-510X(73)90045-2 }}</ref><ref>{{cite journal | vauthors = Yang Y, Cheng P, Liu Y | title = Regulation of the Neurospora circadian clock by casein kinase II | journal = Genes & Development | volume = 16 | issue = 8 | pages = 994–1006 | date = April 2002 | pmid = 11959847 | pmc = 152355 | doi = 10.1101/gad.965102 }}</ref>

==== Positive and negative feedback ====

In the [[negative feedback]] loops, CK1ε periodically binds to and phosphorylates the PER proteins ([[PER1]], [[PER2]], and [[PER3]]), which form heterodimers with each other and interact with [[CRY1]] and [[CRY2]].<ref name="BMAL"/> The effects of phosphorylation are two-fold. It has been shown in Drosophila that phosphorylation of the PER proteins increase their ubiquitination, which leads to degradation.<ref name="Knippschild">{{cite journal | vauthors = Knippschild U, Gocht A, Wolff S, Huber N, Löhler J, Stöter M | title = The casein kinase 1 family: participation in multiple cellular processes in eukaryotes | journal = Cellular Signalling | volume = 17 | issue = 6 | pages = 675–89 | date = June 2005 | pmid = 15722192 | doi = 10.1016/j.cellsig.2004.12.011 }}</ref> Phosphorylation of the PER proteins also leaves them unable to enter the nucleus, where they suppress transcription of clock genes.<ref>{{cite journal | vauthors = Virshup DM, Eide EJ, Forger DB, Gallego M, Harnish EV | title = Reversible protein phosphorylation regulates circadian rhythms | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 72 | pages = 413–20 | year = 2007 | pmid = 18419299 | doi = 10.1101/sqb.2007.72.048 | doi-access = free }}</ref> The blocking of nuclear translocation occurs via phosphorylation of PER at the [[nuclear localization signal]], which masks the signal and prevents nuclear entry. However, this CK1ε-mediated constraint to the cytoplasm can be overcome when the PER protein complex is bound to CRY.<ref name="BMAL">{{cite journal | vauthors = Eide EJ, Vielhaber EL, Hinz WA, Virshup DM | title = The circadian regulatory proteins BMAL1 and cryptochromes are substrates of casein kinase Iepsilon | journal = The Journal of Biological Chemistry | volume = 277 | issue = 19 | pages = 17248–54 | date = May 2002 | pmid = 11875063 | pmc = 1513548 | doi = 10.1074/jbc.M111466200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Vielhaber E, Eide E, Rivers A, Gao ZH, Virshup DM | title = Nuclear entry of the circadian regulator mPER1 is controlled by mammalian casein kinase I epsilon | journal = Molecular and Cellular Biology | volume = 20 | issue = 13 | pages = 4888–99 | date = July 2000 | pmid = 10848614 | pmc = 85940 | doi = 10.1128/MCB.20.13.4888-4899.2000 }}</ref> CK1ε has been shown to phosphorylate CRY when both CK1ε and CRY are complexed with PER in vitro, but the functional significance of this remains undetermined.<ref name="BMAL"/>

CK1ε may also have a role in [[positive feedback]]; the transcription factor [[BMAL1]] is a CK1ε substrate in vitro, and increased CK1ε activity has been shown to positively regulate transcription of genes under the influence of BMAL1-dependent circadian gene [[Promoter (biology)|promoter]]s.<ref name="BMAL"/> This has not yet been studied [[in vivo]].

==== Significance in disease ====

CK1δ and CK1ε have been shown to be relevant in human disease. Recent findings indicate that pharmaceutical inhibition of CK1 may be a promising therapeutic for aberrant circadian rhythm.<ref name="Functional consequences of a CKIdel">{{cite journal | vauthors = Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, Saigoh N, Saigoh K, Ptácek LJ, Fu YH | title = Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome | journal = Nature | volume = 434 | issue = 7033 | pages = 640–4 | date = March 2005 | pmid = 15800623 | doi = 10.1038/nature03453 | bibcode = 2005Natur.434..640X | s2cid = 4416575 }}</ref> Mutations and variants of the CK1ε phosphorylation site of PER2 are associated with cases of [[advanced sleep phase syndrome#Familial advanced sleep phase syndrome|Familial Advanced Sleep Phase Syndrome]] (FASPS).<ref name="Functional consequences of a CKIdel"/><ref>{{cite journal | vauthors = Meng QJ, Maywood ES, Bechtold DA, Lu WQ, Li J, Gibbs JE, Dupré SM, Chesham JE, Rajamohan F, Knafels J, Sneed B, Zawadzke LE, Ohren JF, Walton KM, Wager TT, Hastings MH, Loudon AS | title = Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 34 | pages = 15240–5 | date = August 2010 | pmid = 20696890 | pmc = 2930590 | doi = 10.1073/pnas.1005101107 | bibcode = 2010PNAS..10715240M | doi-access = free }}</ref><ref name="longdaysin">{{cite journal | vauthors = Hirota T, Lee JW, Lewis WG, Zhang EE, Breton G, Liu X, Garcia M, Peters EC, Etchegaray JP, Traver D, Schultz PG, Kay SA | title = High-throughput chemical screen identifies a novel potent modulator of cellular circadian rhythms and reveals CKIα as a clock regulatory kinase | journal = PLOS Biology | volume = 8 | issue = 12 | pages = e1000559 | date = December 2010 | pmid = 21179498 | pmc = 3001897 | doi = 10.1371/journal.pbio.1000559 | doi-access = free }}</ref>  Similarly, length variations in the CK1ε phosphorylation site of PER3 have been found to correlate with 'morningness' and 'eveningness'; longer alleles are associated with early risers while shorter alleles are associated with late risers.  Additionally, 75% of patients with [[Delayed sleep phase syndrome]] are homozygous for the shorter allele.<ref>{{cite journal |pages=412–415 |doi= 10.1093/sleep/26.4.413|pmid= 12841365|title=A Length Polymorphism in the Circadian Clock Gene Per3 is Linked to Delayed Sleep Phase Syndrome and Extreme Diurnal Preference |year=2003 |last1=Archer |first1=Simon N. |last2=Robilliard |first2=Donna L. |last3=Skene |first3=Debra J. |last4=Smits |first4=Marcel |last5=Williams |first5=Adrian |last6=Arendt |first6=Josephine |last7=von Schantz |first7=Malcolm|journal=Sleep |volume=26 |issue=4|doi-access=free }}</ref>

Mutations in CK1 have been shown to alter circadian behavior in other mammals, as well.  In 1988, the golden hamster ''tau'' mutant, which has a freerunning period of 22hrs,  was the first mammalian circadian mutant discovered.<ref>{{cite journal | vauthors = Ralph MR, Menaker M | title = A mutation of the circadian system in golden hamsters | journal = Science | volume = 241 | issue = 4870 | pages = 1225–7 | date = September 1988 | pmid = 3413487 | doi = 10.1126/science.3413487 | bibcode = 1988Sci...241.1225R }}</ref> Twelve years later in 2000, the ''tau'' mutation was mapped to CK1ε.<ref>{{cite journal | vauthors = Lowrey PL, Shimomura K, Antoch MP, Yamazaki S, Zemenides PD, Ralph MR, Menaker M, Takahashi JS | title = Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau | journal = Science | volume = 288 | issue = 5465 | pages = 483–92 | date = April 2000 | pmid = 10775102 | pmc = 3869379 | doi = 10.1126/science.288.5465.483 | bibcode = 2000Sci...288..483L }}</ref> Since its discovery, the ''tau'' mutant has proven to be a valuable research tool in circadian biology. CK1ɛ<sup>tau</sup>, a T178C substitution, is a gain-of function mutation that causes an increase in degradation of PER, but not CRY.<ref name="Etchegaray"/> This creates a disruption in the PER-regulated feedback loop and consequently an acceleration of molecular oscillations. [[Zygosity#Homozygous|Homozygous]] mutants (CK1ε(''tau/tau'')) show a significant decrease in period, both in vivo (behaviorally) and in vitro (measured by firing rates of the [[suprachiasmatic nucleus]]).<ref>{{cite journal | vauthors = Meng QJ, Logunova L, Maywood ES, Gallego M, Lebiecki J, Brown TM, Sládek M, Semikhodskii AS, Glossop NR, Piggins HD, Chesham JE, Bechtold DA, Yoo SH, Takahashi JS, Virshup DM, Boot-Handford RP, Hastings MH, Loudon AS | title = Setting clock speed in mammals: the CK1 epsilon tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins | journal = Neuron | volume = 58 | issue = 1 | pages = 78–88 | date = April 2008 | pmid = 18400165 | pmc = 3756141 | doi = 10.1016/j.neuron.2008.01.019 }}</ref> Recent research has also identified a link between mutations in the CK1δ gene and familial migraine and advanced sleep phase, a finding that was replicated in mice migraine models.<ref>{{cite journal | vauthors = Brennan KC, Bates EA, Shapiro RE, Zyuzin J, Hallows WC, Huang Y, Lee HY, Jones CR, Fu YH, Charles AC, Ptáček LJ | title = Casein kinase iδ mutations in familial migraine and advanced sleep phase | journal = Science Translational Medicine | volume = 5 | issue = 183 | pages = 183ra56, 1–11 | date = May 2013 | pmid = 23636092 | pmc = 4220792 | doi = 10.1126/scitranslmed.3005784 }}</ref>

==== Roles of isoforms ====

CK1δ and CK1ε were thought to be generally redundant in circadian cycle length and protein stability.<ref name="Etchegaray"/> Recent research, however, has shown that CK1δ deficiency lengthens circadian period while CK1ε deficiency does not.<ref name="Etchegaray">{{cite journal | vauthors = Etchegaray JP, Machida KK, Noton E, Constance CM, Dallmann R, Di Napoli MN, DeBruyne JP, Lambert CM, Yu EA, Reppert SM, Weaver DR | title = Casein kinase 1 delta regulates the pace of the mammalian circadian clock | journal = Molecular and Cellular Biology | volume = 29 | issue = 14 | pages = 3853–66 | date = July 2009 | pmid = 19414593 | pmc = 2704743 | doi = 10.1128/MCB.00338-09 }}</ref> Also, CK1α has recently been suggested to play a role redundant to CK1δ in phosphorylating PER1<ref name= "longdaysin"/> although this is not consistent with other data<ref>{{Cite journal|last1=Vielhaber|first1=E.|last2=Eide|first2=E.|last3=Rivers|first3=A.|last4=Gao|first4=Z.-H.|last5=Virshup|first5=D. M.|date=2000-07-01|title=Nuclear Entry of the Circadian Regulator mPER1 Is Controlled by Mammalian Casein Kinase I varepsilon|journal=Molecular and Cellular Biology|language=en|volume=20|issue=13|pages=4888–4899|doi=10.1128/MCB.20.13.4888-4899.2000|pmid=10848614|pmc=85940|issn=0270-7306}}</ref>

=== Nucleo-cytoplasmic regulation of transcription factors ===

CKIα or CKIδ is essential in modulating the nuclear export of eukaryotic translation initiation factor 6 ([[eIF6]]), a protein with essential nuclear and cytoplasmic roles in [[biogenesis]] of the [[60S]] subunit of the eukaryotic [[ribosome]].<ref name="Biswas">{{cite journal | vauthors = Biswas A, Mukherjee S, Das S, Shields D, Chow CW, Maitra U | title = Opposing action of casein kinase 1 and calcineurin in nucleo-cytoplasmic shuttling of mammalian translation initiation factor eIF6 | journal = The Journal of Biological Chemistry | volume = 286 | issue = 4 | pages = 3129–38 | date = January 2011 | pmid = 21084295 | pmc = 3024805 | doi = 10.1074/jbc.M110.188565 | doi-access = free }}</ref> Phosphorylation of Ser-174 and Ser-175 by CKI promotes nuclear export of eIF6 while dephosphorylation by [[calcineurin]] promotes nuclear accumulation of eIF6.<ref name="Biswas"/> It is unclear whether the same mechanism is responsible for eIF6 cycling in yeast and if other kinases also play roles in these processes.

CKI homologs are also implicated in cytoplasmic shuttling of nuclear factor of activated T-cells ([[NFAT]]) through observation that the transcription factor Crz1p is phosphorylated by a CKI homolog in yeast.<ref>{{cite journal | vauthors = Kafadar KA, Zhu H, Snyder M, Cyert MS | title = Negative regulation of calcineurin signaling by Hrr25p, a yeast homolog of casein kinase I | journal = Genes & Development | volume = 17 | issue = 21 | pages = 2698–708 | date = November 2003 | pmid = 14597664 | pmc = 280619 | doi = 10.1101/gad.1140603 }}</ref>

=== Interphase, mitosis and DNA repair ===

CKIδ activity is implicated in [[mitosis]] and in response to DNA damage.<ref name="Behrend">{{cite journal | vauthors = Behrend L, Stöter M, Kurth M, Rutter G, Heukeshoven J, Deppert W, Knippschild U | title = Interaction of casein kinase 1 delta (CK1delta) with post-Golgi structures, microtubules and the spindle apparatus | journal = European Journal of Cell Biology | volume = 79 | issue = 4 | pages = 240–51 | date = April 2000 | pmid = 10826492 | doi = 10.1078/S0171-9335(04)70027-8 }}</ref> During [[interphase]], CKIδ associates with the [[Golgi Apparatus]] and appears to regulate the budding of [[clathrin]] coated [[Vesicle (biology)|vesicles]] from the TGN; it also appears to associate with [[tubulin]].<ref name="Behrend"/> While undamaged mitotic cells shows no CKIδ association with [[tubulin]], the kinase was recruited during mitosis in cells with DNA damage, indicative of a role for CKIδ in arranging the [[microtubule]] network during mitosis.<ref name="Behrend"/> The mechanisms for these biochemical interactions remain unknown.

== See also ==
*[[Casein kinase 2]] — a distinct protein kinase family

== References ==
{{reflist|35em}}

{{Cell signaling}}
{{Serine/threonine-specific protein kinases}}

{{DEFAULTSORT:Casein Kinase 1}}
[[Category:Signal transduction]]
[[Category:Protein kinases]]