Casein kinase 1
The Casein kinase 1 family of protein kinase
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...

s are serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...

Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...

-selective enzymes that function as regulators of signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...

 pathways in most eukaryotic cell types. CK1 isoforms are involved in Wnt signaling, circadian rhythms, nucleo-cytoplasmic shuttling of transcription factors, DNA repair, and DNA transcription.


By the early 1950s it was known from metabolic labeling studies using radioactive phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...

 that phosphate groups attached to phosphoprotein
Phosphoproteins are proteins that are physically bonded to a substance containing phosphoric acid . This category of organic molecules includes Fc receptors, Ulks, Calcineurins, K chips, and urocortins....

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
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

s involved in attaching and removing phosphate from proteins, there was a need for convenient substrates
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...

 for protein kinase
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...

s and protein phosphatases. Casein
Casein is the name for a family of related phosphoprotein proteins . These proteins are commonly found in mammalian milk, making up 80% of the proteins in cow milk and between 60% and 65% of the proteins in human milk....

 has been used as a substrate since the earliest days of research on protein phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....

. By the late 1960s, cyclic AMP-dependent protein kinase
CAMP-dependent protein kinase
In cell biology, Protein kinase A refers to a family of enzymes whose activity is dependent on cellular levels of cyclic AMP . PKA is also known as cAMP-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
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...

 of mammary glands was first characterized in 1974, and its activity was shown to not depend on cyclic AMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...


CK1 Family

The CK1 family of monomeric serine–threonine protein kinases is found in eukaryotic organisms from yeast
Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...

 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 kDa
DA, da, or dA may refer to:* Da , a Tony-winning play by Hugh Leonard* Da , a movie adaptation of the play by Hugh Leonard* Adi Da, a spiritual leader once known as Da Free John, and Da Love-Ananda...

 and have been identified in the membranes, nucleus, and cytoplasm of eukaryotes and additionally in the mitotic spindle in mammalian cells. 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. The family members appear to have similar substrate specificity in vitro, 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. 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. A single acidic residue in the n − 3 position is not sufficient for CKI phosphorylation. In contrast, in several important targets, NF-AT and beta-catenin, 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.


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 epsilon has been suggested to play a role in phosphorylation of Disheveled in the Wnt signaling pathway
Wnt signaling pathway
The Wnt signaling pathway is a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.-Discovery:...

In humans there are three casein kinase 1 gamma enzymes. Working with the Xenopus
Xenopus is a genus of highly aquatic frogs native to Sub-Saharan Africa. There are 19 species in the Xenopus genus...

 system, Davidson et al. screened for proteins that can regulate the Wnt signaling pathway by interacting with the Wnt receptor LRP. They reported that 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. is both necessary and sufficient to transduce LRP6 signaling in vertebrates and Drosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...

 cells. Wnt binding to LRP causes a rapid increase in phosphorylation of the cytoplasmic domain of LRP by CK1gamma. Davidson et al. proposed that phosphorylation of LRP6 by CK1gamma promotes binding of Axin to LRP and activation of the Wnt signaling pathway.

Circadian Rhythm

CK1ε and CK1δ are essential in the genetic transcription-translation (and post-translation) feedback loops that generate circadian rhythm in mammals.

The previously-characterized CK1ε isoform was first implicated as a clock gene when its Drosophila homolog, double-time (DBT (gene)
DBT (gene)
Lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, mitochondrial is an enzyme that in humans is encoded by the DBT gene.-Further reading:...

), was discovered in 1998. Double-time is 86% identical to human CK1ε. 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 PER
Per or PER may refer to:* Per , a Scandinavian form of Peter* Per , a storm in Sweden, in January 2007* the IOC country code for Peru* the IATA code for Perth Airport in Western Australia...

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
Period (gene)
Period is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving...

 in Drosophila, and its mammalian homologs appear to play a similar role.


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. 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. 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
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...

 to serine substitution at residue 47 [P47S], shortens period length by about 6 h. dbtL contains an amino acid substitution of isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....

 for methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...

 at residue 80 (M80I) and lengthens period to 29 h. A third mutation, dbtAR, is associated with a change from histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...

 126 to tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...

 and causes arrhythmia. PER protein in this mutant is hypophosphorylated. 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.

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. 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.
A similar function for casein kinase 2
Casein kinase 2
The Casein kinase 2 is a serine/threonine-selective protein kinase that is a tetramer of two alpha subunits and two beta subunits. The alpha subunits have the catalytic kinase domain...

 has been reported in Arabidopsis thaliana
Arabidopsis thaliana
Arabidopsis thaliana is a small flowering plant native to Europe, Asia, and northwestern Africa. A spring annual with a relatively short life cycle, arabidopsis is popular as a model organism in plant biology and genetics...

, Drosophila, and Neurospora
Neurospora is a genus of Ascomycete fungi. The genus name, meaning "nerve spore" refers to the characteristic striations on the spores that resemble axons....


Positive and negative feedback

In the negative feedback loops, CK1ε periodically binds to and phosphorylates the PER proteins (PER1
Period circadian protein homolog 1 is a protein that in humans is encoded by the PER1 gene....

, PER2
Period circadian protein homolog 2 is a protein that in humans is encoded by the PER2 gene.PER2 contains glucocorticoid response elements and a GRE within the core clock gene Per2 is continuously occupied during rhythmic expression and essential for glucocorticoid regulation of PER2 in vivo...

, and PER3
Period circadian protein homolog 3 is a protein that in humans is encoded by the PER3 gene....

), which form heterodimers with each other and interact with CRY1 and CRY2. 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. Phosphorylation of the PER proteins also leaves them unable to enter the nucleus, where they suppress transcription of clock genes. The blocking of nuclear translocation occurs via phosphorylation of PER at the nuclear localization signal
Nuclear localization signal
A nuclear localization signal or sequence is an amino acid sequence which 'tags' a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of one or more short sequences of positively charged lysines or arginines exposed on the protein surface. Different...

, 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. 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.

CK1ε may also have a role in positive feedback
Positive feedback
Positive feedback is a process in which the effects of a small disturbance on a system include an increase in the magnitude of the perturbation. That is, A produces more of B which in turn produces more of A. In contrast, a system that responds to a perturbation in a way that reduces its effect is...

; 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 promoters. This has not yet been studied in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...


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. Mutations and variants of the CK1ε phosphorylation site of PER2 are associated with cases of Familial Advanced Sleep Phase Syndrome (FASPS). 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
Delayed sleep phase syndrome
Delayed sleep-phase syndrome , also known as delayed sleep-phase disorder or delayed sleep-phase type , is a circadian rhythm sleep disorder, a chronic disorder of the timing of sleep, peak period of alertness, the core body temperature rhythm, hormonal and other daily rhythms, compared to the...

 are homozygous for the shorter allele.

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. Twelve years later in 2000, the tau mutation was mapped to CK1ε. Since its discovery, the tau mutant has proven to be a valuable research tool in circadian biology. CK1ɛtau, a T178C substitution, is a gain-of function mutation that causes an increase in degradation of PER, but not CRY. This creates a disruption in the PER-regulated feedback loop and consequently an acceleration of molecular oscillations. 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
Suprachiasmatic nucleus
The suprachiasmatic nucleus or nuclei, abbreviated SCN, is a tiny region on the brain's midline, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms...


Roles of isoforms

CK1δ and CK1ε were thought to be generally redundant in circadian cycle length and protein stability. Recent research, however, has shown that CK1δ deficiency lengthens circadian period while CK1ε deficiency does not. Also, CK1α has recently been shown to play a role reduntant to CK1δ in phosphorylating PER1.

Nucleo-cytoplasmic shutting of transcription factors

A 2010 study by Biswas et al has shown that CKIα or CKIδ is essential in modulating the nuclear export of eukaryotic translation initiation factor 6 (eIF6
Eukaryotic translation initiation factor 6 , also known as Integrin beta 4 binding protein , is a human gene....

), a protein with essential nuclear and cytoplasmic roles in biogenesis
Biogenesis is the law that living things come only from other living things, e.g. a spider lays eggs, which develop into spiders. It may also refer to biochemical processes of production in living organisms.-Spontaneous generation:...

 of the 60S
60S is the large ribosomal subunit in eukaryotes. It corresponds to 50S in prokaryotes.It consists of the following:* 5S* 28S* 5.8SThe following is a list of proteins contained within the 60S ribosome:...

 subunit of the eukaryotic ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....

. Phosphorylation of Ser-174 and Ser-175 by CKI promotes nuclear export of eIF6 while dephosphorylation by calcineurin
Calcineurin is a protein phosphatase also known as protein phosphatase 3, PPP3CA, and calcium-dependent serine-threonine phosphatase, and formerly known as protein phosphatase 2B . It activates the T cells of the immune system and can be blocked by drugs...

 promotes nuclear accumulation of eIF6. 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
Nuclear factor of activated T-cells is a general name applied to a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system...

) through observation that the transcription factor Crz1p is phosphorylated by a CKI homolog in yeast.

Interphase, mitosis and DNA repair

A study by Behrend et al on mouse cells has implicated CKIδ activity during mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...

 and in response to DNA damage. During interphase
Interphase is the phase of the cell cycle in which the cell spends the majority of its time and performs the majority of its purposes including preparation for cell division. In preparation for cell division, it increases its size and makes a copy of its DNA...

, CKIδ associates with the Golgi Apparatus
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....

 and appears to regulate the budding of clathrin
Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1975. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskelia interact they form a polyhedral lattice...

 coated vesicles
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...

 from the TGN; it also appears to associate with tubulin
Tubulin is one of several members of a small family of globular proteins. The most common members of the tubulin family are α-tubulin and β-tubulin, the proteins that make up microtubules. Each has a molecular weight of approximately 55 kiloDaltons. Microtubules are assembled from dimers of α- and...

. While undamaged mitotic cells shows no CKIδ association with tubulin
Tubulin is one of several members of a small family of globular proteins. The most common members of the tubulin family are α-tubulin and β-tubulin, the proteins that make up microtubules. Each has a molecular weight of approximately 55 kiloDaltons. Microtubules are assembled from dimers of α- and...

, the kinase was recruited during mitosis in cells with DNA damage, indicative of a role for CKIδ in arranging the microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...

network during mitosis. The mechanisms for these biochemical interactions remain unknown.
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