Casein kinase 1

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The Casein kinase 1 family (EC 2.7.11.1) of protein kinases 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, circadian rhythms, nucleo-cytoplasmic shuttling of transcription factors, DNA repair, and DNA transcription. [1]

Contents

Discovery

By the early 1950s it was known from metabolic labeling studies using radioactive phosphate that phosphate groups attached to phosphoproteins 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 enzymes involved in attaching and removing phosphate from proteins, there was a need for convenient substrates for protein kinases and protein phosphatases. Casein has been used as a substrate since the earliest days of research on protein phosphorylation. [2] By the late 1960s, 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 AMP. [3]

CK1 family

casein kinase 1, alpha 1
Human casein kinase 1 alpha PDB 6GZD.png
Human casein kinase 1 alpha bound to inhibitor (black). PDB: 6GZD
Identifiers
SymbolCSNK1A1
NCBI gene 1452
OMIM 600505
UniProt P48729
Search for
Structures Swiss-model
Domains InterPro

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 kDa and have been identified in the membranes, nucleus, and cytoplasm of eukaryotes and additionally in the mitotic spindle in mammalian cells. [4] 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. [5] The family members appear to have similar substrate specificity in vitro, [6] 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. [7] [8] 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. [6] [9] A single acidic residue in the n − 3 position is not sufficient for CKI phosphorylation. In contrast, in several important targets, NF-AT [10] and beta-catenin, [11] [12] 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. [13]

Roles

casein kinase 1, gamma 1
Human casein kinase 1 gamma 1 PDB 2CMW.png
Human casein kinase 1 gamma 1 bound to inhibitor (black). PDB: 2CMW
Identifiers
SymbolCSNK1G1
NCBI gene 53944
OMIM 606274
UniProt Q9HCP0
Search for
Structures Swiss-model
Domains InterPro
casein kinase 1, gamma 2
Human casein kinase 1 gamma 2 PDB 2C47.png
Human casein kinase 1 gamma 2 bound to 5-iodotubercidin. PDB: 2C47
Identifiers
SymbolCSNK1G2
NCBI gene 1455
OMIM 602214
UniProt P78368
Search for
Structures Swiss-model
Domains InterPro
casein kinase 1, gamma 3
Human casein kinase 1 gamma 3 PDB 2CHL.png
Human casein kinase 1 gamma 3 bound to inhibitor (black). PDB: 2CHL
Identifiers
SymbolCSNK1G3
NCBI gene 1456
OMIM 604253
UniProt Q9Y6M4
Search for
Structures Swiss-model
Domains InterPro
casein kinase 1, delta
Human casein kinase 1 delta PDB 4TWC.png
Human casein kinase 1 delta bound to inhibitor (black). PDB: 4TWC
Identifiers
SymbolCSNK1D
Alt. symbolsHCKID; CSNK1D
NCBI gene 1453
OMIM 600864
UniProt P8730
Search for
Structures Swiss-model
Domains InterPro
casein kinase 1, epsilon
Human casein kinase 1 epsilon PDB 4HNI.png
Human casein kinase 1 epsilon bound to inhibitor PF-4800567 (black). PDB: 4HNI
Identifiers
SymbolCSNK1E
Alt. symbolsHCKIE
NCBI gene 1454
OMIM 600863
UniProt P49674
Search for
Structures Swiss-model
Domains InterPro

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. [14] Casein kinase 1 alpha (CK1α) binds to and phosphorylates β‑catenin [15]

In plants the phosphorylation of protein Jade-1 is regulated by casein kinase 1. [16] In humans there are three casein kinase 1 gamma enzymes.

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 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. [17]

Circadian rhythm

CK1ε and CK1δ are essential in the genetic transcription-translation (and post-translation) feedback loops that generate circadian rhythm in mammals. [18]

The previously-characterized CK1ε isoform was first implicated as a clock gene when its Drosophila homolog, double-time (Doubletime (gene)), was discovered in 1998. [4] [19] [20] Double-time is 86% identical to human CK1ε. [1] 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 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 in Drosophila.

The role of CK1 in mammalian circadian rhythms was first identified through a spontaneous mutation in hamsters. [21] Homologs were subsequently identified in mice, [22] and characterisation shows it plays a similar role to that proposed for Drosophila. [23] [24]

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". [25] [26]

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. [27] 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. [27] 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. [27] A third mutation, dbtAR, is associated with a change from histidine 126 to tyrosine and causes arrhythmia. PER protein in this mutant is hypophosphorylated. [27] 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. [27]

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. [1] 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. [28] A similar function for casein kinase 2 has been reported in Arabidopsis thaliana , Drosophila, and Neurospora . [29] [30] [31]

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. [32] 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. [28] Phosphorylation of the PER proteins also leaves them unable to enter the nucleus, where they suppress transcription of clock genes. [33] 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. [32] [34] 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. [32]

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 promoters. [32] 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. [35] Mutations and variants of the CK1ε phosphorylation site of PER2 are associated with cases of Familial Advanced Sleep Phase Syndrome (FASPS). [35] [36] [37] 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. [38]

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. [39] Twelve years later in 2000, the tau mutation was mapped to CK1ε. [40] 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. [41] 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). [42] 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. [43]

Roles of isoforms

CK1δ and CK1ε were thought to be generally redundant in circadian cycle length and protein stability. [41] Recent research, however, has shown that CK1δ deficiency lengthens circadian period while CK1ε deficiency does not. [41] Also, CK1α has recently been suggested to play a role redundant to CK1δ in phosphorylating PER1 [37] although this is not consistent with other data [44]

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. [45] Phosphorylation of Ser-174 and Ser-175 by CKI promotes nuclear export of eIF6 while dephosphorylation by calcineurin promotes nuclear accumulation of eIF6. [45] 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. [46]

Interphase, mitosis and DNA repair

CKIδ activity is implicated in mitosis and in response to DNA damage. [47] During interphase, CKIδ associates with the Golgi Apparatus and appears to regulate the budding of clathrin coated vesicles from the TGN; it also appears to associate with tubulin. [47] 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. [47] The mechanisms for these biochemical interactions remain unknown.

See also

Related Research Articles

Advanced Sleep Phase Disorder (ASPD), also known as the advanced sleep-phase type (ASPT) of circadian rhythm sleep disorder, is a condition that is characterized by a recurrent pattern of early evening sleepiness and very early morning awakening. This sleep phase advancement can interfere with daily social and work schedules, and results in shortened sleep duration and excessive daytime sleepiness. The timing of sleep and melatonin levels are regulated by the body's central circadian clock, which is located in the suprachiasmatic nucleus in the hypothalamus.

<span class="mw-page-title-main">CREB</span> Class of proteins

CREB-TF is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first described in 1987 as a cAMP-responsive transcription factor regulating the somatostatin gene.

A circadian clock, or circadian oscillator, also known as one’s internal alarm clock is a biochemical oscillator that cycles with a stable phase and is synchronized with solar time.

<span class="mw-page-title-main">CLOCK</span> Human protein and coding gene

CLOCK is a gene encoding a basic helix-loop-helix-PAS transcription factor that is known to affect both the persistence and period of circadian rhythms.

Timeless (tim) is a gene in multiple species but is most notable for its role in Drosophila for encoding TIM, an essential protein that regulates circadian rhythm. Timeless mRNA and protein oscillate rhythmically with time as part of a transcription-translation negative feedback loop involving the period (per) gene and its protein.

Period (per) 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 circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm.

<span class="mw-page-title-main">PER2</span> Protein-coding gene in the species Homo sapiens

PER2 is a protein in mammals encoded by the PER2 gene. PER2 is noted for its major role in circadian rhythms.

<span class="mw-page-title-main">CSNK1D</span> Protein-coding gene in the species Homo sapiens

Casein kinase I isoform delta also known as CKI-delta or CK1δ is an enzyme that in humans is encoded by the gene CSNK1D, which is located on chromosome 17 (17q25.3). It is a member of the CK1 family of serine/threonine specific eukaryotic protein kinases encompassing seven distinct isoforms as well as various post-transcriptionally processed splice variants in mammalians. Meanwhile, CK1δ homologous proteins have been isolated from organisms like yeast, basidiomycetes, plants, algae, and protozoa.

<span class="mw-page-title-main">CSNK1E</span>

Casein kinase I isoform epsilon is an enzyme that in humans is encoded by the CSNK1E gene.

<span class="mw-page-title-main">Period circadian protein homolog 1</span> Protein-coding gene in the species Homo sapiens

Period circadian protein homolog 1 is a protein in humans that is encoded by the PER1 gene.

<span class="mw-page-title-main">Basic helix-loop-helix ARNT-like protein 1</span> Human protein and coding gene

Basic helix-loop-helix ARNT-like protein 1 or aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL), or brain and muscle ARNT-like 1 is a protein that in humans is encoded by the BMAL1 gene on chromosome 11, region p15.3. It's also known as MOP3, and, less commonly, bHLHe5, BMAL, BMAL1C, JAP3, PASD3, and TIC.

In molecular biology, an oscillating gene is a gene that is expressed in a rhythmic pattern or in periodic cycles. Oscillating genes are usually circadian and can be identified by periodic changes in the state of an organism. Circadian rhythms, controlled by oscillating genes, have a period of approximately 24 hours. For example, plant leaves opening and closing at different times of the day or the sleep-wake schedule of animals can all include circadian rhythms. Other periods are also possible, such as 29.5 days resulting from circalunar rhythms or 12.4 hours resulting from circatidal rhythms. Oscillating genes include both core clock component genes and output genes. A core clock component gene is a gene necessary for to the pacemaker. However, an output oscillating gene, such as the AVP gene, is rhythmic but not necessary to the pacemaker.

The frequency (frq) gene encodes the protein frequency (FRQ) that functions in the Neurospora crassa circadian clock. The FRQ protein plays a key role in circadian oscillator, serving to nucleate the negative element complex in the auto regulatory transcription-translation negative feedback-loop (TTFL) that is responsible for circadian rhythms in N. crassa. Similar rhythms are found in mammals, Drosophila and cyanobacteria. Recently, FRQ homologs have been identified in several other species of fungi. Expression of frq is controlled by the two transcription factors white collar-1 (WC-1) and white collar-2 (WC-2) that act together as the White Collar Complex (WCC) and serve as the positive element in the TTFL. Expression of frq can also be induced through light exposure in a WCC dependent manner. Forward genetics has generated many alleles of frq resulting in strains whose circadian clocks vary in period length.

Doubletime (DBT), also known as discs overgrown (DCO), is a gene that encodes the doubletime protein in fruit flies. Michael Young and his team at Rockefeller University first identified and characterized the gene in 1998.

<span class="mw-page-title-main">Michael W. Young</span> American biologist and geneticist (born 1949)

Michael Warren Young is an American biologist and geneticist. He has dedicated over three decades to research studying genetically controlled patterns of sleep and wakefulness within Drosophila melanogaster.

<span class="mw-page-title-main">Casein kinase 1 isoform epsilon</span> Protein and coding gene in humans

Casein kinase I isoform epsilon or CK1ε, is an enzyme that is encoded by the CSNK1E gene in humans. It is the mammalian homolog of doubletime. 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, of which there are seven mammalian isoforms. CK1ε is most similar to CK1δ in structure and function as the two enzymes maintain a high sequence similarity on their regulatory C-terminal and catalytic domains. This gene is a major component of the mammalian oscillator which controls cellular circadian rhythms. CK1ε has also been implicated in modulating various human health issues such as cancer, neurodegenerative diseases, and diabetes.

Jeffrey L. Price is an American researcher and author in the fields of circadian rhythms and molecular biology. His chronobiology work with Drosophila melanogaster has led to the discoveries of the circadian genes timeless (tim) and doubletime (dbt), and the doubletime regulators spaghetti (SPAG) and bride of doubletime (BDBT).

<i>Drosophila</i> circadian rhythm

Drosophila circadian rhythm is a daily 24-hour cycle of rest and activity in the fruit flies of the genus Drosophila. The biological process was discovered and is best understood in the species Drosophila melanogaster. Other than normal sleep-wake activity, D. melanogaster has two unique daily behaviours, namely regular vibration during the process of hatching from the pupa, and during mating. Locomotor activity is maximum at dawn and dusk, while eclosion is at dawn.

Transcription-translation feedback loop (TTFL) is a cellular model for explaining circadian rhythms in behavior and physiology. Widely conserved across species, the TTFL is auto-regulatory, in which transcription of clock genes is regulated by their own protein products.

Carrie L. Partch is an American protein biochemist and circadian biologist. Partch is currently a Professor in the Department of Chemistry and Biochemistry at the University of California, Santa Cruz. She is noted for her work using biochemical and biophysical techniques to study the mechanisms of circadian rhythmicity across multiple organisms. Partch applies principles of chemistry and physics to further her research in the field of biological clocks.

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