CSNK1E

Official Full Name

casein kinase 1 epsilon

Organism

Homo sapiens

GeneID

1454

Background

The protein encoded by this 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. The encoded protein is found in the cytoplasm as a monomer and can phosphorylate a variety of proteins, including itself. This protein has been shown to phosphorylate period, a circadian rhythm protein. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Feb 2014]

Synonyms

CKIe; HCKIE; CKIepsilon;

Bio Chemical Class

Kinase

Protein Sequence

MELRVGNKYRLGRKIGSGSFGDIYLGANIASGEEVAIKLECVKTKHPQLHIESKFYKMMQGGVGIPSIKWCGAEGDYNVMVMELLGPSLEDLFNFCSRKFSLKTVLLLADQMISRIEYIHSKNFIHRDVKPDNFLMGLGKKGNLVYIIDFGLAKKYRDARTHQHIPYRENKNLTGTARYASINTHLGIEQSRRDDLESLGYVLMYFNLGSLPWQGLKAATKRQKYERISEKKMSTPIEVLCKGYPSEFSTYLNFCRSLRFDDKPDYSYLRQLFRNLFHRQGFSYDYVFDWNMLKFGAARNPEDVDRERREHEREERMGQLRGSATRALPPGPPTGATANRLRSAAEPVASTPASRIQPAGNTSPRAISRVDRERKVSMRLHRGAPANVSSSDLTGRQEVSRIPASQTSVPFDHLGK

Open

Disease

Diffuse large B-cell lymphoma, Follicular lymphoma, Malignant haematopoietic neoplasm, Mature B-cell leukaemia, Mature B-cell lymphoma, Pancreatic cancer

Approved Drug

1 +

Clinical Trial Drug

3 +

Discontinued Drug

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Detailed Information

A serine/threonine protein kinase, the CSNK1E gene codes for a protein that phosphoryzes substrates. Among the important enzymes catalyzing numerous biological events are protein kinases. Transferring the γ-phosphate group from ATP to serine, threonine, or tyrosine residues on the substrates helps them control the activity of substrate proteins. By controlling the phosphorylation of fundamental clock proteins such as PER1 and PER2, the protein carried by the CSNK1E gene mostly affects the circadian rhythm cycle.

There are seven members in the CK1 family among mammals: CK1α, CK1β, CK1γ1, CK1γ2, CK1δ, and CK1ε. While all these members have highly conserved sequences in their kinase domains, CK1δ and CK1ε show more similarities in their C-terminal regions—not conserved in other CK1 isoforms. The biological clock is crucially regulated by these two kinases. CK1ε and CK1δ phosphorylate the PER proteins and control the rates of degradation of PER1 and PER2, therefore affecting the duration of the circadian rhythm cycle.

Figure 1. CK1δ/ε-phosphorylation of PER proteins: pathways to degradation and nuclear translocation in circadian rhythms. (Yang Y, et al., 2017)

Role of CSNK1E in Circadian Clock Regulation

An organism's natural mechanism controlling its circadian rhythm is its biological clock. This process is mediated by the kinase encoded by the CSNK1E gene, mostly via controlling the Period proteins (such as PER1 and PER2) to preserve the regular running of the biological clock. Core clock proteins called PER1 and PER2 regulate animal stability and transport speed via phosphorylation changes. Key players in this process include CK1ε and CK1δ, particularly in the control of PER protein phosphorylation, therefore influencing their breakdown and nuclear transport. For mouse embryonic fibroblasts (MEF), for instance, the deletion of CK1δ produces a period extension of around one hour, whereas the loss of CK1ε produces a little extension of the period, thereby confirming the redundant functions of both kinases in control of the circadian rhythm.

Apart from their function in the phosphorylation of PER proteins, CK1ε and CK1δ also help to control other fundamental clock proteins like BMAL1 and CRY proteins. Together with PER proteins, they constitute the primary transcription-translation feedback loop (TTFL) of the biological clock, therefore maintaining the synchronization of the clock with the alternating of day and night.

Biological Significance of CSNK1E

The CSNK1E gene has purposes other than just controlling the circadian clock. It also takes part in several biological mechanisms connected to human welfare. Research on the CSNK1E gene has linked mutations to the beginning of many disorders, including developmental and epileptic encephalopathies (like West syndrome). Additionally, tightly connected to the onset of illnesses like cancer, diabetes, neurological diseases, and pain is the CSNK1E gene. Starting and progressing these illnesses depends on CSNK1E as it controls cell cycle, cell proliferation, microtubule dynamics, and immune response.

In these disorders, CK1ε's action is not limited to just phosphorylating and controlling the activity of associated proteins but may also entail controlling their distribution in various cellular compartments to impact cellular processes. For example, CK1ε regulates tight junctions and engages in intercellular communication in interaction with cell junction proteins like occludin. Moreover, physiological factors control CK1ε's activity as well, particularly in processes of DNA repair, intracellular protein transport, and cell division.

Regulatory Mechanism of the CSNK1E Gene

The expression of the CSNK1E gene is tissue-specific, and its expression and activity can change during processes like cell differentiation, proliferation, and aging. In mouse models, CK1ε expression is especially high in the brain, lungs, and endocrine organs, while in certain immune cells, such as granulocytes and lymphocytes, CK1δ activity is higher, which may be related to the proliferative state of these cells. Through immunohistochemistry and Northern blotting, researchers have found that CK1ε is widely expressed in multiple human tissues, while CK1δ is more abundant in specific tissues such as the spleen.

Further research has revealed that the kinase activities of CK1ε and CK1δ are not only regulated by their expression levels but also by their own phosphorylation. CK1ε regulates its activity through autophosphorylation, which can be modulated by dephosphorylation or other modifications in different physiological environments. Additionally, the intracellular localization of CK1ε and CK1δ also affects their kinase activities. During different stages of the cell cycle, they may regulate their activity through different mechanisms.

Crosstalk between CSNK1E and Other Cellular Pathways

CK1ε and CK1δ not only play a key role in regulating the biological clock but also interact with other cellular signaling pathways, especially in the Wnt signaling pathway. Studies have shown that CK1ε phosphorylates key proteins in the Wnt pathway, such as DVL1 and DVL2, to regulate Wnt pathway activity. Moreover, the roles of CK1ε and CK1δ in the nervous system should not be underestimated. Research indicates that they can regulate the proliferation, differentiation, and migration of neural cells, contributing to the onset of neurodegenerative diseases.

References:

Dhillon S, Keam SJ. Umbralisib: First Approval. Drugs. 2021 May;81(7):857-866.
Li SS, Dong YH, et al. Recent Advances in the Development of Casein Kinase 1 Inhibitors. Curr Med Chem. 2021;28(8):1585-1604.
Yang Y, Xu T, et al. Molecular basis for the regulation of the circadian clock kinases CK1δ and CK1ε. Cell Signal. 2017 Feb;31:58-65.

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