[16] Ever since, CK1δ was investigated and described in various animals, plants, as well as parasites (Caenorhabditis elegans, 1998;[17] Drosophila melanogaster, 1998;[18] Mus musculus, 2002;[19] Xenopus laevis, 2002.

[20]) So far, three different transcription variants (TVs) have been described for CK1δ in humans (Homo sapiens), mice (Mus musculus), and rats (Rattus norvegicus), which are highly homologous.

The first variant consists of 415 amino acids across all three organisms and is called TV1 in human and rat, while the murine counterpart is named CRAa.

Like eukaryotic protein kinases (ePKs) the different isoforms of the CK1 family consist of a N-terminal and a C-terminal lobe (N- and C-lobe, respectively), which are connected via a hinge region.

While the N-lobe is mainly composed by β-sheet strands, the larger C-lobe predominantly consists of α-helical and loop structures.

[15][36][37] Rigorous control of CK1δ expression and kinase activity is crucial due to its involvement in important cellular signal transduction pathways.

[34][39][40][41] On protein level, CK1δ activity can be regulated by sequestration to particular subcellular compartments bringing the kinase together with distinct pools of substrates in order to guide its cellular function.

[36][42] DDX3X promotes CK1ε-mediated phosphorylation of Dishevelled (Dvl) in the canonical Wnt pathway but has also been demonstrated to stimulate CK1δ- and ε-specific kinase activity by up to five orders of magnitude.

[46][50] On the contrary, proteins being homologous to CK1BP (e.g. dysbindin or BLOC-1 [biogenesis of lysosome-related organelles complex-1]) are able to inhibit CK1δ kinase activity in a dose dependent manner.

Although CK1δ in solution is always purified as monomers, biological relevance of dimerization could be demonstrated by showing that the binding of dominant-negative mutant CK1δ to wild type CK1δ resulted in the total reduction of CK1δ-specific kinase activity.

Upon autophosphorylation sequence motifs within the C-terminal domain are generated, which are able to block the catalytic center of the kinase by acting as a pseudosubstrate.

As a consequence of altered kinase activity of a CK1δ S370A mutant, subsequently affected Wnt/β-catenin signal transduction resulted in development of an ectopic dorsal axis in Xenopus laevis embryos.

Mutation of identified target sites to the non-posphorylatable amino acid alanine leads to significant effects on catalytic parameters of CK1δ in most cases, at least in vitro.

[23][59][60] These findings indicate, that site-specific phosphorylation mediated by Chk1, PKCα, and CDKs actually results in reduced cellular CK1-specific kinase activity.

Phosphorylation of numerous substrates is enabled due to the existence of several consensus motifs, which can be recognized by CK1 isoforms.

Temporarily, CK1δ can also be localized to membranes, receptors, transport vesicles, components of the cytoskeleton, centrosomes or spindle poles.

[74][96][97][98][99] CK1δ can be also activated by genotoxic stress and DNA damage in a p53-dependent manner, and phosphorylate key regulatory proteins in response to these processes.

[110][111] Additionally, the activity of topoisomerase II α (TOPOII-α), one of the main regulators of DNA replication, results increased after its CK1δ-mediated phosphorylation on Ser-1106.

In fact, CK1δ phosphorylates a main regulator of DNA methylation, the ubiquitin-like containing PHD and RING finger domains 1 protein (UHRF1), on Ser-108, increasing its proteasomal degradation.

Hrr25, the CK1δ orthologue in Saccharomyces cerevisiae, can be found localized to P-bodies – RNA/protein granules identified in cytoplasm of meiotic cells – and seems to be necessary for meiosis progression.

[119][120] CK1δ is involved in the regulation of microtubule polymerization and stability of the spindle apparatus and centrosomes during mitosis by directly phosphorylating α-, β-, and γ-tubulin.

[142] In the Hpo pathway, CK1δ can phosphorylate yes-associated protein (YAP), the down-stream co-activator of Hpo-responsive gene transcription on Ser-381, which influences its proteasomal degradation.

[147][151] Additionally, β-catenin can be retained into the cytoplasm after binding to YAP, which results in lower transcription of Wnt-responsive genes.

[51] The two CK1δ mutations, R324H and T67S identified in intestinal mucosa and in a colorectal tumor, respectively, exhibit increased carcinogenic potential.

[166] Based on these studies, CK1δ could be recognized as a hallmark as well as a potential target for AD treatment and may be further useful for diagnostic and therapeutic purpose in the future.

[167] Familial advanced sleep phase syndrome (FASPS) is another neurological disease associated with CK1δ-mediated phosphorylation of the mammalian clock protein PER2.

CK1s from Plasmodium and Leishmania are most studied: Due to the fact that CK1δ is involved in regulation of various cellular processes there is high attempts to influence its activity.

N-benzothiazolyl-2-phenyl acetamide derivatives developed by Salado and co-workers show protective effects on in vivo hTDP-43 neurotoxicity in Drosophila.

[199] Since small molecule inhibitors often have various disadvantages, including low bioavailability, off-target effects as well as severe side effects, the interest in the development and validation of new biological tools like identification of biological active peptides either able to inhibit CK1δ activity or the interaction of CK1δ with cellular proteins is more and more growing.

[200] In 2018, the interaction between Axin1, a scaffold protein exhibiting important roles in Wnt signaling, and CK1δ/ε were fine-mapped using a peptide library.