| 2005 |
CKIepsilon phosphorylates PER2 at a specific site that recruits the ubiquitin ligase adapter protein beta-TrCP, leading to PER2 ubiquitination and degradation by the 26S proteasome; dominant negative beta-TrCP blocks this phosphorylation-dependent degradation, and CKIepsilon inhibition slows PER2 degradation and lengthens circadian period in Rat-1 cells. |
Cell-based PER2 degradation assay, proteasome inhibitor treatment, CKIepsilon inhibitor treatment, dominant-negative beta-TrCP expression, circadian period measurement in Rat-1 cells |
Molecular and cellular biology |
High |
15767683
|
| 2002 |
CKIepsilon phosphorylates mPer1, mPer2, and mPer3, causing their rapid degradation via the ubiquitin-proteasome pathway and inducing nuclear translocation of mPer3 in a manner dependent on its nuclear localization signal; mutation of potential CKIepsilon phosphorylation sites on mPer3 reduced both nuclear translocation and degradation; CKIepsilon affects the inhibitory effect of mPer proteins (but not mCry proteins) on BMAL1-CLOCK transcriptional activity. |
Cell-based phosphorylation and degradation assays, ubiquitin-proteasome pathway inhibition, site-directed mutagenesis of mPer3 phosphorylation sites, subcellular localization imaging, transcriptional reporter assay |
Molecular and cellular biology |
High |
11865049
|
| 2009 |
CKIepsilon/delta-dependent phosphorylation of PER2 controls the rate of PER2 degradation in living clock cells; this degradation rate is temperature-insensitive in cells and in vitro with a synthetic peptide, revealing that CKIepsilon/delta-dependent phosphorylation is a temperature-insensitive, period-determining step in the mammalian circadian clock. |
Cell-based bioluminescence period assay with pharmacological CKI inhibitors (1,260 compound screen), in vitro CKI phosphorylation of synthetic peptide at varying temperatures, central and peripheral clock tissue analysis |
Proceedings of the National Academy of Sciences of the United States of America |
High |
19805222
|
| 2007 |
AMPK phosphorylates CKIepsilon at Ser-389, increasing CKIepsilon kinase activity, which in turn phosphorylates and induces degradation of mPer2, shortening the circadian period; metformin (via AMPK activation) causes mPer2 degradation and circadian phase advance in wild-type but not AMPK alpha2 knockout mice. |
In vitro kinase assay, site-specific phosphorylation mapping (Ser-389), mPer2 degradation assay in fibroblasts, metformin treatment of wild-type and AMPK alpha2 KO mice, circadian expression analysis in peripheral tissues |
The Journal of biological chemistry |
High |
17525164
|
| 2004 |
Direct and stable interaction between mPER proteins and CKIepsilon is critical for circadian clock function; mPER3 lacks this direct stable interaction with CKIepsilon (shown by chimeric protein in vitro studies), which contributes to its inability to support clock function; the CKIepsilon-binding domain of PER proteins is required not only for phosphorylation but for clock function. |
In vitro chimeric protein binding studies, in vivo phosphorylation and subcellular localization analysis in mouse liver, co-immunoprecipitation of clock proteins, analysis of Per double-mutant mice |
Molecular and cellular biology |
High |
14701732
|
| 2009 |
CKIepsilon is essential for the mammalian circadian clockwork: disruption of both CKIdelta and CKIepsilon (via dominant-negative CKIepsilon in CKIdelta-deficient MEFs) eliminates circadian bioluminescence rhythms and severely compromises PER abundance and phosphorylation rhythms; overexpression of the CKIepsilon/delta-binding domain of PER2 (CKBD-P2) abolishes circadian rhythms and dramatically lowers PER levels, whereas kinase-inactive DN-CKIepsilon (which still binds PER) does not lower PER levels, suggesting a non-catalytic stabilizing role of CKIepsilon for PER. |
Dominant-negative CKIepsilon overexpression in CKIdelta-deficient Per2-Luc MEFs, bioluminescence rhythm recording, immunoblot for PER phosphorylation and abundance, CKI-binding domain (CKBD-P2) overexpression |
Proceedings of the National Academy of Sciences of the United States of America |
High |
19948962
|
| 2009 |
CKIepsilon binds and phosphorylates both Period (circadian pathway) and Dishevelled (planar cell polarity pathway); two key residues in CKIalpha's kinase domain prevent binding of these substrates to CKIalpha; the unique C-terminus of CKIepsilon plays an auxiliary role in stabilizing (but is not essential for) substrate binding; autophosphorylation of CKIepsilon's C-terminal tail prevents substrate binding and phosphorylation through a phosphorylation-dependent interaction between the C-terminal tail and the kinase domain. |
GST pull-down assays, mass spectrometry (autophosphorylation site mapping), chemical crosslinking, site-directed mutagenesis of CKIalpha kinase domain residues, in vitro kinase assay |
PloS one |
High |
19274088
|
| 2006 |
In Drosophila, DBT (CKIepsilon homolog) activity is required for phase-specific hyperphosphorylation and enhanced degradation of CLK in vivo; DBT directly hyperphosphorylates CLK and evokes modest inhibition of CLK-dependent transactivation in cultured Drosophila cells; DBT functions in partnership with PER-relevant protein phosphatase 2A to establish dynamic equilibrium between hypo- and hyperphosphorylated CLK isoforms; DBT also alters CLK subcellular localization from nuclear to cytoplasmic in the presence of PER. |
In vivo CLK phosphorylation analysis, cultured Drosophila cell transfection with DBT, transcriptional reporter assay, protein stability assay, subcellular localization imaging |
Proceedings of the National Academy of Sciences of the United States of America |
Medium |
16603629
|
| 2005 |
In Drosophila, DBT (CKIepsilon homolog) and CKIalpha cooperatively phosphorylate Ci (Gli homolog) at three clusters of serine residues primed by PKA and GSK3; this CKI phosphorylation creates binding sites for the F-box protein Slimb/beta-TRCP, recruiting the SCF(Slimb) ubiquitin ligase for Ci proteolytic processing; CKI phosphorylation sites act cooperatively in vivo. |
In vivo genetic analysis in Drosophila, in vitro phosphorylation assay, co-immunoprecipitation for Slimb/beta-TRCP binding, site-directed mutagenesis of Ci phosphorylation clusters, canonical beta-TRCP motif substitution |
Developmental cell |
High |
16326393
|
| 2006 |
In Drosophila in vivo, CKIepsilon (discs overgrown) acts positively in both Wnt/beta-catenin and Fz/PCP signaling pathways; kinase activity of CKIepsilon is required for peak Wnt/beta-catenin signaling but CKIepsilon may act through a kinase-independent mechanism in the Fz/PCP pathway; the primary CKIepsilon phosphorylation target residue on Dishevelled was identified. |
Loss-of-function and coexpression assays in Drosophila in vivo, identification of primary kinase target residue on Dsh |
Current biology : CB |
Medium |
16824922
|
| 2011 |
Csnk1e functions as a negative regulator of sensitivity to psychostimulants (methamphetamine) and opioids (fentanyl): Csnk1e null mice and mice treated with a selective CKIepsilon inhibitor (PF-4800567) both showed increased locomotor activity following MA and fentanyl administration. |
Csnk1e knockout mice, selective pharmacological inhibitor (PF-4800567), locomotor activity assay, QTL mapping with congenic lines |
Neuropsychopharmacology |
Medium |
22089318
|
| 2023 |
CHCHD2 T61I mutant (mislocalized to cytosol) recruits Csnk1e/d, which then phosphorylates neurofilament and alpha-Synuclein, forming cytosolic aggresomes in dopaminergic neurons; a Csnk1e/d inhibitor substantially suppressed phosphorylation of these substrates, reduced cellular damage in CHCHD2-T61I-expressing cells, and improved neurodegenerative phenotypes in knock-in mice. |
Cell transfection (Neuro2a), knock-in and transgenic mouse models, co-immunoprecipitation/localization of Csnk1e/d with CHCHD2-T61I, phosphorylation assays for alpha-Synuclein and neurofilament, Csnk1e/d inhibitor treatment, patient-derived iPS cell-derived dopaminergic neurons, postmortem PD brain analysis |
EMBO molecular medicine |
High |
37578019
|
| 2023 |
CSNK1E is upregulated in stemlike drug-persistent DLBCL cells in part through activation of the APRIL-TNFRSF13B axis; CSNK1E inhibition impaired growth and tumor-initiating capacity of drug-persistent cells and potentiated R-CHOP efficacy both in vitro and in vivo. |
Single-cell RNA sequencing, B-cell receptor sequencing on paired patient samples, CSNK1E inhibition in vitro and in vivo xenograft models, clonogenicity assay, tumor-initiating capacity assay |
Blood |
Medium |
41758931
|
| 2025 |
Pathogenic DVL frameshift variants interfere with CSNK1E-induced phosphorylation of DVL, offering a mechanism for impaired WNT signaling response; mutant DVL proteins fail to change their localization in response to WNT ligands and fail to activate canonical WNT signaling. |
TOPFlash reporter assay, immunocytochemistry for DVL localization, in vitro transfection of WT and frameshift DVL constructs, assessment of CSNK1E-induced phosphorylation |
bioRxivpreprint |
Low |
bio_10.1101_2025.08.02.668297
|