Affinage

CSNK1G3

Casein kinase I isoform gamma-3 · UniProt Q9Y6M4

Length
447 aa
Mass
51.4 kDa
Annotated
2026-06-09
12 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 2/2 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CSNK1G3 (casein kinase I gamma 3) is a kinase implicated in pro-survival signaling in cancer cells, where its knockdown sensitizes cells to Akt inhibition and reduces Akt Ser-473 and ribosomal protein S6 phosphorylation, marking it as an Akt-cooperating kinase required for full Akt pathway activity (PMID:16247451). Beyond these functional links, its direct substrates and catalytic mechanism have not been characterized in the available corpus. All additional findings carry only Low-confidence support: a role in promoting aminoglycoside-mediated stop-codon readthrough (PMID:29177465), modulation of the AKT/apoptosis/EMT axis in triple-negative breast cancer cells (PMID:39127154), occurrence as an oncogenic CSNK1G3-ALK gene fusion in lung squamous cell carcinoma (PMID:40783309), and placement in TNF-α/necroptosis and Wnt/β-catenin/pyroptosis signaling in hippocampal neurons under post-transcriptional control of a cognate circRNA-Csnk1g3 acting on its 3'-UTR (PMID:39920301, PMID:41633109).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2006 Medium

    Established that CSNK1G3 is functionally required to support Akt pathway activity and cancer cell survival, framing it as a kinase that cooperates with Akt rather than acting independently.

    Evidence Kinome-wide siRNA screen with viability and phosphorylation (Akt Ser-473, S6) readouts under Akt inhibitor A-443654

    PMID:16247451

    Open questions at the time
    • No direct substrate of CSNK1G3 identified
    • Whether CSNK1G3 acts upstream or in parallel to Akt is unresolved
    • No structural or enzymatic reconstitution of its kinase activity
  2. 2018 Low

    Connected CSNK1G3 to translational fidelity by showing its knockdown reduces stop-codon readthrough, implicating its kinase activity in competition with translation termination.

    Evidence siRNA knockdown in a dual-reporter high-throughput readthrough assay

    PMID:29177465

    Open questions at the time
    • Single siRNA knockdown assay, single lab, no mechanistic follow-up
    • No identification of the relevant phosphorylation target in the termination/readthrough machinery
  3. 2024 Low

    Tested CSNK1G3 as a druggable node in the AKT axis by showing a curcumin derivative targeting CSNK1G3 suppresses p-AKT(S473) and modulates apoptosis and EMT in breast cancer cells.

    Evidence Small-molecule (N17) targeting with proliferation, apoptosis, p-AKT and EMT marker assays in triple-negative breast cancer cells

    PMID:39127154

    Open questions at the time
    • Pharmacological inhibitor study without enzymatic or structural validation; mechanism inferred from inhibitor effect
    • Specificity of the inhibitor for CSNK1G3 over other kinases not biochemically confirmed
  4. 2025 Low

    Identified CSNK1G3 as a fusion partner driving oncogenesis, showing a CSNK1G3-ALK fusion behaves as an ALK-TKI-responsive oncogenic driver.

    Evidence DNA-based NGS detecting the fusion plus PDX model treated with ALK-TKIs (alectinib, crizotinib, lorlatinib) with tumor shrinkage readout

    PMID:40783309

    Open questions at the time
    • Single case/PDX model with no biochemical characterization of the fusion protein's kinase activity
    • Contribution of the CSNK1G3 portion versus ALK kinase domain to oncogenicity unknown
  5. 2026 Low

    Defined post-transcriptional regulation of CSNK1G3 and placed it in neuronal cell-death pathways, showing a cognate circRNA targets its 3'-UTR while elevated CSNK1G3 correlates with necroptosis, Wnt/β-catenin and NLRP3-pyroptosis signaling in hippocampal neurons.

    Evidence FISH, dual-luciferase, RIP, siRNA knockdown, adenoviral overexpression, western blot and IF in HT22 cells and epileptic mouse model

    PMID:39920301 PMID:41633109

    Open questions at the time
    • Pathway placement is correlative via marker expression, not direct enzymatic linkage
    • Direct substrates of CSNK1G3 in necroptosis/Wnt/pyroptosis pathways not identified
    • Mechanism by which the circRNA regulates CSNK1G3 transcription versus mRNA stability is not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The direct substrates, catalytic mechanism, and structural basis of CSNK1G3 kinase activity remain unknown across all documented contexts.
  • No phosphorylation substrate directly demonstrated
  • No structural model or active-site characterization
  • Mechanistic basis for its many proposed pathway roles unestablished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 1
Pathway
R-HSA-162582 Signal Transduction 1

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 siRNA knockdown of CSNK1G3 significantly enhanced cancer cell killing in the presence of Akt inhibitor A-443654 and caused decreases in Akt Ser-473 and ribosomal protein S6 phosphorylation, identifying CSNK1G3 as an Akt-cooperating kinase required for Akt pathway activity in cancer cells. siRNA screen (kinome-wide RNAi library) with cell viability and phosphorylation readouts (Akt Ser-473, S6 phosphorylation) Oncogene Medium 16247451
2018 siRNA knockdown of CSNK1G3 negatively regulated aminoglycoside-mediated translation readthrough, indicating that CSNK1G3 kinase activity promotes readthrough at stop codons in competition with translation termination. siRNA knockdown in dual reporter-based high-throughput readthrough assay (enzymatic and fluorescence activities) Human molecular genetics Low 29177465
2024 The curcumin derivative N17 inhibits p-AKT(S473) by specifically targeting CSNK1G3 protein, and CSNK1G3 was shown to regulate the AKT signaling axis controlling apoptosis and epithelial-mesenchymal transition in triple-negative breast cancer cells. Small-molecule targeting of CSNK1G3 with cell proliferation, apoptosis, and phosphorylation assays (p-AKT Ser473); EMT marker analysis Biochemical pharmacology Low 39127154
2025 A novel CSNK1G3-ALK gene fusion was identified in a lung squamous cell carcinoma patient, functioning as an oncogenic driver responsive to ALK tyrosine kinase inhibitors (alectinib, crizotinib, lorlatinib) in both the patient and a patient-derived xenograft model. DNA-based next-generation sequencing (NGS) identifying fusion; patient-derived xenograft (PDX) model treated with ALK-TKIs with tumor shrinkage readout Clinical lung cancer Low 40783309
2025 circRNA-Csnk1g3 directly targets the 3'-UTR of Csnk1g3 mRNA and promotes its transcription, as demonstrated by dual-luciferase and RNA immunoprecipitation (RIP) assays; Csnk1g3 (CK1γ3) protein participates in the TNF-α/necroptosis (RIP1/RIP3/MLKL) signaling pathway in hippocampal neurons. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP), qRT-PCR, western blot, flow cytometry, in vivo EEG/histopathology in epileptic mouse model Scientific reports Low 39920301
2026 circRNA-Csnk1g3 distributes in both nucleus and cytoplasm and directly targets the 3'-UTR of Csnk1g3, promoting its transcription; elevated Csnk1g3 expression is associated with activation of the Wnt/β-catenin pathway and NLRP3 inflammasome-mediated pyroptosis in hippocampal neurons, effects reversed by circRNA-Csnk1g3 knockdown. FISH (subcellular localization of circRNA), dual-luciferase assay, RIP assay, siRNA knockdown, adenoviral overexpression, western blot, immunofluorescence, qRT-PCR in HT22 cells Journal of ethnopharmacology Low 41633109

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Estimation of genetic parameters and detection of chromosomal regions affecting the major milk proteins and their post translational modifications in Danish Holstein and Danish Jersey cattle. BMC genetics 53 27485317
2006 RNAi-based screening of the human kinome identifies Akt-cooperating kinases: a new approach to designing efficacious multitargeted kinase inhibitors. Oncogene 44 16247451
2018 Aminoglycoside-mediated promotion of translation readthrough occurs through a non-stochastic mechanism that competes with translation termination. Human molecular genetics 18 29177465
2021 Detecting Genetic Ancestry and Adaptation in the Taiwanese Han People. Molecular biology and evolution 14 33170928
2020 Autoimmune response against tyrosinase induces depigmentation in C57BL/6 black mice. Autoimmunity 13 33084421
2025 Differential analysis of testicular LncRNA in Kazakh horses of different ages. International journal of biological macromolecules 8 40706934
2017 Gene-centric analysis implicates nuclear encoded mitochondrial protein gene variants in migraine susceptibility. Molecular genetics & genomic medicine 6 28361102
2025 Clinical Outcomes of Patients With Advanced ALK-Rearranged Lung Squamous Cell Carcinoma Treated With ALK Tyrosine Kinase Inhibitors. Clinical lung cancer 3 40783309
2024 Novel curcumin derivatives N17 exert anti-cancer effects through the CSNK1G3/AKT axis in triple-negative breast cancer. Biochemical pharmacology 3 39127154
2025 Dietary Influence on Urolithiasis Risk Mediated by Plasma Metabolites: A Mendelian Randomization and Experimental Study Linking Genes, Metabolites, and Clinical Outcomes. Food science & nutrition 2 40842671
2025 Mitigating effects of Jiawei Chaihu Shugan decoction on necroptosis and inflammation of hippocampal neurons in epileptic mice. Scientific reports 1 39920301
2026 Investigating the effect of Dingxian Pill on hippocampal neuronal pyroptosis in epilepsy through regulation of the circRNA-Csnk1g3/Wnt/β-catenin pathway. Journal of ethnopharmacology 0 41633109

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