| 2020 |
UCK2 promotes HCC metastasis through a non-metabolic (catalysis-independent) mechanism: in response to EGF, UCK2 physically interacts with EGFR to block EGF-induced EGFR ubiquitination and degradation, resulting in elevated EGFR-AKT pathway activation. Site-directed mutagenesis confirmed this function is independent of UCK2 catalytic activity. |
Site-directed mutagenesis, Co-immunoprecipitation, functional metastasis assays, pharmacological inhibition |
Oncogenesis |
High |
33277463
|
| 2025 |
mTORC1 controls UCK2 protein stability (half-life) in the pyrimidine salvage pathway: when mTORC1 is inhibited, UCK2 is degraded via the CTLH-WDR26 E3 ubiquitin ligase complex; active mTORC1 prevents this degradation. Additionally, UCK1 (an isoform) influences UCK2 turnover by affecting its cellular localization. |
Protein stability/turnover assays, genetic knockdown/knockout of CTLH-WDR26 components, subcellular fractionation, pyrimidine salvage flux assays |
Cell reports |
High |
39808525
|
| 2025 |
Under glucose limitation, AMPK phosphorylates GART at Ser440, which facilitates GART binding to UCK2. GART binding (and its production of tetrahydrofolate, THF) inhibits ILKAP phosphatase activity, thereby maintaining AKT1-mediated UCK2-Ser254 phosphorylation. Loss of UCK2-Ser254 phosphorylation promotes TRIM21-mediated UCK2 polyubiquitination and proteasomal degradation. |
Phosphosite mutagenesis, Co-immunoprecipitation, ubiquitination assays, AMPK kinase assays, in vivo tumor models |
Oncogene |
High |
39865175
|
| 2025 |
GLI2 transcriptionally activates HRD1 (an E3 ubiquitin ligase), which in turn mediates ubiquitination and degradation of UCK2, reducing UCK2 protein levels and conferring 5-FU resistance in gastric cancer cells. UCK2 was identified as a critical gene for 5-FU sensitivity via genome-wide CRISPR knockout screen. |
CRISPR knockout screen (GeCKO v2), overexpression/knockdown functional assays, ubiquitination assays, luciferase reporter for GLI2-HRD1 transcriptional activation, in vivo xenograft |
Translational oncology |
Medium |
40414119
|
| 2022 |
UCK2 is a homotetrameric enzyme with an allosteric site at the intersubunit interface. Two classes of inhibitors were identified that noncompetitively inhibit UCK2 by reducing kcat without altering KM, confirming the allosteric (not active-site competitive) mechanism. |
Structure-based drug design, enzyme kinetics (kcat, KM measurements), in vitro enzymatic inhibition assays |
Biochemistry |
High |
36190114
|
| 2025 |
UCK2 forms a physical complex with UCKL1 (Uridine-Cytidine Kinase Like-1) that functions as a molecular scaffold independent of metabolic activity. This UCK2/UCKL1 complex recruits E3 ubiquitin ligase TRIM21, orchestrating ubiquitination and degradation of Smurf2, thereby sustaining Smad3 phosphorylation and amplifying fibrogenic TGF-β signaling in cardiac fibroblasts. |
Co-immunoprecipitation, genetic silencing (siRNA/shRNA), AAV-mediated knockdown in murine MI model, western blotting for pathway components, murine cardiac fibrosis model |
Molecular biomedicine |
Medium |
41457201
|
| 2025 |
UCK2 (and UCK1) phosphorylate N4-hydroxycytidine (NHC), the active compound of the antiviral molnupiravir. UCK2 displays 9-fold higher catalytic efficiency than UCK1 for NHC. siRNA-mediated knockdown of UCK2 in SARS-CoV-2-infected cells reduced intracellular triphosphate NHC metabolite accumulation and decreased antiviral efficacy 10-fold, establishing UCK2 as the rate-limiting kinase for molnupiravir bioactivation. |
Target engagement assays, enzyme kinetic assays with recombinant UCK1/UCK2, siRNA knockdown in SARS-CoV-2-infected cells, intracellular metabolite quantification |
bioRxivpreprint |
Medium |
bio_10.1101_2025.05.13.653844
|
| 2025 |
UCK2-mediated phosphorylation of cytidine is required for CTP uptake by Chlamydia trachomatis: host UCK2 must convert cytidine to its phosphorylated form prior to incorporation into bacterial nucleic acids, indicating nucleosides are phosphorylated in the host cytoplasm before translocation into the bacterial inclusion. |
Click chemistry coupled with fluorescence microscopy tracking cytidine incorporation, UCK2-dependent phosphorylation assay in infected cells |
microPublication biology |
Medium |
40415900
|
| 2025 |
Overexpression of UCK2 in donor cells enhanced 5-ethynyl uridine (5-EU) incorporation into nascent RNA, demonstrating that UCK2 kinase activity directly controls the intracellular availability of this uridine analog for RNA incorporation. This establishes UCK2 as the rate-limiting kinase for uridine analog phosphorylation in living cells. |
UCK2 overexpression, metabolic labeling with 5-EU, click chemistry fluorescence detection, quantification in isolated extracellular vesicles |
bioRxivpreprint |
Low |
bio_10.1101_2025.08.28.672797
|
| 2025 |
Cytotoxicity of epigenetic ribopyrimidines in human cells is mediated primarily by UCK2 kinase activity, as demonstrated by identification of UCK2 as the metabolic regulator governing incorporation of these modified nucleosides into cellular RNA. |
Cell growth assays with UCK2 modulation, quantification of misincorporation into cellular RNAs, metabolic regulator screening |
bioRxivpreprint |
Low |
bio_10.1101_2025.06.11.659152
|
| 1976 |
UMPK (UCK2) enzyme activity declines during red cell aging; the lower activity of the UMPK2 allelic variant compared to UMPK1 is explained by more rapid catabolism of the UMPK2 gene product, not by a difference in intrinsic specific activity. |
Red cell fractionation by age, enzyme activity measurement across red cell age cohorts |
American journal of human genetics |
Low |
178178
|
| 2026 |
UCK2 physically interacts with the small GTPase RHEB and regulates mTOR signaling in lung adenocarcinoma cells, promoting cell proliferation and migration. |
Co-immunoprecipitation, overexpression functional assays, pathway analysis |
Oncology research |
Low |
42232606
|
| 2024 |
UCK2 promotes intrahepatic cholangiocarcinoma progression and cisplatin resistance by activating the PI3K/AKT/mTOR signaling pathway, which inhibits autophagy. |
UCK2 knockdown/overexpression, western blotting for PI3K/AKT/mTOR/autophagy markers, in vivo and in vitro cisplatin sensitivity assays |
Cell death discovery |
Low |
39179560
|