Affinage

AK4

Adenylate kinase 4, mitochondrial · UniProt P27144

Length
223 aa
Mass
25.3 kDa
Annotated
2026-06-09
20 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 4/5 claims corpus-supported (80%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AK4 is a metabolic enzyme that influences cellular bioenergetics, stress responses, and survival across vascular and cancer contexts (PMID:40506332, PMID:39982744). In vascular smooth muscle cells, AK4 physically interacts with AMPKα and promotes its activating phosphorylation at Thr172, reducing mitochondrial oxidative damage and improving mitochondrial function; a phospho-dead AMPKα T172A mutant fails to support this effect, establishing AMPKα activation as the operative downstream signal (PMID:40506332). In cancer, AK4 acts as a pro-tumorigenic node: it co-localizes with NNT and upregulates NLRP3 and IL-1β to activate NLRP3 inflammasome signaling, driving migration, invasion, EMT, and resistance to taxol-induced apoptosis (PMID:40593461), and in adult T cell leukemia it promotes oncogenic Myc-target pathways and sphingomyelin production, with ATL cells showing selective dependence on AK4 (PMID:39982744). AK4 also restrains apoptosis through p-AKT/p-mTOR signaling and limits ROS accumulation (PMID:40819488). A recurrent theme is post-transcriptional control of AK4 abundance: it is directly targeted by multiple miRNAs including miR-199a-3p, miR-634, and miR-124 (PMID:29866054, PMID:30479565, PMID:40819488, PMID:37932484), transcriptionally activated downstream of STAT3 (PMID:33361582), and stabilized by RNA-binding complexes—hnRNPC together with LINC00662 (PMID:32549791) and DDX3X recruited via miR-2355-3p/TRIM29 (PMID:33898107)—linking AK4 levels to drug resistance, radioresistance, and tumor progression.

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2018 Medium

    Established that AK4 is not merely a metabolic enzyme but a functional driver of therapy resistance, and is held under direct miRNA control by miR-199a-3p.

    Evidence Luciferase target validation plus drug-resistance and radioresistance assays with NF-κB/pathway readouts in osteosarcoma and esophageal cancer cells

    PMID:29866054 PMID:30479565

    Open questions at the time
    • Mechanism linking AK4 enzymatic activity to NF-κB and resistance not resolved
    • Whether resistance depends on AK4 catalytic function untested
  2. 2020 Medium

    Showed AK4 abundance is set post-transcriptionally by mRNA stabilization, identifying the LINC00662/hnRNPC axis as a route to radioresistance.

    Evidence RIP confirming hnRNPC binding to LINC00662 and AK4 mRNA, with knockdown and rescue in oral squamous cell carcinoma

    PMID:32549791

    Open questions at the time
    • Binding site on AK4 transcript not mapped
    • Downstream effector of stabilized AK4 not defined
  3. 2021 Medium

    Extended post-transcriptional regulation to a second RNA-binding mechanism (DDX3X via miR-2355-3p/TRIM29) and connected AK4 to bioenergetic control of proliferation and invasion.

    Evidence mRNA stability assays, miR-2355-3p manipulation, and DDX3X recruitment to AK4 transcript in pancreatic cancer cells

    PMID:33898107

    Open questions at the time
    • Direct DDX3X-AK4 transcript binding interface not defined
    • How altered AK4 changes bioenergetics mechanistically unresolved
  4. 2021 Low

    Placed AK4 downstream of STAT3 transcriptional activation, adding a transcriptional layer to its regulation.

    Evidence Luciferase reporter (miR-3666 targeting STAT3), western blot, and AK4 rescue in ovarian carcinoma cells

    PMID:33361582

    Open questions at the time
    • STAT3 regulation of AK4 inferred indirectly through miR-3666/rescue, not by direct promoter binding
    • Single lab, indirect transcriptional evidence
  5. 2023 Low

    Proposed an AK4/ATF3 axis as a neuroprotective target, broadening AK4 relevance beyond cancer to neuronal injury.

    Evidence Luciferase/target validation, rat subarachnoid hemorrhage model, and primary neuron hemoglobin stimulation with miR-124 mimic/inhibitor

    PMID:37932484

    Open questions at the time
    • Direct miR-124/AK4 binding rigor not detailed
    • How AK4 regulates ATF3 mechanistically unknown
  6. 2025 Medium

    Defined AK4's mechanism in vascular biology by showing it acts through a physical interaction with AMPKα and Thr172 phosphorylation to protect mitochondrial function.

    Evidence Co-IP, phospho-AMPKα Thr172 western blot, pharmacological rescue (metformin/AICAR), and WT vs. T172A mutant overexpression in human aortic smooth muscle cells

    PMID:40506332

    Open questions at the time
    • How AK4 promotes Thr172 phosphorylation (direct vs. indirect) not resolved
    • Whether the interaction depends on AK4 catalytic activity untested
  7. 2025 Medium

    Identified an inflammasome arm of AK4 oncogenic signaling, linking AK4-NNT co-localization to NLRP3/IL-1β-driven EMT and chemoresistance.

    Evidence Co-localization, gain/loss-of-function, NLRP3/IL-1β western blot, and apoptosis/migration/invasion assays in nasopharyngeal carcinoma cells

    PMID:40593461

    Open questions at the time
    • Mechanism connecting AK4-NNT to NLRP3 activation undefined
    • Whether co-localization reflects direct binding unknown
  8. 2025 Medium

    Revealed a selective metabolic dependency in adult T cell leukemia, tying AK4 to Myc-target pathways and sphingomyelin metabolism and an anti-apoptotic AKT/mTOR program in another model.

    Evidence miR-455-3p/miR-634 target identification, transcriptome/metabolome analyses, and in vitro/in vivo AK4 knockdown/overexpression with AKT/mTOR and ROS readouts

    PMID:39982744 PMID:40819488

    Open questions at the time
    • Mechanism by which AK4 enhances sphingomyelin production not established
    • Basis of ATL-selective AK4 dependence unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether AK4's catalytic (nucleotide kinase) activity, rather than scaffolding/protein interactions, underlies its bioenergetic and signaling functions remains unresolved across all contexts.
  • No catalytic-dead AK4 mutant tested in any phenotype
  • No structural model of AK4 partner interactions
  • Direct enzymatic substrate dependence of signaling effects unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005739 mitochondrion 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-1430728 Metabolism 2 R-HSA-8953854 Metabolism of RNA 2
Partners
AMPKΑDDX3XHNRNPCNNT

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2025 AK4 interacts physically with AMPKα (protein kinase AMP-activated catalytic subunit alpha) and promotes phosphorylation of AMPKα at Thr172, thereby reducing mitochondrial oxidative damage and improving mitochondrial function in vascular smooth muscle cells; AMPKα activation reverses the inhibitory effects of AK4 deficiency on VSMC phenotypic switching, while a phospho-dead AMPKα T172A mutant does not. Co-immunoprecipitation (AK4-AMPKα interaction), western blot (phospho-AMPKα Thr172), AMPKα activators (metformin/AICAR) rescue assay, wild-type vs. T172A AMPKα mutant overexpression, AK4 knockdown/overexpression in HASMCs Atherosclerosis Medium 40506332
2025 AK4 co-localizes with NNT (nicotinamide nucleotide transhydrogenase) in nasopharyngeal carcinoma cells and upregulates NLRP3 and IL-1β to activate the NLRP3 inflammasome signaling pathway, promoting cell migration, invasion, EMT phenotype, and resistance to taxol-induced apoptosis; AK4 knockdown reverses these effects. Co-localization assay, stable overexpression and knockdown in NPC cell lines, western blot (NLRP3, IL-1β), apoptosis assay, migration/invasion assays Cell death & disease Medium 40593461
2021 TRIM29 knockdown destabilizes the AK4 mRNA transcript via downregulation of miR-2355-3p; miR-2355-3p normally facilitates recruitment of the RNA helicase DDX3X to the AK4 transcript to stabilize it. Loss of AK4 alters bioenergetics and suppresses proliferation and invasion of pancreatic cancer cells. Global screening, qRT-PCR, western blot, AK4 mRNA stability assay, miR-2355-3p manipulation, DDX3X recruitment to AK4 transcript Molecular therapy. Nucleic acids Medium 33898107
2021 STAT3 transcriptionally activates AK4 expression; miR-3666 targets STAT3 and thereby indirectly represses AK4, suppressing ovarian carcinoma cell proliferation and migration. Luciferase reporter assay (miR-3666 targeting STAT3), western blot (AK4, STAT3), rescue experiments with AK4 overexpression Cancer biomarkers : section A of Disease markers Low 33361582
2025 miR-634 targets AK4 (validated by dual luciferase reporter assay) and downregulates AK4 expression; AK4 overexpression activates p-AKT and p-mTOR signaling and inhibits apoptosis in HEI-OC1 cells, while miR-634 mimic or AK4 knockdown promotes apoptosis and increases ROS. Dual luciferase reporter assay, miR-634 mimic transfection, AK4 overexpression and knockdown, western blot (Caspase-3/7, Bax, Bcl-2, p-AKT, p-mTOR), flow cytometry (apoptosis), ROS measurement Hearing research Medium 40819488
2018 miR-199a-3p directly targets AK4 (validated by luciferase reporter assay); AK4 is a positive regulator of multi-drug resistance in osteosarcoma, and forced changes in miR-199a-3p levels drastically alter NF-κB signaling pathway activity. qRT-PCR, western blot, luciferase reporter assay, drug resistance profiling assay, NF-κB pathway activity measurement BMC cancer Medium 29866054
2018 miR-199a-3p directly targets AK4 (validated by luciferase reporter assay) and AK4 promotes radioresistance of esophageal cancer cells; reversal of miR-199a-3p or AK4 levels alters multiple signaling pathway activities. Luciferase reporter assay, survival fraction experiments, wound-healing, invasion assay, forced expression/inhibition of miR-199a-3p and AK4 Cancer cell international Medium 30479565
2020 LINC00662 stabilizes AK4 mRNA through binding to the RNA-binding protein hnRNPC; the LINC00662/hnRNPC/AK4 axis promotes radioresistance of oral squamous cell carcinoma cells, and LINC00662 knockdown reduces AK4 expression and attenuates radioresistance. RIP (RNA immunoprecipitation) assay confirming hnRNPC binding to LINC00662 and AK4 mRNA, qRT-PCR, western blot, CCK-8, colony formation, flow cytometry, rescue experiments Cancer cell international Medium 32549791
2025 AK4 and RHOC are identified as direct targets of the tumor-suppressive miR-455-3p in adult T cell leukemia (ATL); AK4 promotes oncogenic Myc target pathways and enhances production of sphingomyelin; ATL cells show selective sensitivity to AK4 depletion compared to other T cell malignancies. miRNA target identification, in vitro and in vivo functional assays (AK4 knockdown/overexpression), transcriptome and metabolome analyses Proceedings of the National Academy of Sciences of the United States of America Medium 39982744
2023 miR-124 directly targets AK4; AK4 in turn regulates ATF3 (activating transcription factor 3) downstream; in rat subarachnoid hemorrhage models and primary neuron hemoglobin stimulation models, miR-124 exerts neuroprotective effects via inhibition of the AK4/ATF3 axis. In vitro luciferase/target validation, rat SAH model, mouse embryonic primary neuron hemoglobin stimulation model, miR-124 inhibitor and mimic transfection, in vivo and in vitro phenotype observation Experimental brain research Low 37932484

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Knockdown of circ-ABCB10 promotes sensitivity of lung cancer cells to cisplatin via miR-556-3p/AK4 axis. BMC pulmonary medicine 46 31931771
2018 MiR-199a-3p affects the multi-chemoresistance of osteosarcoma through targeting AK4. BMC cancer 43 29866054
2018 The miR-199a-3p regulates the radioresistance of esophageal cancer cells via targeting the AK4 gene. Cancer cell international 28 30479565
2019 AK4 Promotes the Progression of HER2-Positive Breast Cancer by Facilitating Cell Proliferation and Invasion. Disease markers 24 31827645
2020 Knockdown of LINC00662 represses AK4 and attenuates radioresistance of oral squamous cell carcinoma. Cancer cell international 19 32549791
2019 Microstructural changes in the brain mediate the association of AK4, IGFBP5, HSPB2, and ITPK1 with cognitive decline. Neurobiology of aging 19 31479860
2021 TRIM29 alters bioenergetics of pancreatic cancer cells via cooperation of miR-2355-3p and DDX3X recruitment to AK4 transcript. Molecular therapy. Nucleic acids 14 33898107
2022 Association of AK4 Protein From Stem Cell-Derived Neurons With Cognitive Reserve: An Autopsy Study. Neurology 13 35948448
2021 MiR-3666 serves as a tumor suppressor in ovarian carcinoma by down-regulating AK4 via targeting STAT3. Cancer biomarkers : section A of Disease markers 9 33361582
2020 Identification of AK4 as a novel therapeutic target for serous ovarian cancer. Oncology letters 9 33123257
2025 Identification of AK4 and RHOC as potential oncogenes addicted by adult T cell leukemia. Proceedings of the National Academy of Sciences of the United States of America 3 39982744
2024 Identification and verification of AK4 as a protective immune-related biomarker in adipose-derived stem cells and breast cancer. Heliyon 3 38560200
2024 Rational design and synthesis of novel N-benzylindole-based epalrestat analogs as selective aldose reductase inhibitors: An unexpected discovery of a new glucose-lowering agent (AK-4) acting as a mitochondrial uncoupler. European journal of medicinal chemistry 3 39536493
2023 MicroRNA-124 conducts neuroprotective effect via inhibiting AK4/ATF3 after subarachnoid hemorrhage. Experimental brain research 3 37932484
2025 Adenylate kinase 4 (AK4) deficiency prevents vascular smooth muscle cell phenotypic switching by regulating mitochondrial dysfunction through AMPKα inactivation. Atherosclerosis 2 40506332
2025 MiRNA-634 promotes apoptosis in HEI-OC1 cells by regulating AK4 and AKT/mTOR signaling pathways. Hearing research 2 40819488
2025 AK4 promotes nasopharyngeal carcinoma metastasis and chemoresistance by activating NLRP3 inflammatory complex. Cell death & disease 1 40593461
2025 Circ-06958 Is Involved in Meat Quality by Regulating Cell Proliferation Through miR-31-5p/AK4 Axis in Pigs. Cells 1 41002382
2026 Genome-Guided Identification of an OTA-Degrading Amidohydrolase AMH2102 from Acinetobacter kookii AK4 with Enhanced Soluble Expression in Escherichia coli. Toxins 0 41745767
2025 RETRACTION: AK4 Promotes the Progression of HER2-Positive Breast Cancer by Facilitating Cell Proliferation and Invasion. Disease markers 0 40371196

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