Affinage

NUAK2

NUAK family SNF1-like kinase 2 · UniProt Q9H093

Length
628 aa
Mass
69.6 kDa
Annotated
2026-06-10
52 papers in source corpus 25 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NUAK2 (SNARK) is an LKB1-activated, AMPK-related serine/threonine kinase that functions as a metabolic and mechanical stress sensor coupling stress signals to actomyosin contractility and cytoskeletal organization (PMID:11284715, PMID:20713714, PMID:22689267). Its kinase activity is stimulated by AMP/AICAriboside and a broad range of stresses including glucose and glutamine deprivation, ER stress, hyperosmotic and oxidative stress, and is downregulated by metformin (PMID:11284715, PMID:15893879). A central mechanistic axis is its control of myosin light chain phosphorylation: NUAK2 phosphorylates MYPT1 at sites distinct from the Rho-kinase sites Thr696/Thr853 (PMID:18023418), and through association with MRIP it is targeted to actin stress fibers to inhibit MYPT1-mediated MLC dephosphorylation in a kinase-independent manner (PMID:21242312), together promoting MLC phosphorylation, stress fiber formation, and apical constriction. NUAK2 and NUAK1 cooperatively organize the apical actomyosin network during neural tube closure, and human loss-of-function NUAK2 mutations that abolish catalytic activity cause defective Hippo signaling, cytoplasmic YAP retention, and impaired apical constriction and nucleokinesis in patient-derived neural models (PMID:22689267, PMID:32845958). NUAK2 is itself a direct transcriptional target of YAP and feeds back through actin polymerization and myosin activity to amplify YAP signaling (PMID:30446657). In skeletal muscle and heart, NUAK2 is activated by contraction, exercise, and ischemia and is required for contraction- and ischemia-stimulated glucose transport independently of insulin (PMID:20713714, PMID:30256437), and it supports myocyte survival under metabolic stress via Rho kinase signaling (PMID:26690705). Beyond contractility, NUAK2 suppresses GPX4 at the RNA level to sensitize cells to ferroptosis, kinase-independently (PMID:35523770), and maintains cell-surface ACE2 to facilitate coronavirus entry downstream of the IRE1α-XBP1 UPR branch through actin cytoskeleton regulation (PMID:37421942). NUAK2 is recurrently co-opted in cancer, acting downstream of NF-κB and YAP and promoting proliferation, migration, and matrix-dependent invasion across melanoma, glioblastoma, and pancreatic tumors (PMID:21460252, PMID:30446657, PMID:38510132, PMID:40770117).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2001 High

    Established NUAK2 as a catalytically active AMPK-related kinase whose activity is tuned by metabolic stress, defining its identity as a stress-sensing serine/threonine kinase.

    Evidence In vitro kinase assays (autophosphorylation, SAMS peptide) with AMP/AICAriboside and glucose-deprivation modulation

    PMID:11284715

    Open questions at the time
    • No physiological substrate identified beyond the synthetic SAMS peptide
    • Upstream activating kinase not yet defined
  2. 2003 Medium

    Linked NUAK2 catalytic activity to cytoskeletal/adhesion remodeling, showing its kinase domain drives F-actin disassembly and cell-cell detachment under metabolic stress.

    Evidence Overexpression with catalytic-domain deletion mutants in HepG2 cells, morphological and Western analysis

    PMID:14575707

    Open questions at the time
    • Direct cytoskeletal substrate not identified
    • Phenotype from overexpression rather than physiological loss-of-function
  3. 2005 Medium

    Mapped the breadth of stresses that regulate NUAK2 activity in a cell-type-dependent manner and identified metformin as a negative regulator.

    Evidence IP kinase assays across multiple cell lines under diverse stress and pharmacological conditions

    PMID:15893879

    Open questions at the time
    • Molecular basis of differential cell-type regulation unknown
    • Whether metformin acts directly on NUAK2 or via upstream signaling unresolved
  4. 2007 High

    Identified MYPT1 as a direct NUAK2 substrate phosphorylated at novel sites, providing the biochemical entry point to NUAK2 control of myosin phosphatase and contractility.

    Evidence In vitro kinase assay with HPLC-based de novo substrate screening and site mutagenesis

    PMID:18023418

    Open questions at the time
    • Exact MYPT1 residues not defined
    • Functional consequence of these phosphosites on phosphatase activity not directly tested in this study
  5. 2010 High

    Placed NUAK2 downstream of LKB1 in vivo and established it as the contraction-specific, insulin-independent regulator of skeletal muscle glucose transport.

    Evidence Dominant-negative and heterozygous knockout mice, in vivo electroporation, C2C12 siRNA, glucose transport assays with LKB1 KO epistasis

    PMID:20713714

    Open questions at the time
    • Substrates linking NUAK2 to glucose uptake machinery unknown
    • Heterozygous knockout leaves residual function unaddressed
  6. 2011 High

    Revealed a kinase-independent mode in which MRIP scaffolds NUAK2 onto stress fibers to inhibit MYPT1-mediated MLC dephosphorylation, expanding NUAK2 function beyond catalysis.

    Evidence Reciprocal Co-IP, kinase-dead mutant, siRNA epistasis with MRIP and MYPT1, immunofluorescence

    PMID:21242312

    Open questions at the time
    • Structural basis of NUAK2-MRIP interaction unknown
    • How a kinase-dead protein inhibits the phosphatase mechanistically unresolved
  7. 2011 Medium

    Implicated NUAK2 in tumor cell proliferation and survival, showing its loss induces senescence and suppresses melanoma growth.

    Evidence siRNA knockdown, cell cycle and migration assays, xenograft model

    PMID:21460252

    Open questions at the time
    • Mechanism linking NUAK2 to mTOR downregulation unknown
    • Direct targets in senescence pathway not identified
  8. 2012 High

    Demonstrated in vivo that NUAK1 and NUAK2 cooperatively drive apical actomyosin organization required for neural tube closure.

    Evidence Double-knockout mouse genetics with immunofluorescence for pMLC2, F-actin, cortactin, tubulin

    PMID:22689267

    Open questions at the time
    • Relative contributions of NUAK1 vs NUAK2 not separated
    • Direct substrate in neuroepithelium not defined
  9. 2013 Medium

    Showed NUAK2 promotes TGF-β signaling in a phosphorylation- and kinase-dependent manner and identified disulfiram as a noncompetitive inhibitor.

    Evidence siRNA, phospho/kinase-dead mutant complementation, luciferase reporters, HCV replicon; in vitro kinase assay for inhibitor

    PMID:23831117 PMID:27602492

    Open questions at the time
    • Direct substrate in TGF-β pathway not identified
    • Disulfiram selectivity over related kinases not established
  10. 2015 Medium

    Positioned NUAK2 upstream of CDK2 in PTEN-deficient melanoma, defining a context-specific oncogenic dependency.

    Evidence Combined siRNA and pharmacological inhibition, growth assays, xenografts, IHC

    PMID:25832654

    Open questions at the time
    • Molecular link from NUAK2 to CDK2 expression unknown
    • Restricted to PTEN-deficient/NUAK2-amplified context
  11. 2016 High

    Established NUAK2 as a survival factor for myocytes under metabolic stress acting upstream of ROCK signaling.

    Evidence siRNA, dominant-negative transgenic mice, apoptosis assays, Western blot for Rho kinase components

    PMID:26690705

    Open questions at the time
    • Mechanism by which NUAK2 sustains ROCK signaling unknown
    • Direct substrate mediating survival not identified
  12. 2016 Medium

    Defined miR-143 as a direct post-transcriptional repressor of NUAK2 controlling glioblastoma cell behavior and stemness.

    Evidence 3'-UTR luciferase reporter, knockdown/overexpression, proliferation/migration/invasion assays

    PMID:27081712

    Open questions at the time
    • Downstream effectors of NUAK2 in stemness not identified
    • Single-lab functional rescue
  13. 2018 High

    Identified NUAK2 as a direct YAP transcriptional target forming a positive feedback loop that amplifies YAP activity via actin and myosin.

    Evidence YAP ChIP-seq at NUAK2 locus, knockdown/overexpression, in vivo liver YAP models, actin/myosin assays, pharmacological inhibition

    PMID:30446657

    Open questions at the time
    • Precise cytoskeletal substrate feeding back to YAP not defined
    • Whether feedback requires kinase activity not fully resolved here
  14. 2018 Medium

    Extended the contraction-glucose role to heart, mapping Thr208 as an exercise/ischemia-responsive phosphosite required for insulin-independent cardiac glucose transport.

    Evidence Phospho-specific Western (Thr208), siRNA, heterozygous knockout mice, glucose transport in HL1 cardiomyocytes

    PMID:30256437

    Open questions at the time
    • Kinase phosphorylating Thr208 not directly confirmed
    • Downstream glucose transport effectors unknown
  15. 2020 High

    Provided human disease genetics linking catalytically dead NUAK2 mutations to defective Hippo/YAP signaling and impaired apical constriction in neural development.

    Evidence In vitro kinase assay of patient mutant, patient iPSC-derived neural progenitors and cerebral organoids, YAP localization and cytoskeletal imaging

    PMID:32845958

    Open questions at the time
    • How loss of kinase activity retains YAP in cytoplasm mechanistically unresolved
    • Genotype-phenotype spectrum across patients not established
  16. 2021 Medium

    Connected NUAK2 to mitochondrial regulation through a miR-696–Pgc1α axis in muscle.

    Evidence Gain/loss-of-function in C2C12, muscle-specific transgenic mice, miR-696 and respiration measurements

    PMID:33812060

    Open questions at the time
    • Mechanism by which NUAK2 controls miR-696 transcription unknown
    • Single-lab finding
  17. 2022 Medium

    Placed NUAK2 downstream of GPR65-cAMP-PKA-LKB1 signaling as a restraint on Th1/Th17 differentiation in T cells.

    Evidence RNA-seq, NUAK2 siLencing rescue in Gpr65 KO and WT T cells, pathway inhibitors, differentiation assays

    PMID:35343079

    Open questions at the time
    • Direct NUAK2 substrate in T cell differentiation unknown
    • Whether effect requires kinase activity untested
  18. 2022 Medium

    Revealed a kinase-independent role for NUAK2 in suppressing GPX4 at the RNA level to sensitize cells to ferroptosis.

    Evidence siRNA, kinase-dead mutant, GPX4 RT-qPCR, ferroptosis inducers and cell death assays

    PMID:35523770

    Open questions at the time
    • Mechanism of GPX4 mRNA suppression unknown
    • How a kinase-dead protein represses GPX4 unresolved
  19. 2022 Low

    Reported NUAK2 binding to CYFIP2 and acting upstream of it to drive cervical cancer cell phenotypes.

    Evidence Single Co-IP, NUAK2 and CYFIP2 knockdown, rescue and functional assays

    PMID:34558636

    Open questions at the time
    • Single Co-IP without reciprocal or structural validation of direct binding
    • Whether interaction is kinase-dependent untested
  20. 2023 High

    Defined NUAK2 as a host entry factor for multiple coronaviruses, induced by IRE1α-XBP1 and required to maintain surface ACE2 via actin regulation.

    Evidence siRNA, kinase inhibitors, IRE1α inhibitors, virus entry and receptor surface assays, confocal/EM across multiple coronaviruses

    PMID:37421942

    Open questions at the time
    • Direct cytoskeletal substrate controlling receptor surface levels not identified
    • Relative roles of kinase-dependent and -independent activity not fully separated
  21. 2024 Medium

    Placed NUAK2 downstream of NF-κB and upstream of SMAD2/3 and FAK signaling in pancreatic cancer.

    Evidence NF-κB promoter ChIP, siRNA, Western blot for SMAD/FAK, nuclear fractionation for SMAD4

    PMID:38510132

    Open questions at the time
    • Mechanism linking NUAK2 to SMAD2/3 levels unknown
    • Direct substrate not identified
  22. 2024 Medium

    Showed NUAK2 promotes glioblastoma proliferation and ECM-dependent migration, validated by CRISPR deletion and pharmacological inhibition.

    Evidence CRISPR-Cas9 knockout, overexpression, proliferation/migration assays, xenografts, pharmacological inhibition

    PMID:40770117

    Open questions at the time
    • Specific ECM components modulated not defined mechanistically
    • Direct substrate driving migration unknown
  23. 2025 Medium

    Implicated NUAK2 in pre-mRNA splicing through engagement of core spliceosome components, affecting EZH2 and TTK splicing in neuroendocrine prostate cancer.

    Evidence Phosphoproteomics, interactome co-IP/MS, splicing analysis, inhibition and knockdown (preprint)

    PMID:41292858

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Which spliceosome components are direct NUAK2 phosphorylation substrates unresolved
  24. 2026 Medium

    Connected metabolic-epigenetic signaling to NUAK2 induction, showing lactate-driven H4K12 lactylation at a NUAK2 super-enhancer promotes myofibroblast activation and fibrosis.

    Evidence PDHA1 acetyl-mimic mutants, H4K12la ChIP at NUAK2 locus, NUAK2 inhibition, myofibroblast and in vivo fibrosis rescue

    PMID:41784683

    Open questions at the time
    • NUAK2 effectors driving myofibroblast activation not defined
    • Single-lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • The direct physiological substrates that link NUAK2 to its many phenotypes remain largely undefined, and the molecular basis distinguishing its kinase-dependent contractility roles from its kinase-independent roles (MRIP scaffolding, GPX4 suppression) is not resolved.
  • No comprehensive cellular substrate catalog beyond MYPT1
  • Structural basis of partner interactions (MRIP, CYFIP2, spliceosome) unknown
  • Mechanism unifying kinase-dependent and kinase-independent functions unestablished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0016740 transferase activity 2 GO:0140299 molecular sensor activity 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0005856 cytoskeleton 3 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1430728 Metabolism 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-168256 Immune System 1 R-HSA-8953854 Metabolism of RNA 1
Partners
CYFIP2LKB1MRIPMYPT1YAP

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 NUAK2 (SNARK) is a serine/threonine kinase that exhibits autophosphorylation in vitro and phosphotransferase activity toward the synthetic peptide SAMS. Its activity is increased by AMP and AICAriboside, and by glucose deprivation, placing it in the AMPK-related kinase family as a metabolic stress sensor. In vitro kinase assay (autophosphorylation, SAMS peptide phosphorylation), Western blot, cell-based activity assay The Biochemical journal High 11284715
2003 Human NUAK2 (SNARK) phosphorylates GST-SAMS in an AMP-dependent manner. Overexpression in HepG2 cells causes acute cell-cell detachment under glucose starvation, accompanied by conversion of F-actin to G-actin and suppression of FAK and PKC phosphorylation. Deletion mutant analysis showed the catalytic domain is required for cell-cell detachment. In vitro kinase assay, overexpression with deletion mutants, Western blot, morphological analysis Biochemical and biophysical research communications Medium 14575707
2005 NUAK2 (SNARK) kinase activity is regulated in a cell-type-dependent manner by glucose deprivation, glutamine deprivation, ER stress (homocysteine, DTT), elevated AMP/depleted ATP, hyperosmotic stress, salt stress, UVB radiation, and oxidative stress (H2O2). Metformin downregulates SNARK activity in hepatocytes in a dose- and time-dependent manner. Immunoprecipitation kinase assay in multiple cell lines, pharmacological treatment (metformin) Biochimica et biophysica acta Medium 15893879
2007 NUAK2 phosphorylates MYPT1 (myosin phosphatase target subunit 1) at site(s) distinct from the known Rho-kinase phosphorylation sites (Thr696 and Thr853), as identified by in vitro kinase assay combined with HPLC-based de novo substrate screening. In vitro kinase assay, HPLC-based substrate screening, mutagenesis of known phosphorylation sites Biochemical and biophysical research communications High 18023418
2010 NUAK2 (SNARK) is activated by muscle contraction and is required for contraction-stimulated (but not insulin-stimulated) glucose transport in skeletal muscle. Expression of a dominant-negative SNARK mutant in tibialis anterior impaired contraction-stimulated glucose transport; SNARK heterozygous knockout mice showed the same defect. LKB1 knockout blunted contraction-induced SNARK activation, placing SNARK downstream of LKB1. Dominant-negative transgenic mouse, heterozygous knockout mouse, glucose transport assay, in vivo electroporation, siRNA knockdown in C2C12 cells Proceedings of the National Academy of Sciences of the United States of America High 20713714
2011 NUAK2 associates with MRIP (myosin phosphatase Rho-interacting protein), which targets NUAK2 to actin stress fibers. This association promotes MLC phosphorylation and stress fiber formation by inhibiting MYPT1-mediated MLC dephosphorylation. The activity does not require NUAK2 kinase activity but depends on both MRIP and MYPT1, revealing a kinase-independent mechanism. Co-immunoprecipitation, kinase-dead mutant overexpression, siRNA knockdown, immunofluorescence, Western blot Journal of cell science High 21242312
2011 Knockdown of NUAK2 in melanoma cells induces senescence, reduces S-phase entry, decreases migration, and downregulates mTOR expression. In vivo, NUAK2 knockdown suppresses melanoma tumor growth in mice. siRNA knockdown, cell cycle analysis, migration assay, xenograft mouse model, Western blot Proceedings of the National Academy of Sciences of the United States of America Medium 21460252
2012 NUAK1 and NUAK2 double-knockout mice develop exencephaly, facial clefting, and spina bifida. In the double mutant neuroepithelium, apical concentration of phosphorylated MLC2, F-actin, and cortactin is lost and acetylated α-tubulin-positive microtubules fail to develop, demonstrating that NUAK1 and NUAK2 cooperatively regulate apical constriction and apico-basal elongation during neural tube closure. Double-mutant mouse genetics, immunofluorescence for pMLC2, F-actin, cortactin, tubulin Developmental dynamics High 22689267
2013 NUAK2 (SNARK) promotes TGF-β signaling in a manner dependent on both its phosphorylation status and kinase activity; unphosphorylated or kinase-deficient mutants fail to rescue HCV replication or TGF-β signaling upon SNARK knockdown. Disulfiram was subsequently found to inhibit SNARK kinase activity in vitro in a noncompetitive manner and suppresses SNARK-mediated TGF-β signaling. siRNA knockdown, site-directed mutagenesis of phosphorylation and kinase-dead mutants, luciferase reporter assay, HCV replicon system; in vitro luminescence kinase assay (disulfiram study) Journal of hepatology; Oncotarget Medium 23831117 27602492
2015 In PTEN-deficient melanoma cells, NUAK2 silencing combined with PI3K pathway inactivation efficiently controls CDK2 expression, and CDK2 inactivation specifically abrogates growth of NUAK2-amplified, PTEN-deficient melanoma cells. NUAK2 functionally operates upstream of CDK2 in this context. siRNA knockdown, pharmacological inhibition, in vitro growth assay, in vivo xenograft, immunohistochemistry Cancer research Medium 25832654
2016 SNARK (NUAK2) is required for myocyte survival under metabolic stress. Decreased endogenous SNARK (siRNA) increases apoptosis in cultured muscle cells under stress; muscle-specific dominant-negative SNARK transgenic mice display increased myonuclear apoptosis, severe age-accelerated muscle atrophy, and increased adiposity. Reduced SNARK activity causes downregulation of the Rho kinase signaling pathway, placing SNARK upstream of ROCK-mediated survival signaling. siRNA knockdown, dominant-negative transgenic mice, apoptosis assays, Western blot for Rho kinase pathway components The Journal of clinical investigation High 26690705
2016 miR-143 directly targets the 3'-UTR of NUAK2, downregulates NUAK2 protein, and inhibits proliferation, migration, and invasion of glioblastoma cells. NUAK2 regulates cancer stem cell-related gene expression in glioblastoma. 3'-UTR luciferase reporter assay, Western blot, siRNA/shRNA knockdown, overexpression, proliferation/migration/invasion assays International journal of molecular medicine Medium 27081712
2018 NUAK2 is a direct transcriptional target of YAP in liver cancer. NUAK2 participates in a positive feedback loop to maximize YAP activity via promotion of actin polymerization and myosin activity. Pharmacological inactivation of NUAK2 suppresses YAP-dependent cancer cell proliferation and liver overgrowth in vivo. ChIP-seq (YAP binding to NUAK2 locus), genetic knockdown/overexpression, in vivo liver-specific YAP activation models, actin polymerization and myosin activity assays, pharmacological inhibition Nature communications High 30446657
2018 SNARK (NUAK2) is phosphorylated on Thr208 in heart in response to exercise and ischemia (but not insulin). SNARK knockdown significantly decreases ischemia-stimulated glucose transport in cardiomyocytes; SNARK heterozygous knockout mice have ~50% reduced exercise-stimulated cardiac glucose transport. SNARK does not affect insulin-stimulated glucose transport in the heart. Phospho-specific Western blot (Thr208), siRNA knockdown, SNARK+/- heterozygous knockout mice, glucose transport assay in HL1 cardiomyocytes Journal of cellular biochemistry Medium 30256437
2020 Loss-of-function NUAK2 mutations (in-frame 21-bp deletion causing 7-aa truncation) completely abolish kinase catalytic activity as shown by in vitro kinase assay. In patient-derived neural progenitor cells and cerebral organoids, loss of NUAK2 leads to decreased Hippo signaling via cytoplasmic YAP retention, disruption of the apical actomyosin network, impaired nucleokinesis, and impaired apical constriction during neural tube closure. In vitro kinase assay with patient-derived mutant, patient-derived iPSC-derived neural progenitors and cerebral organoids, immunofluorescence for YAP localization and actomyosin network, live imaging The Journal of experimental medicine High 32845958
2021 SNARK (NUAK2) overexpression in C2C12 muscle cells increases miR-696 transcription, while SNARK knockdown decreases it. Muscle-specific SNARK transgenic mice exhibit lower Pgc1α expression, elevated miR-696, and reduced spontaneous activity. miR-696 directly inhibits Pgc1α, reducing mitochondrial function. This places SNARK upstream of a miR-696–Pgc1α axis controlling mitochondrial activity. Overexpression and siRNA knockdown in C2C12, muscle-specific transgenic mice, miR-696 expression assay, mitochondrial respiration measurement, in silico 3'UTR analysis Molecular metabolism Medium 33812060
2021 GPR65 deficiency promotes NUAK2 expression via the cAMP-PKA-C-Raf-ERK1/2-LKB1 signaling pathway in CD4+ T cells. NUAK2 acts as a functional downstream target of GPR65 to restrict Th1 and Th17 cell differentiation; silencing of NUAK2 in GPR65-deficient T cells restores Th1/Th17 differentiation, confirming epistatic placement of NUAK2 downstream of GPR65-cAMP-LKB1 signaling. RNA-seq, siRNA knockdown of NUAK2, conditional Gpr65 knockout mice, pathway inhibitor experiments, T cell differentiation assays Clinical and translational medicine Medium 35343079
2022 NUAK2 suppresses GPX4 expression at the RNA level and promotes ferroptotic cell death in breast cancer cells. This activity is independent of NUAK2 kinase activity. siRNA-mediated NUAK2 silencing reduces sensitivity to small-molecule GPX4 inhibitors. siRNA knockdown, kinase-dead mutant, RT-qPCR for GPX4 mRNA, ferroptosis inducers, cell death assays Cell death discovery Medium 35523770
2022 NUAK2 binds directly to CYFIP2 (co-immunoprecipitation), and NUAK2 knockdown upregulates CYFIP2 expression in cervical cancer cells. The effects of NUAK2 on cell proliferation, migration, invasion, and EMT are reversed by CYFIP2 inhibition, placing NUAK2 upstream of CYFIP2. Co-immunoprecipitation, siRNA knockdown of NUAK2 and CYFIP2, rescue experiments, functional assays (proliferation, migration, invasion, EMT markers) Molecular medicine reports Low 34558636
2023 SARS-CoV-2 infection activates the IRE1α-XBP1 UPR branch, which upregulates NUAK2 expression. NUAK2 is required for SARS-CoV-2, HCoV-229E, and MERS-CoV entry; reducing NUAK2 abundance or kinase activity impairs viral particle binding and internalization by decreasing cell surface levels of viral receptors (ACE2) and disrupting viral trafficking, likely through modulation of the actin cytoskeleton. siRNA knockdown, kinase inhibitors, virus entry assays, receptor surface quantification, IRE1α inhibitors, confocal/electron microscopy Molecular cell High 37421942
2024 NF-κB transcriptionally regulates NUAK2 by binding to the NUAK2 promoter. NUAK2 knockdown reduces p-SMAD2/3 and SMAD2/3 expression and decreases nuclear translocation of SMAD4; in SMAD4-negative cells, NUAK2 knockdown impacts FAK signaling by downregulating SMAD2/3, placing NUAK2 downstream of NF-κB and upstream of SMAD2/3 and FAK signaling in pancreatic cancer. Chromatin immunoprecipitation (NF-κB promoter binding), siRNA knockdown, Western blot for SMAD2/3 and FAK pathway, nuclear fractionation for SMAD4 iScience Medium 38510132
2024 NUAK2 modulates extracellular matrix (ECM) components to facilitate migratory behavior in glioblastoma cells. CRISPR-Cas9 deletion of NUAK2 suppresses GBM cell proliferation and inhibits ECM-dependent migration; pharmacological NUAK2 inhibition is sufficient to impede both proliferation and migration. CRISPR-Cas9 knockout, overexpression, proliferation and migration assays in vitro, in vivo xenograft, pharmacological inhibition, integrated downstream pathway analysis EMBO molecular medicine Medium 40770117
2025 Integrated phospho-target and interactome analyses demonstrate that NUAK2 engages core spliceosome components to regulate pre-mRNA splicing. NUAK2 inhibition perturbs splicing of EZH2 and TTK pre-mRNAs, leading to reduced translation of these proteins in neuroendocrine prostate cancer. Phosphoproteomics, interactome (co-IP/MS), splicing analysis (RT-PCR/RNA-seq), Western blot for protein levels, pharmacological inhibition and genetic knockdown bioRxivpreprint Medium 41292858
2026 SIRT3 deacetylase activity on PDHA1 normally prevents PDHA1 K83 hyperacetylation; loss of SIRT3 leads to PDHA1 K83ac, which inhibits PDH activity, increases glycolysis and lactate. Lactate drives H4K12 lactylation at a super-enhancer at the NUAK2 locus, markedly upregulating NUAK2 expression. Genetic or pharmacological NUAK2 inhibition suppresses myofibroblast activation and fibrosis, and rescue of PDHA1 K83ac-driven fibrosis is blocked by NUAK2 knockdown. Acetylation-mimicking and deacetylation-mimicking mutants of PDHA1, ChIP for H4K12la at NUAK2 locus, siRNA/pharmacological inhibition of NUAK2, myofibroblast differentiation assays, in vivo fibrosis model Cellular and molecular life sciences Medium 41784683

Source papers

Stage 0 corpus · 52 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 NUAK2 is a critical YAP target in liver cancer. Nature communications 119 30446657
2010 Sucrose nonfermenting AMPK-related kinase (SNARK) mediates contraction-stimulated glucose transport in mouse skeletal muscle. Proceedings of the National Academy of Sciences of the United States of America 78 20713714
2001 Identification and characterization of a novel sucrose-non-fermenting protein kinase/AMP-activated protein kinase-related protein kinase, SNARK. The Biochemical journal 61 11284715
2011 AMP kinase-related kinase NUAK2 affects tumor growth, migration, and clinical outcome of human melanoma. Proceedings of the National Academy of Sciences of the United States of America 56 21460252
2022 GPR65 promotes intestinal mucosal Th1 and Th17 cell differentiation and gut inflammation through downregulating NUAK2. Clinical and translational medicine 48 35343079
2020 A loss-of-function NUAK2 mutation in humans causes anencephaly due to impaired Hippo-YAP signaling. The Journal of experimental medicine 45 32845958
2005 Regulation of SNARK activity in response to cellular stresses. Biochimica et biophysica acta 44 15893879
2011 An association between NUAK2 and MRIP reveals a novel mechanism for regulation of actin stress fibers. Journal of cell science 42 21242312
2003 Induction of cell-cell detachment during glucose starvation through F-actin conversion by SNARK, the fourth member of the AMP-activated protein kinase catalytic subunit family. Biochemical and biophysical research communications 37 14575707
2007 Identification of a novel substrate for TNFalpha-induced kinase NUAK2. Biochemical and biophysical research communications 34 18023418
2012 Neural tube defects by NUAK1 and NUAK2 double mutation. Developmental dynamics : an official publication of the American Association of Anatomists 32 22689267
2015 NUAK2 Amplification Coupled with PTEN Deficiency Promotes Melanoma Development via CDK Activation. Cancer research 31 25832654
2013 The AMPK-related kinase SNARK regulates hepatitis C virus replication and pathogenesis through enhancement of TGF-β signaling. Journal of hepatology 29 23831117
2009 Regulation of skeletal muscle sucrose, non-fermenting 1/AMP-activated protein kinase-related kinase (SNARK) by metabolic stress and diabetes. Diabetologia 28 19652946
2021 lncRNA FGD5‑AS1 promotes breast cancer progression by regulating the hsa‑miR‑195‑5p/NUAK2 axis. Molecular medicine reports 26 33880593
2007 Susceptibility of Snark-deficient mice to azoxymethane-induced colorectal tumorigenesis and the formation of aberrant crypt foci. Cancer science 26 18307533
2016 The AMPK-related kinase SNARK regulates muscle mass and myocyte survival. The Journal of clinical investigation 24 26690705
2016 miR-143 inhibits oncogenic traits by degrading NUAK2 in glioblastoma. International journal of molecular medicine 23 27081712
2023 Enhanced SARS-CoV-2 entry via UPR-dependent AMPK-related kinase NUAK2. Molecular cell 22 37421942
2021 NUAK1 and NUAK2 Fine-Tune TGF-β Signaling. Cancers 22 34282782
2016 Expression of NUAK2 in gastric cancer tissue and its effects on the proliferation of gastric cancer cells. Experimental and therapeutic medicine 20 28352350
2021 NUAK2 silencing inhibits the proliferation, migration and epithelial‑to‑mesenchymal transition of cervical cancer cells via upregulating CYFIP2. Molecular medicine reports 19 34558636
2023 AICAR Ameliorates Non-Alcoholic Fatty Liver Disease via Modulation of the HGF/NF-κB/SNARK Signaling Pathway and Restores Mitochondrial and Endoplasmic Reticular Impairments in High-Fat Diet-Fed Rats. International journal of molecular sciences 18 36834782
2021 The MicroRNA miR-696 is regulated by SNARK and reduces mitochondrial activity in mouse skeletal muscle through Pgc1α inhibition. Molecular metabolism 18 33812060
2021 NUAK2 and RCan2 participate in the p53 mutant pro-tumorigenic network. Biology direct 18 34348766
2008 SNARK, a novel downstream molecule of EBV latent membrane protein 1, is associated with resistance to cancer cell death. Leukemia & lymphoma 17 18452098
2011 NUAK2: an emerging acral melanoma oncogene. Oncotarget 16 21911917
2007 The T cell antigen receptor: "The Hunting of the Snark". European journal of immunology 15 17972349
2022 The AMPK-related kinase NUAK2 suppresses glutathione peroxidase 4 expression and promotes ferroptotic cell death in breast cancer cells. Cell death discovery 14 35523770
2024 The NF-κB/NUAK2 signaling axis regulates pancreatic cancer progression by targeting SMAD2/3. iScience 12 38510132
2023 OTUD7B deubiquitinates and stabilizes YAP1 to upregulate NUAK2 expression, thus accelerating gastric cancer procession. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 12 37429790
2020 NUAK2 localization in normal skin and its expression in a variety of skin tumors with YAP. Journal of dermatological science 10 32001115
2023 Glycyrrhizic Acid Protects Glomerular Podocytes Induced by High Glucose by Modulating SNARK/AMPK Signaling Pathway. Current medical science 8 37450070
2016 Anti-hepatocellular carcinoma properties of the anti-alcoholism drug disulfiram discovered to enzymatically inhibit the AMPK-related kinase SNARK in vitro. Oncotarget 8 27602492
2014 Analysis of NUAK1 and NUAK2 expression during early chick development reveals specific patterns in the developing head. The International journal of developmental biology 8 25354459
2023 Circ_0000033 up-regulates NUAK2 by sequestering miR-378a-3p to promote breast tumorigenesis. Environmental and molecular mutagenesis 6 37357410
2022 MiR-1179 represses cell proliferation, migration and invasion of hepatocellular carcinoma through suppression of NUAK2. American journal of translational research 5 35173840
2019 Reduced sucrose nonfermenting AMPK-related kinase (SNARK) activity aggravates cancer-induced skeletal muscle wasting. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 5 31387190
2018 Sucrose nonfermenting AMPK-related kinase (SNARK) regulates exercise-stimulated and ischemia-stimulated glucose transport in the heart. Journal of cellular biochemistry 5 30256437
2025 Ferroptosis and low-grade Glioma: The breakthrough potential of NUAK2. Free radical biology & medicine 4 40286882
2024 NUAK2 Inhibitors, KHKI-01128 and KHKI-01215, Exhibit Potent Anticancer Activity Against SW480 Colorectal Cancer Cells. Anticancer research 4 38925848
2025 A fetal oncogene NUAK2 is an emerging therapeutic target in glioblastoma. bioRxiv : the preprint server for biology 3 39803558
2024 Depletion of NUAK2 blocks the stemness and angiogenesis and facilitates senescence of lung adenocarcinoma cells via enhancing ferroptosis. Cell division 3 39068449
2017 Expression of genes encoding IGFBPs, SNARK, CD36, and PECAM1 in the liver of mice treated with chromium disilicide and titanium nitride nanoparticles. Endocrine regulations 3 28609285
2026 Mitochondrial PDHA1 acetylation orchestrates lactate-dependent epigenetic reprogramming to promote fibrosis via NUAK2. Cellular and molecular life sciences : CMLS 1 41784683
2025 A fetal oncogene NUAK2 is an emerging therapeutic target in glioblastoma. EMBO molecular medicine 1 40770117
2025 NUAK2 Pathogenic Variants Are Definitively Associated with Neural Tube Defects in Humans: New Genotype-Phenotype Correlation and Review of the Literature. Diagnostics (Basel, Switzerland) 1 41008661
2024 Hunting the Cell Cycle Snark. Life (Basel, Switzerland) 1 39459514
2025 [Retracted] lncRNA FGD5‑AS1 promotes breast cancer progression by regulating the hsa‑miR‑195‑5p/NUAK2 axis. Molecular medicine reports 0 39950317
2025 NUAK2 is a therapeutically tractable regulator of RNA splicing and tumor progression in neuroendocrine prostate cancer. bioRxiv : the preprint server for biology 0 41292858
2024 NUAK2 mediated regulation of Schwann Cell proliferation and migration in peripheral nerve injury via YAP. Heliyon 0 39071701
2007 Cytometry in monoclonal B-cell lymphocytosis and chronic lymphocytic leukaemia--the Hunting of the Snark? British journal of haematology 0 18021090

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