{"gene":"NUAK2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2001,"finding":"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.","method":"In vitro kinase assay (autophosphorylation, SAMS peptide phosphorylation), Western blot, cell-based activity assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase reconstitution with substrate peptide and mutagenesis-level characterization, single lab but multiple orthogonal methods","pmids":["11284715"],"is_preprint":false},{"year":2003,"finding":"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.","method":"In vitro kinase assay, overexpression with deletion mutants, Western blot, morphological analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytic domain deletion analysis plus cellular phenotype, single lab, multiple methods","pmids":["14575707"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Immunoprecipitation kinase assay in multiple cell lines, pharmacological treatment (metformin)","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunoprecipitation kinase assay across multiple cell lines and stress conditions, single lab","pmids":["15893879"],"is_preprint":false},{"year":2007,"finding":"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.","method":"In vitro kinase assay, HPLC-based substrate screening, mutagenesis of known phosphorylation sites","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with novel substrate identification protocol (HPLC), direct biochemical demonstration, single lab","pmids":["18023418"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Dominant-negative transgenic mouse, heterozygous knockout mouse, glucose transport assay, in vivo electroporation, siRNA knockdown in C2C12 cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models (dominant-negative, knockout, siRNA) with consistent phenotype, epistasis established via LKB1 KO, replicated across in vivo and in vitro systems","pmids":["20713714"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Co-immunoprecipitation, kinase-dead mutant overexpression, siRNA knockdown, immunofluorescence, Western blot","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, kinase-dead mutant analysis, siRNA epistasis with MRIP and MYPT1, multiple orthogonal methods in single study","pmids":["21242312"],"is_preprint":false},{"year":2011,"finding":"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.","method":"siRNA knockdown, cell cycle analysis, migration assay, xenograft mouse model, Western blot","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple cellular readouts and in vivo validation, single lab","pmids":["21460252"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Double-mutant mouse genetics, immunofluorescence for pMLC2, F-actin, cortactin, tubulin","journal":"Developmental dynamics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via double knockout with multiple molecular readouts, in vivo model","pmids":["22689267"],"is_preprint":false},{"year":2013,"finding":"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.","method":"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":"Journal of hepatology; Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis combined with reporter assay and complementation, single lab; kinase assay for inhibitor confirmed independently","pmids":["23831117","27602492"],"is_preprint":false},{"year":2015,"finding":"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.","method":"siRNA knockdown, pharmacological inhibition, in vitro growth assay, in vivo xenograft, immunohistochemistry","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via combined knockdown/inhibitor experiments, in vitro and in vivo, single lab","pmids":["25832654"],"is_preprint":false},{"year":2016,"finding":"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.","method":"siRNA knockdown, dominant-negative transgenic mice, apoptosis assays, Western blot for Rho kinase pathway components","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models (siRNA, transgenic dominant-negative), consistent phenotype in vitro and in vivo, pathway placement via Rho kinase","pmids":["26690705"],"is_preprint":false},{"year":2016,"finding":"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.","method":"3'-UTR luciferase reporter assay, Western blot, siRNA/shRNA knockdown, overexpression, proliferation/migration/invasion assays","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — luciferase reporter plus functional rescue experiments, single lab","pmids":["27081712"],"is_preprint":false},{"year":2018,"finding":"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.","method":"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","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq for direct transcriptional target, in vivo mouse models, multiple cellular mechanism assays, replicated across multiple cancer cell lines","pmids":["30446657"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Phospho-specific Western blot (Thr208), siRNA knockdown, SNARK+/- heterozygous knockout mice, glucose transport assay in HL1 cardiomyocytes","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation site identified, genetic models (KO mice, siRNA), consistent glucose transport phenotype, single lab","pmids":["30256437"],"is_preprint":false},{"year":2020,"finding":"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.","method":"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","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay demonstrating loss of catalytic activity, patient-derived disease models, multiple orthogonal mechanistic readouts (YAP localization, cytoskeletal assays, nucleokinesis)","pmids":["32845958"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Overexpression and siRNA knockdown in C2C12, muscle-specific transgenic mice, miR-696 expression assay, mitochondrial respiration measurement, in silico 3'UTR analysis","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function in vitro and in vivo, consistent phenotype, single lab","pmids":["33812060"],"is_preprint":false},{"year":2021,"finding":"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.","method":"RNA-seq, siRNA knockdown of NUAK2, conditional Gpr65 knockout mice, pathway inhibitor experiments, T cell differentiation assays","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis confirmed by rescue experiments in both KO and WT T cells, multiple pathway inhibitors, single lab","pmids":["35343079"],"is_preprint":false},{"year":2022,"finding":"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.","method":"siRNA knockdown, kinase-dead mutant, RT-qPCR for GPX4 mRNA, ferroptosis inducers, cell death assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-dead mutant establishes mechanism is kinase-independent, mRNA-level regulation demonstrated, single lab","pmids":["35523770"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown of NUAK2 and CYFIP2, rescue experiments, functional assays (proliferation, migration, invasion, EMT markers)","journal":"Molecular medicine reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP plus epistasis by knockdown, single lab, no structural or orthogonal validation of direct binding","pmids":["34558636"],"is_preprint":false},{"year":2023,"finding":"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.","method":"siRNA knockdown, kinase inhibitors, virus entry assays, receptor surface quantification, IRE1α inhibitors, confocal/electron microscopy","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (siRNA, kinase inhibition, IRE1α inhibition), multiple coronaviruses, mechanistic readouts (receptor surface levels, actin cytoskeleton), replicated across infection models","pmids":["37421942"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Chromatin immunoprecipitation (NF-κB promoter binding), siRNA knockdown, Western blot for SMAD2/3 and FAK pathway, nuclear fractionation for SMAD4","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for direct promoter binding plus downstream pathway analysis, single lab, multiple readouts","pmids":["38510132"],"is_preprint":false},{"year":2024,"finding":"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.","method":"CRISPR-Cas9 knockout, overexpression, proliferation and migration assays in vitro, in vivo xenograft, pharmacological inhibition, integrated downstream pathway analysis","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO plus overexpression plus pharmacological inhibition with consistent phenotype, single lab","pmids":["40770117"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Phosphoproteomics, interactome (co-IP/MS), splicing analysis (RT-PCR/RNA-seq), Western blot for protein levels, pharmacological inhibition and genetic knockdown","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics plus interactome plus functional splicing validation, but preprint, single lab","pmids":["41292858"],"is_preprint":true},{"year":2026,"finding":"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.","method":"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","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for epigenetic activation of NUAK2 locus plus genetic rescue epistasis, single lab, multiple orthogonal methods","pmids":["41784683"],"is_preprint":false}],"current_model":"NUAK2 (SNARK) is an LKB1-activated AMPK-related serine/threonine kinase that senses metabolic and mechanical stress: it phosphorylates MYPT1 at novel sites to inhibit MLC phosphatase and thereby promotes actomyosin contractility, actin stress fiber formation, and apical constriction during neural tube closure; it also associates with MRIP in a kinase-independent manner to further counteract MYPT1-mediated MLC dephosphorylation. Downstream of YAP (and transcriptionally upregulated by both YAP and NF-κB), NUAK2 feeds back to amplify YAP activity through actin polymerization and myosin activation. In skeletal muscle and heart, NUAK2 is required for contraction- and ischemia-stimulated glucose transport independently of insulin. In muscle, NUAK2 promotes cell survival under metabolic stress via Rho kinase signaling. NUAK2 additionally suppresses GPX4 expression (kinase-independently) to sensitize cells to ferroptosis, engages spliceosome components to regulate pre-mRNA splicing, and facilitates SARS-CoV-2 entry by maintaining ACE2 surface levels through actin cytoskeleton regulation downstream of IRE1α-XBP1."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2001,"claim":"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","pmids":["11284715"],"confidence":"High","gaps":["No physiological substrate identified beyond the synthetic SAMS peptide","Upstream activating kinase not yet defined"]},{"year":2003,"claim":"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","pmids":["14575707"],"confidence":"Medium","gaps":["Direct cytoskeletal substrate not identified","Phenotype from overexpression rather than physiological loss-of-function"]},{"year":2005,"claim":"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","pmids":["15893879"],"confidence":"Medium","gaps":["Molecular basis of differential cell-type regulation unknown","Whether metformin acts directly on NUAK2 or via upstream signaling unresolved"]},{"year":2007,"claim":"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","pmids":["18023418"],"confidence":"High","gaps":["Exact MYPT1 residues not defined","Functional consequence of these phosphosites on phosphatase activity not directly tested in this study"]},{"year":2010,"claim":"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","pmids":["20713714"],"confidence":"High","gaps":["Substrates linking NUAK2 to glucose uptake machinery unknown","Heterozygous knockout leaves residual function unaddressed"]},{"year":2011,"claim":"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","pmids":["21242312"],"confidence":"High","gaps":["Structural basis of NUAK2-MRIP interaction unknown","How a kinase-dead protein inhibits the phosphatase mechanistically unresolved"]},{"year":2011,"claim":"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","pmids":["21460252"],"confidence":"Medium","gaps":["Mechanism linking NUAK2 to mTOR downregulation unknown","Direct targets in senescence pathway not identified"]},{"year":2012,"claim":"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","pmids":["22689267"],"confidence":"High","gaps":["Relative contributions of NUAK1 vs NUAK2 not separated","Direct substrate in neuroepithelium not defined"]},{"year":2013,"claim":"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","pmids":["23831117","27602492"],"confidence":"Medium","gaps":["Direct substrate in TGF-β pathway not identified","Disulfiram selectivity over related kinases not established"]},{"year":2015,"claim":"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","pmids":["25832654"],"confidence":"Medium","gaps":["Molecular link from NUAK2 to CDK2 expression unknown","Restricted to PTEN-deficient/NUAK2-amplified context"]},{"year":2016,"claim":"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","pmids":["26690705"],"confidence":"High","gaps":["Mechanism by which NUAK2 sustains ROCK signaling unknown","Direct substrate mediating survival not identified"]},{"year":2016,"claim":"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","pmids":["27081712"],"confidence":"Medium","gaps":["Downstream effectors of NUAK2 in stemness not identified","Single-lab functional rescue"]},{"year":2018,"claim":"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","pmids":["30446657"],"confidence":"High","gaps":["Precise cytoskeletal substrate feeding back to YAP not defined","Whether feedback requires kinase activity not fully resolved here"]},{"year":2018,"claim":"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","pmids":["30256437"],"confidence":"Medium","gaps":["Kinase phosphorylating Thr208 not directly confirmed","Downstream glucose transport effectors unknown"]},{"year":2020,"claim":"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","pmids":["32845958"],"confidence":"High","gaps":["How loss of kinase activity retains YAP in cytoplasm mechanistically unresolved","Genotype-phenotype spectrum across patients not established"]},{"year":2021,"claim":"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","pmids":["33812060"],"confidence":"Medium","gaps":["Mechanism by which NUAK2 controls miR-696 transcription unknown","Single-lab finding"]},{"year":2022,"claim":"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","pmids":["35343079"],"confidence":"Medium","gaps":["Direct NUAK2 substrate in T cell differentiation unknown","Whether effect requires kinase activity untested"]},{"year":2022,"claim":"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","pmids":["35523770"],"confidence":"Medium","gaps":["Mechanism of GPX4 mRNA suppression unknown","How a kinase-dead protein represses GPX4 unresolved"]},{"year":2022,"claim":"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","pmids":["34558636"],"confidence":"Low","gaps":["Single Co-IP without reciprocal or structural validation of direct binding","Whether interaction is kinase-dependent untested"]},{"year":2023,"claim":"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","pmids":["37421942"],"confidence":"High","gaps":["Direct cytoskeletal substrate controlling receptor surface levels not identified","Relative roles of kinase-dependent and -independent activity not fully separated"]},{"year":2024,"claim":"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","pmids":["38510132"],"confidence":"Medium","gaps":["Mechanism linking NUAK2 to SMAD2/3 levels unknown","Direct substrate not identified"]},{"year":2024,"claim":"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","pmids":["40770117"],"confidence":"Medium","gaps":["Specific ECM components modulated not defined mechanistically","Direct substrate driving migration unknown"]},{"year":2025,"claim":"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)","pmids":["41292858"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Which spliceosome components are direct NUAK2 phosphorylation substrates unresolved"]},{"year":2026,"claim":"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","pmids":["41784683"],"confidence":"Medium","gaps":["NUAK2 effectors driving myofibroblast activation not defined","Single-lab finding"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,14]},{"term_id":"GO:0016740","term_label":"transferase 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Induces cell-cell detachment by increasing F-actin conversion to G-actin. Expression is induced by CD95 or TNF, via NF-kappa-B. Protects cells from CD95-mediated apoptosis and is required for the increased motility and invasiveness of CD95-activated tumor cells. Phosphorylates LATS1 and LATS2. Plays a key role in neural tube closure during embryonic development through LATS2 phosphorylation and regulation of the nuclear localization of YAP1 a critical downstream regulatory target in the Hippo signaling pathway (PubMed:32845958)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9H093/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NUAK2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NUAK2","total_profiled":1310},"omim":[{"mim_id":"619452","title":"ANENCEPHALY 2; ANPH2","url":"https://www.omim.org/entry/619452"},{"mim_id":"608131","title":"NUAK FAMILY, SNF1-LIKE KINASE, 2; NUAK2","url":"https://www.omim.org/entry/608131"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"cervix","ntpm":37.5},{"tissue":"esophagus","ntpm":55.1},{"tissue":"vagina","ntpm":42.5}],"url":"https://www.proteinatlas.org/search/NUAK2"},"hgnc":{"alias_symbol":["SNARK","FLJ90349"],"prev_symbol":[]},"alphafold":{"accession":"Q9H093","domains":[{"cath_id":"3.30.200.20","chopping":"42-130","consensus_level":"high","plddt":90.0574,"start":42,"end":130},{"cath_id":"1.10.510.10","chopping":"136-314","consensus_level":"high","plddt":93.696,"start":136,"end":314}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H093","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H093-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H093-F1-predicted_aligned_error_v6.png","plddt_mean":62.28},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NUAK2","jax_strain_url":"https://www.jax.org/strain/search?query=NUAK2"},"sequence":{"accession":"Q9H093","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H093.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H093/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H093"}},"corpus_meta":[{"pmid":"30446657","id":"PMC_30446657","title":"NUAK2 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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.\",\n      \"method\": \"In vitro kinase assay (autophosphorylation, SAMS peptide phosphorylation), Western blot, cell-based activity assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase reconstitution with substrate peptide and mutagenesis-level characterization, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"11284715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, overexpression with deletion mutants, Western blot, morphological analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic domain deletion analysis plus cellular phenotype, single lab, multiple methods\",\n      \"pmids\": [\"14575707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Immunoprecipitation kinase assay in multiple cell lines, pharmacological treatment (metformin)\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunoprecipitation kinase assay across multiple cell lines and stress conditions, single lab\",\n      \"pmids\": [\"15893879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, HPLC-based substrate screening, mutagenesis of known phosphorylation sites\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with novel substrate identification protocol (HPLC), direct biochemical demonstration, single lab\",\n      \"pmids\": [\"18023418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Dominant-negative transgenic mouse, heterozygous knockout mouse, glucose transport assay, in vivo electroporation, siRNA knockdown in C2C12 cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models (dominant-negative, knockout, siRNA) with consistent phenotype, epistasis established via LKB1 KO, replicated across in vivo and in vitro systems\",\n      \"pmids\": [\"20713714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, kinase-dead mutant overexpression, siRNA knockdown, immunofluorescence, Western blot\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, kinase-dead mutant analysis, siRNA epistasis with MRIP and MYPT1, multiple orthogonal methods in single study\",\n      \"pmids\": [\"21242312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, cell cycle analysis, migration assay, xenograft mouse model, Western blot\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple cellular readouts and in vivo validation, single lab\",\n      \"pmids\": [\"21460252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Double-mutant mouse genetics, immunofluorescence for pMLC2, F-actin, cortactin, tubulin\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via double knockout with multiple molecular readouts, in vivo model\",\n      \"pmids\": [\"22689267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, site-directed mutagenesis of phosphorylation and kinase-dead mutants, luciferase reporter assay, HCV replicon system; in vitro luminescence kinase assay (disulfiram study)\",\n      \"journal\": \"Journal of hepatology; Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis combined with reporter assay and complementation, single lab; kinase assay for inhibitor confirmed independently\",\n      \"pmids\": [\"23831117\", \"27602492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, pharmacological inhibition, in vitro growth assay, in vivo xenograft, immunohistochemistry\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via combined knockdown/inhibitor experiments, in vitro and in vivo, single lab\",\n      \"pmids\": [\"25832654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, dominant-negative transgenic mice, apoptosis assays, Western blot for Rho kinase pathway components\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models (siRNA, transgenic dominant-negative), consistent phenotype in vitro and in vivo, pathway placement via Rho kinase\",\n      \"pmids\": [\"26690705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"3'-UTR luciferase reporter assay, Western blot, siRNA/shRNA knockdown, overexpression, proliferation/migration/invasion assays\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — luciferase reporter plus functional rescue experiments, single lab\",\n      \"pmids\": [\"27081712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq for direct transcriptional target, in vivo mouse models, multiple cellular mechanism assays, replicated across multiple cancer cell lines\",\n      \"pmids\": [\"30446657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Phospho-specific Western blot (Thr208), siRNA knockdown, SNARK+/- heterozygous knockout mice, glucose transport assay in HL1 cardiomyocytes\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation site identified, genetic models (KO mice, siRNA), consistent glucose transport phenotype, single lab\",\n      \"pmids\": [\"30256437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay demonstrating loss of catalytic activity, patient-derived disease models, multiple orthogonal mechanistic readouts (YAP localization, cytoskeletal assays, nucleokinesis)\",\n      \"pmids\": [\"32845958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression and siRNA knockdown in C2C12, muscle-specific transgenic mice, miR-696 expression assay, mitochondrial respiration measurement, in silico 3'UTR analysis\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function in vitro and in vivo, consistent phenotype, single lab\",\n      \"pmids\": [\"33812060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"RNA-seq, siRNA knockdown of NUAK2, conditional Gpr65 knockout mice, pathway inhibitor experiments, T cell differentiation assays\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis confirmed by rescue experiments in both KO and WT T cells, multiple pathway inhibitors, single lab\",\n      \"pmids\": [\"35343079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, kinase-dead mutant, RT-qPCR for GPX4 mRNA, ferroptosis inducers, cell death assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead mutant establishes mechanism is kinase-independent, mRNA-level regulation demonstrated, single lab\",\n      \"pmids\": [\"35523770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of NUAK2 and CYFIP2, rescue experiments, functional assays (proliferation, migration, invasion, EMT markers)\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP plus epistasis by knockdown, single lab, no structural or orthogonal validation of direct binding\",\n      \"pmids\": [\"34558636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, kinase inhibitors, virus entry assays, receptor surface quantification, IRE1α inhibitors, confocal/electron microscopy\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (siRNA, kinase inhibition, IRE1α inhibition), multiple coronaviruses, mechanistic readouts (receptor surface levels, actin cytoskeleton), replicated across infection models\",\n      \"pmids\": [\"37421942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Chromatin immunoprecipitation (NF-κB promoter binding), siRNA knockdown, Western blot for SMAD2/3 and FAK pathway, nuclear fractionation for SMAD4\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for direct promoter binding plus downstream pathway analysis, single lab, multiple readouts\",\n      \"pmids\": [\"38510132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR-Cas9 knockout, overexpression, proliferation and migration assays in vitro, in vivo xenograft, pharmacological inhibition, integrated downstream pathway analysis\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO plus overexpression plus pharmacological inhibition with consistent phenotype, single lab\",\n      \"pmids\": [\"40770117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Phosphoproteomics, interactome (co-IP/MS), splicing analysis (RT-PCR/RNA-seq), Western blot for protein levels, pharmacological inhibition and genetic knockdown\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics plus interactome plus functional splicing validation, but preprint, single lab\",\n      \"pmids\": [\"41292858\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for epigenetic activation of NUAK2 locus plus genetic rescue epistasis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41784683\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUAK2 (SNARK) is an LKB1-activated AMPK-related serine/threonine kinase that senses metabolic and mechanical stress: it phosphorylates MYPT1 at novel sites to inhibit MLC phosphatase and thereby promotes actomyosin contractility, actin stress fiber formation, and apical constriction during neural tube closure; it also associates with MRIP in a kinase-independent manner to further counteract MYPT1-mediated MLC dephosphorylation. Downstream of YAP (and transcriptionally upregulated by both YAP and NF-κB), NUAK2 feeds back to amplify YAP activity through actin polymerization and myosin activation. In skeletal muscle and heart, NUAK2 is required for contraction- and ischemia-stimulated glucose transport independently of insulin. In muscle, NUAK2 promotes cell survival under metabolic stress via Rho kinase signaling. NUAK2 additionally suppresses GPX4 expression (kinase-independently) to sensitize cells to ferroptosis, engages spliceosome components to regulate pre-mRNA splicing, and facilitates SARS-CoV-2 entry by maintaining ACE2 surface levels through actin cytoskeleton regulation downstream of IRE1α-XBP1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #4, #7]. 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 [#0, #2]. 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 [#3], and through association with MRIP it is targeted to actin stress fibers to inhibit MYPT1-mediated MLC dephosphorylation in a kinase-independent manner [#5], 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 [#7, #14]. NUAK2 is itself a direct transcriptional target of YAP and feeds back through actin polymerization and myosin activity to amplify YAP signaling [#12]. 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 [#4, #13], and it supports myocyte survival under metabolic stress via Rho kinase signaling [#10]. Beyond contractility, NUAK2 suppresses GPX4 at the RNA level to sensitize cells to ferroptosis, kinase-independently [#17], and maintains cell-surface ACE2 to facilitate coronavirus entry downstream of the IRE1\\u03b1-XBP1 UPR branch through actin cytoskeleton regulation [#19]. NUAK2 is recurrently co-opted in cancer, acting downstream of NF-\\u03baB and YAP and promoting proliferation, migration, and matrix-dependent invasion across melanoma, glioblastoma, and pancreatic tumors [#6, #12, #20, #21].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro kinase assays (autophosphorylation, SAMS peptide) with AMP/AICAriboside and glucose-deprivation modulation\",\n      \"pmids\": [\"11284715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No physiological substrate identified beyond the synthetic SAMS peptide\", \"Upstream activating kinase not yet defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Linked NUAK2 catalytic activity to cytoskeletal/adhesion remodeling, showing its kinase domain drives F-actin disassembly and cell-cell detachment under metabolic stress.\",\n      \"evidence\": \"Overexpression with catalytic-domain deletion mutants in HepG2 cells, morphological and Western analysis\",\n      \"pmids\": [\"14575707\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cytoskeletal substrate not identified\", \"Phenotype from overexpression rather than physiological loss-of-function\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Mapped the breadth of stresses that regulate NUAK2 activity in a cell-type-dependent manner and identified metformin as a negative regulator.\",\n      \"evidence\": \"IP kinase assays across multiple cell lines under diverse stress and pharmacological conditions\",\n      \"pmids\": [\"15893879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of differential cell-type regulation unknown\", \"Whether metformin acts directly on NUAK2 or via upstream signaling unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified MYPT1 as a direct NUAK2 substrate phosphorylated at novel sites, providing the biochemical entry point to NUAK2 control of myosin phosphatase and contractility.\",\n      \"evidence\": \"In vitro kinase assay with HPLC-based de novo substrate screening and site mutagenesis\",\n      \"pmids\": [\"18023418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact MYPT1 residues not defined\", \"Functional consequence of these phosphosites on phosphatase activity not directly tested in this study\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed NUAK2 downstream of LKB1 in vivo and established it as the contraction-specific, insulin-independent regulator of skeletal muscle glucose transport.\",\n      \"evidence\": \"Dominant-negative and heterozygous knockout mice, in vivo electroporation, C2C12 siRNA, glucose transport assays with LKB1 KO epistasis\",\n      \"pmids\": [\"20713714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrates linking NUAK2 to glucose uptake machinery unknown\", \"Heterozygous knockout leaves residual function unaddressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed a kinase-independent mode in which MRIP scaffolds NUAK2 onto stress fibers to inhibit MYPT1-mediated MLC dephosphorylation, expanding NUAK2 function beyond catalysis.\",\n      \"evidence\": \"Reciprocal Co-IP, kinase-dead mutant, siRNA epistasis with MRIP and MYPT1, immunofluorescence\",\n      \"pmids\": [\"21242312\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of NUAK2-MRIP interaction unknown\", \"How a kinase-dead protein inhibits the phosphatase mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Implicated NUAK2 in tumor cell proliferation and survival, showing its loss induces senescence and suppresses melanoma growth.\",\n      \"evidence\": \"siRNA knockdown, cell cycle and migration assays, xenograft model\",\n      \"pmids\": [\"21460252\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking NUAK2 to mTOR downregulation unknown\", \"Direct targets in senescence pathway not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated in vivo that NUAK1 and NUAK2 cooperatively drive apical actomyosin organization required for neural tube closure.\",\n      \"evidence\": \"Double-knockout mouse genetics with immunofluorescence for pMLC2, F-actin, cortactin, tubulin\",\n      \"pmids\": [\"22689267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of NUAK1 vs NUAK2 not separated\", \"Direct substrate in neuroepithelium not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed NUAK2 promotes TGF-\\u03b2 signaling in a phosphorylation- and kinase-dependent manner and identified disulfiram as a noncompetitive inhibitor.\",\n      \"evidence\": \"siRNA, phospho/kinase-dead mutant complementation, luciferase reporters, HCV replicon; in vitro kinase assay for inhibitor\",\n      \"pmids\": [\"23831117\", \"27602492\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate in TGF-\\u03b2 pathway not identified\", \"Disulfiram selectivity over related kinases not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Positioned NUAK2 upstream of CDK2 in PTEN-deficient melanoma, defining a context-specific oncogenic dependency.\",\n      \"evidence\": \"Combined siRNA and pharmacological inhibition, growth assays, xenografts, IHC\",\n      \"pmids\": [\"25832654\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link from NUAK2 to CDK2 expression unknown\", \"Restricted to PTEN-deficient/NUAK2-amplified context\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established NUAK2 as a survival factor for myocytes under metabolic stress acting upstream of ROCK signaling.\",\n      \"evidence\": \"siRNA, dominant-negative transgenic mice, apoptosis assays, Western blot for Rho kinase components\",\n      \"pmids\": [\"26690705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which NUAK2 sustains ROCK signaling unknown\", \"Direct substrate mediating survival not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined miR-143 as a direct post-transcriptional repressor of NUAK2 controlling glioblastoma cell behavior and stemness.\",\n      \"evidence\": \"3'-UTR luciferase reporter, knockdown/overexpression, proliferation/migration/invasion assays\",\n      \"pmids\": [\"27081712\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors of NUAK2 in stemness not identified\", \"Single-lab functional rescue\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified NUAK2 as a direct YAP transcriptional target forming a positive feedback loop that amplifies YAP activity via actin and myosin.\",\n      \"evidence\": \"YAP ChIP-seq at NUAK2 locus, knockdown/overexpression, in vivo liver YAP models, actin/myosin assays, pharmacological inhibition\",\n      \"pmids\": [\"30446657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise cytoskeletal substrate feeding back to YAP not defined\", \"Whether feedback requires kinase activity not fully resolved here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended the contraction-glucose role to heart, mapping Thr208 as an exercise/ischemia-responsive phosphosite required for insulin-independent cardiac glucose transport.\",\n      \"evidence\": \"Phospho-specific Western (Thr208), siRNA, heterozygous knockout mice, glucose transport in HL1 cardiomyocytes\",\n      \"pmids\": [\"30256437\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase phosphorylating Thr208 not directly confirmed\", \"Downstream glucose transport effectors unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided human disease genetics linking catalytically dead NUAK2 mutations to defective Hippo/YAP signaling and impaired apical constriction in neural development.\",\n      \"evidence\": \"In vitro kinase assay of patient mutant, patient iPSC-derived neural progenitors and cerebral organoids, YAP localization and cytoskeletal imaging\",\n      \"pmids\": [\"32845958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How loss of kinase activity retains YAP in cytoplasm mechanistically unresolved\", \"Genotype-phenotype spectrum across patients not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected NUAK2 to mitochondrial regulation through a miR-696\\u2013Pgc1\\u03b1 axis in muscle.\",\n      \"evidence\": \"Gain/loss-of-function in C2C12, muscle-specific transgenic mice, miR-696 and respiration measurements\",\n      \"pmids\": [\"33812060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which NUAK2 controls miR-696 transcription unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed NUAK2 downstream of GPR65-cAMP-PKA-LKB1 signaling as a restraint on Th1/Th17 differentiation in T cells.\",\n      \"evidence\": \"RNA-seq, NUAK2 siLencing rescue in Gpr65 KO and WT T cells, pathway inhibitors, differentiation assays\",\n      \"pmids\": [\"35343079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NUAK2 substrate in T cell differentiation unknown\", \"Whether effect requires kinase activity untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a kinase-independent role for NUAK2 in suppressing GPX4 at the RNA level to sensitize cells to ferroptosis.\",\n      \"evidence\": \"siRNA, kinase-dead mutant, GPX4 RT-qPCR, ferroptosis inducers and cell death assays\",\n      \"pmids\": [\"35523770\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of GPX4 mRNA suppression unknown\", \"How a kinase-dead protein represses GPX4 unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reported NUAK2 binding to CYFIP2 and acting upstream of it to drive cervical cancer cell phenotypes.\",\n      \"evidence\": \"Single Co-IP, NUAK2 and CYFIP2 knockdown, rescue and functional assays\",\n      \"pmids\": [\"34558636\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal or structural validation of direct binding\", \"Whether interaction is kinase-dependent untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined NUAK2 as a host entry factor for multiple coronaviruses, induced by IRE1\\u03b1-XBP1 and required to maintain surface ACE2 via actin regulation.\",\n      \"evidence\": \"siRNA, kinase inhibitors, IRE1\\u03b1 inhibitors, virus entry and receptor surface assays, confocal/EM across multiple coronaviruses\",\n      \"pmids\": [\"37421942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct cytoskeletal substrate controlling receptor surface levels not identified\", \"Relative roles of kinase-dependent and -independent activity not fully separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed NUAK2 downstream of NF-\\u03baB and upstream of SMAD2/3 and FAK signaling in pancreatic cancer.\",\n      \"evidence\": \"NF-\\u03baB promoter ChIP, siRNA, Western blot for SMAD/FAK, nuclear fractionation for SMAD4\",\n      \"pmids\": [\"38510132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking NUAK2 to SMAD2/3 levels unknown\", \"Direct substrate not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed NUAK2 promotes glioblastoma proliferation and ECM-dependent migration, validated by CRISPR deletion and pharmacological inhibition.\",\n      \"evidence\": \"CRISPR-Cas9 knockout, overexpression, proliferation/migration assays, xenografts, pharmacological inhibition\",\n      \"pmids\": [\"40770117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific ECM components modulated not defined mechanistically\", \"Direct substrate driving migration unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated NUAK2 in pre-mRNA splicing through engagement of core spliceosome components, affecting EZH2 and TTK splicing in neuroendocrine prostate cancer.\",\n      \"evidence\": \"Phosphoproteomics, interactome co-IP/MS, splicing analysis, inhibition and knockdown (preprint)\",\n      \"pmids\": [\"41292858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Which spliceosome components are direct NUAK2 phosphorylation substrates unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected metabolic-epigenetic signaling to NUAK2 induction, showing lactate-driven H4K12 lactylation at a NUAK2 super-enhancer promotes myofibroblast activation and fibrosis.\",\n      \"evidence\": \"PDHA1 acetyl-mimic mutants, H4K12la ChIP at NUAK2 locus, NUAK2 inhibition, myofibroblast and in vivo fibrosis rescue\",\n      \"pmids\": [\"41784683\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NUAK2 effectors driving myofibroblast activation not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 14]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [5, 7, 12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 14, 16, 20]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 13]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 2, 19]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10, 17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MYPT1\", \"MRIP\", \"YAP\", \"CYFIP2\", \"LKB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}