{"gene":"NUAK1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2013,"finding":"LKB1 activates NUAK1, and the LKB1-NUAK1 kinase pathway regulates cortical axon branching by promoting mitochondria immobilization at nascent presynaptic sites; conditional deletion or knockdown of either kinase drastically reduced axon branching in vivo, while overexpression increased it.","method":"Conditional knockout, in vivo knockdown/overexpression, live imaging of mitochondrial transport, genetic epistasis with Syntaphilin","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vivo genetic approaches (conditional KO, KD, OE) with defined cellular phenotype, replicated with Syntaphilin epistasis experiment","pmids":["23791179"],"is_preprint":false},{"year":2024,"finding":"NUAK1 deficiency impairs mitochondrial metabolism and axonal ATP concentration; upregulation of mitochondrial function rescues axonal branching in NUAK1-null neurons. NUAK1 regulates axon branching through the mitochondria-targeted microprotein BRAWNIN, exerting a dual function by controlling both mitochondrial distribution and metabolic activity.","method":"In vitro and in vivo neuronal cultures with NUAK1 knockout, mitochondrial function assays, ATP measurements, rescue experiments with mitochondrial activators, identification of BRAWNIN as downstream effector","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (metabolic assays, in vivo/in vitro KO, rescue experiments), identifies specific downstream effector BRAWNIN","pmids":["38514619"],"is_preprint":false},{"year":2016,"finding":"NUAK1 stabilizes tau by direct phosphorylation specifically at Ser356; inhibition of NUAK1 reduces steady-state tau levels and suppresses neurodegeneration in tau-expressing Drosophila, and NUAK1 haploinsufficiency rescues tauopathy phenotypes in mice.","method":"Parallel cell-based and Drosophila genetic screens, in vitro/in vivo phosphorylation assays, genetic loss-of-function in mouse tauopathy model","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct phosphorylation demonstrated, replicated across Drosophila and mouse models with specific Ser356 site identified","pmids":["27720485"],"is_preprint":false},{"year":2003,"finding":"ARK5 (NUAK1) suppresses cell death by glucose starvation and death receptor stimulation (TRAIL, TNF-α) by inhibiting caspase 8 activation; ARK5 overexpression delayed Bid cleavage, FLIP degradation, and caspase 8 activation. This protective effect was not observed for UV irradiation, camptothecin, or doxorubicin.","method":"ARK5 overexpression in HepG2 cells, Western blotting for Bid cleavage/FLIP degradation/caspase 8 activation, cell death assays under multiple stimuli","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, two orthogonal methods (cell death assays + western blot), mechanistically specific pathway placement","pmids":["13679856"],"is_preprint":false},{"year":2004,"finding":"ARK5 (NUAK1) phosphorylates and inhibits procaspase-6 at Ser257, preventing its activation and subsequent FLIP degradation, thereby mediating resistance to FasL/Fas-induced cell death in colorectal cancer cells; in vitro kinase assay showed ARK5 phosphorylates wild-type but not caspase-6/S257A mutant.","method":"ARK5 antisense RNA knockdown, caspase-6 mutagenesis (Ser257Ala), in vitro kinase assay, Western blotting, cell death assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis confirming specific phosphorylation site, single lab","pmids":["15273717"],"is_preprint":false},{"year":2004,"finding":"ARK5 (NUAK1) promotes tumor invasion downstream of Akt signaling; ARK5 expression induces activation of MMP-2, MMP-9, and new expression of MT1-MMP via rapamycin-sensitive signaling, and ARK5-overexpressing tumor cells show invasion and metastasis in nude mice.","method":"Matrigel invasion assay, MMP activity assays, rapamycin treatment, nude mouse tumor model","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro experiments, multiple readouts, single lab","pmids":["15060171"],"is_preprint":false},{"year":2009,"finding":"NUAK1 promotes cellular senescence and aneuploidization by phosphorylating LATS1 at Ser464, destabilizing LATS1; ectopic NUAK1 expression triggers premature senescence with gross aneuploidies, while NUAK1 depletion extends replicative lifespan and increases LATS1 levels.","method":"Loss-of-function screen in diploid fibroblasts, shRNA depletion, ectopic overexpression, Western blotting, LATS1 phosphorylation assay, dominant-negative LATS1","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific phosphorylation site identified, phenotypic rescue with dominant-negative LATS1 as epistasis, single lab","pmids":["19927127"],"is_preprint":false},{"year":2011,"finding":"NUAK1 directly interacts with and phosphorylates p53 in vitro and in vivo; this requires NUAK1 kinase activity and phosphorylation at Thr211 by LKB1. LKB1/NUAK1 activation leads to G1/S cell cycle arrest by inducing p21/WAF1 expression; NUAK1 binds p53-responsive elements of the p21/WAF1 promoter in the nucleus.","method":"Co-immunoprecipitation, in vitro kinase assay, ChIP on p21/WAF1 promoter, cell cycle analysis, kinase-dead mutants","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay plus co-IP plus ChIP, single lab, multiple orthogonal methods","pmids":["21317932"],"is_preprint":false},{"year":2006,"finding":"NDR2 is an upstream kinase of ARK5 (NUAK1) that directly phosphorylates the conserved Thr211 on the active T-loop of ARK5 during IGF-1 signaling, enabling full ARK5 activation; AKT phosphorylates ARK5 at Ser600 in the regulatory domain as a separate activating event.","method":"In vitro kinase assay with NDR2 and ARK5, phosphorylation site mutagenesis (Thr211), co-immunoprecipitation, IGF-1 stimulation experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis identifying specific phosphorylation site (T211), single lab","pmids":["16488889"],"is_preprint":false},{"year":2014,"finding":"NUAK1 expression is controlled by CDK-PLK-SCFβTrCP E3 ubiquitin ligase complex: CDK phosphorylates NUAK1 at Ser445, triggering PLK binding, which phosphorylates NUAK1 at Ser476 and Ser480, inducing βTrCP binding, ubiquitylation and degradation. NUAK1 also activates PLK1 via inhibition of the PP1β-MYPT1 phosphatase that dephosphorylates PLK1 Thr210.","method":"Co-immunoprecipitation, phosphorylation site mutagenesis (Ser445, Ser476, Ser480), ubiquitylation assays, NUAK1 inhibitors (WZ4003, HTH-01-015), cell cycle synchronization, rescue with phospho-mutant NUAK1","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including mutagenesis, Co-IP, ubiquitylation assays and inhibitor pharmacology, single lab with comprehensive mechanistic dissection","pmids":["24785407"],"is_preprint":false},{"year":2005,"finding":"ARK5 (NUAK1) is a transcriptional target of the Large-MAF family (c-MAF, MAFB) via MAF-recognition element (MARE) sequences in its promoter; ARK5 mediates IGF-1-induced cell invasion in multiple myeloma downstream of MAF transcription factors.","method":"Gene expression profiling, promoter sequence analysis with MARE identification, luciferase reporter with MARE deletion/mutation, chromatin immunoprecipitation (ChIP), ARK5 overexpression in non-expressing cell lines, invasion assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assays plus mutagenesis, single lab, two orthogonal methods for transcriptional regulation","pmids":["16044163"],"is_preprint":false},{"year":2018,"finding":"NUAK1 is activated by oxidative stress and facilitates nuclear import of the antioxidant master regulator NRF2: activated NUAK1 inhibits PP1β, which cooperates with AKT activation to suppress GSK3β-dependent phosphorylation that normally prevents NRF2 nuclear import; deletion of NUAK1 suppresses colorectal tumor formation and induces regression of preexisting autochthonous tumors.","method":"Genetic NUAK1 deletion in autochthonous mouse colorectal cancer model, PP1β inhibition assays, GSK3β phosphorylation analysis, NRF2 nuclear fractionation, pharmacological NUAK1 inhibition","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods in vivo and in vitro, specific pathway dissection (PP1β/AKT/GSK3β/NRF2), autochthonous tumor models","pmids":["29500295"],"is_preprint":false},{"year":2022,"finding":"NUAK1 is a TGF-β-inducible profibrotic kinase; TGF-β rapidly induces NUAK1 in fibroblasts, which in turn promotes profibrotic YAP and TGF-β/SMAD signaling; activated YAP/TAZ further induces NUAK1 expression, creating a positive feedback loop. Fibroblast-specific NUAK1 loss or pharmacologic NUAK1 inhibition attenuates fibrosis in kidney, lung, and liver mouse models.","method":"Fibroblast-specific conditional NUAK1 knockout mice, pharmacological NUAK1 inhibition, multiple organ fibrosis mouse models, YAP/SMAD signaling assays","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO in multiple in vivo fibrosis models, pharmacological validation, mechanistic pathway dissection with positive feedback loop","pmids":["35320001"],"is_preprint":false},{"year":2020,"finding":"NUAK1 is a predominantly nuclear protein that associates with nuclear PP1 interactors including PNUTS (a nuclear regulatory subunit of PP1) and phosphorylates PNUTS; both NUAK1 and PNUTS associate with the splicing machinery. NUAK1 inhibition abolishes chromatin association of PNUTS, reduces spliceosome activity, suppresses nascent RNA synthesis, and in MYC-transformed cells traps non-productive RNAPII at the pause site and first exon-intron boundary.","method":"Nuclear fractionation, Co-IP/proximity proteomics, in vitro phosphorylation of PNUTS, spliceosome activity assays, nascent RNA synthesis measurement, RNAPII ChIP-seq, NUAK1 inhibitors","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including Co-IP, phosphorylation assays, spliceosome activity and genome-wide RNAPII mapping, single lab with comprehensive mechanism","pmids":["32006464"],"is_preprint":false},{"year":2017,"finding":"In tumor cells lacking LKB1, NUAK1 activity is maintained by an alternative pathway: calcium-dependent activation of PKCα phosphorylates and activates NUAK1, supporting AMPK-TORC1 metabolic checkpoint engagement and protecting MYC-overexpressing tumor cells from cell death.","method":"Pharmacological calcium manipulation, PKCα inhibition/knockdown, NUAK1 activity assays, AMPK-TORC1 signaling readouts, MYC-dependent cell viability assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific pathway dissection with pharmacological and genetic approaches, single lab","pmids":["29106388"],"is_preprint":false},{"year":2012,"finding":"NUAK1-deficient muscle shows decreased phosphorylation of IRS1 at Ser1097, leading to enhanced insulin signaling (increased phosphorylation of IRS1 Tyr608, AKT Thr308, TBC1D4 Thr649), suggesting NUAK1 negatively regulates insulin signaling in oxidative muscle through IRS1 Ser1097 phosphorylation.","method":"Muscle-specific NUAK1 knockout mice, quantitative phosphoproteome analysis of soleus muscle, insulin signaling assays, glucose tolerance tests","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — quantitative phosphoproteomics plus in vivo knockout with specific phosphorylation site (IRS1 Ser1097) identified, single lab","pmids":["22418434"],"is_preprint":false},{"year":2012,"finding":"NUAK1 and NUAK2 complementarily function in apical constriction and apico-basal elongation during dorsolateral hinge point formation in cephalic neural plate; NUAK1/NUAK2 double mutants show reduced apical concentration of phosphorylated myosin light chain 2, F-actin, and cortactin, and impaired development of acetylated α-tubulin-positive microtubules.","method":"NUAK1/NUAK2 double mutant mouse analysis, immunostaining for phospho-MLC2, F-actin, cortactin, acetylated α-tubulin","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic double-mutant epistasis with specific cellular phenotype (apical constriction), single lab","pmids":["22689267"],"is_preprint":false},{"year":2019,"finding":"NUAK1 contains a conserved bipartite nuclear localization signal (NLS) at its N-terminal domain and is actively imported into the nucleus by importin-β members KPNB1 (importin-β1), IPO7 (importin-7), and IPO9 (importin-9); oxidative stress induces NUAK1 cytoplasmic accumulation by inhibiting this nuclear transport.","method":"Bioinformatics NLS prediction, subcellular fractionation, NLS deletion mutants, importin knockdown (IPO7, IPO9 siRNA), importazole treatment, mass spectrometry identification of NUAK1-importin interactions, immunofluorescence","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (MS, mutagenesis, knockdown, pharmacological), single lab","pmids":["31090959"],"is_preprint":false},{"year":2020,"finding":"Cytosolic NUAK1 increases ATP levels via increased mitochondrial respiration and maintains glycolytic capacity under mitochondrial inhibition; NUAK1 inhibition leads to 'donut-like' mitochondrial morphology changes indicating NUAK1-dependent mitochondrial morphology regulation. Nuclear NUAK1 appears involved in the metabolic switch to glycolysis.","method":"Subcellular fractionation, mitochondrial respiration assays (Seahorse), ATP measurement, NUAK1 inhibition, mitochondrial morphology imaging","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple metabolic assays plus imaging with compartment-specific NUAK1 variants, single lab","pmids":["32754444"],"is_preprint":false},{"year":2022,"finding":"ARK5 (NUAK1) directly interacts with and phosphorylates hnRNP A1 on serine residues within the F-peptide region; the M9 motif of hnRNP A1 is essential for this interaction and phosphorylation. ARK5-mediated phosphorylation of hnRNP A1 controls its cytoplasmic relocalization during hypertonic stress; ARK5 silencing increases Bcl-xL expression and delays caspase activation.","method":"Immunoprecipitation, in vitro kinase assay, hnRNP A1 domain mutagenesis (M9 motif deletion), subcellular fractionation, siRNA knockdown, caspase activation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus Co-IP plus mutagenesis identifying the interaction domain, single lab","pmids":["35963429"],"is_preprint":false},{"year":2020,"finding":"NUAK1 coordinates growth factor-dependent mTORC2 and Akt activation by two mechanisms: (1) interacting with mTORC2 components and regulating mTOR lysosome positioning; (2) directly phosphorylating Akt at Ser473. NUAK1 selectively promotes Akt-dependent phosphorylation of FOXO1/3a but not TSC2, and is associated with early endosomes.","method":"Co-immunoprecipitation with mTORC2 components, in vitro Akt phosphorylation assays, lysosome positioning analysis, subcellular fractionation (early endosome), NUAK1 inhibitors, specific substrate phosphorylation analysis","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, in vitro kinase assay, organelle positioning), single lab","pmids":["38135881"],"is_preprint":false},{"year":2023,"finding":"NUAK1 governs centrosome duplication in pancreatic cancer via MYPT1/PP1β and GSK3β-dependent regulation of PLK4; loss of NUAK1 triggers genomic instability through inaccurate centrosome duplication, an effect conserved in primary fibroblasts.","method":"NUAK1 inhibition and depletion in PDAC cells, centrosome counting, genomic instability assays, MYPT1/PP1β and GSK3β-PLK4 pathway analysis","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific molecular pathway placement (MYPT1/PP1β/GSK3β/PLK4), multiple cell systems, single lab","pmids":["36975767"],"is_preprint":false},{"year":2024,"finding":"NUAK1 directly phosphorylates NADK (nicotinamide adenine dinucleotide kinase) at Ser64, which mitigates osimertinib-induced ROS accumulation and confers osimertinib resistance in NSCLC; NUAK1-NADK interaction was confirmed by co-immunoprecipitation and in vitro kinase assay.","method":"Co-immunoprecipitation, in vitro kinase assay, phosphorylation site mutagenesis (NADK Ser64), ROS measurement, genetic/pharmacological NUAK1 blockade, in vivo xenograft","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with specific phosphorylation site, Co-IP, in vivo validation, single lab with multiple orthogonal methods","pmids":["39159134"],"is_preprint":false},{"year":2024,"finding":"NUAK1 activates STAT5-mediated transcription and stabilizes GLI1 protein in gastric cancer, promoting cancer cell expansion and chemotherapy resistance through the NUAK1/STAT5/GLI1 signaling axis.","method":"NUAK1 depletion/inhibition, patient-derived xenograft and transgenic mouse models, STAT5 transcriptional activity assays, GLI1 protein stability assays, co-immunoprecipitation","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vivo models (PDX, transgenic), pathway dissection, single lab","pmids":["38996065"],"is_preprint":false},{"year":2020,"finding":"NUAK1 loss in ovarian cancer spheroids dramatically reduces FN1 gene expression (fibronectin), which is required for spheroid integrity; LKB1 maintains NUAK1 phosphorylation and promotes its stabilization; NUAK1KO spheroids show reduced integrity and increased cell death, rescued by co-incubation with soluble fibronectin.","method":"CRISPR NUAK1 KO in EOC cells, LKB1-NUAK1 phosphorylation assays, transcriptome analysis, fibronectin rescue experiments, xenograft metastasis model","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with transcriptomics, fibronectin rescue, xenograft, single lab","pmids":["32429240"],"is_preprint":false},{"year":2020,"finding":"NUAK1 inhibition increases ROS via downregulation of NRF2-mediated antioxidant gene expression, triggering immunogenic cell death (ICD); XBP1s downstream of ICD-induced ER stress activates the mevalonate/cholesterol pathway as a negative feedback mechanism that dampens ROS and ICD.","method":"Kinome-wide CRISPR-Cas9 screen, NRF2 reporter assays, ROS measurement, ICD markers, HMGCR inhibition with simvastatin, cholesterol supplementation experiments","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus mechanistic validation with multiple pathway components, single lab","pmids":["39824180"],"is_preprint":false},{"year":2023,"finding":"NUAK1 promotes ESCC metastasis by enhancing Slug transcription through activation of the JNK/c-Jun pathway; silencing Slug completely abolishes migration and invasion of NUAK1-overexpressing ESCC cells; NUAK1 and Slug interact as shown by co-immunoprecipitation.","method":"Co-immunoprecipitation, dual-luciferase reporter assay for Slug promoter, JNK/c-Jun inhibition, NUAK1 overexpression/knockdown, in vivo pulmonary metastasis model","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, reporter assay, in vivo rescue/epistasis, single lab","pmids":["37919754"],"is_preprint":false},{"year":2022,"finding":"USP9X deubiquitinates and activates ARK5 (NUAK1), promoting TGF-β1-induced myofibroblast transformation via the Rho kinase pathway; USP9X-ARK5 interaction demonstrated by binding and deubiquitination assays.","method":"Myofibroblast-specific USP9X knockout, pharmacological USP9X inhibition, co-immunoprecipitation, deubiquitination assay, ARK5 activation assays, Rho kinase pathway analysis","journal":"JACC. Basic to translational science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific enzyme-substrate relationship (USP9X-ARK5 deubiquitination) with Co-IP and in vivo KO, single lab","pmids":["40310323"],"is_preprint":false},{"year":2024,"finding":"ARK5 (NUAK1) enhances mitochondrial fission in multiple myeloma; ARK5 knockout leads to enhanced mitochondrial fusion (increased MFN1, MFN2, OPA1), reduced phospho-DRP1 (Ser616), lower ATP levels, higher lactate and ROS, showing ARK5 promotes mitochondrial fission for bioenergetic support.","method":"Biallelic ARK5 knockout in MM cell lines, mitochondrial morphology imaging, Western blotting for fusion/fission proteins, ATP measurement, ROS and lactate assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic KO clones with multiple molecular readouts for mitochondrial dynamics, single lab","pmids":["38282096"],"is_preprint":false},{"year":2022,"finding":"In hepatic stellate cells, ARK5 (NUAK1) prevents degradation of TGF-β type I receptor (TβRI) and Smad4 by inhibiting Smurf2 expression, maintaining continuous TGF-β signaling; in hepatocytes, ARK5 induces EMT and promotes secretion of inflammatory factors that further activate HSCs.","method":"ARK5 inhibition with HTH-01-015, siRNA knockdown in HSC and hepatocyte cell lines, TβRI/Smad4 stability assays, Smurf2 expression analysis, CCl4-induced liver fibrosis mouse model","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic inhibition in multiple cell types plus in vivo model, mechanistic pathway dissection, single lab","pmids":["36361872"],"is_preprint":false},{"year":2024,"finding":"NUAK1 promotes MASH-related liver injury by facilitating Caspase 6 activation and triggering pyroptosis; NUAK1/Caspase 6 axis inhibition accelerates interaction between TAK1 and RIPK1, leading to RIPK1 degradation and reduced inflammation.","method":"NUAK1 inhibition in MASH mouse models, Caspase 6 disruption, TAK1-RIPK1 co-immunoprecipitation, RIPK1 degradation assays","journal":"Hepatology communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro experiments with specific pathway placement (Caspase 6-TAK1-RIPK1), single lab","pmids":["38967580"],"is_preprint":false},{"year":2025,"finding":"NUAK1 promotes PD-L1 transcriptional expression in hepatocellular carcinoma by activating GSK3β Ser9 phosphorylation, leading to β-catenin nuclear accumulation and transcriptional activation of PD-L1; knockdown of β-catenin reverses NUAK1-mediated PD-L1 upregulation.","method":"NUAK1 gain/loss-of-function, Western blotting for p-GSK3β/β-catenin, nuclear fractionation, β-catenin knockdown rescue, immunohistochemistry on patient samples","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple molecular readouts, epistasis with β-catenin knockdown, single lab","pmids":["39901136"],"is_preprint":false},{"year":2020,"finding":"Yeast Tda1, the ortholog of human NUAK1, is a direct kinase for histone H3 threonine 11 (H3pT11) upon low glucose stress; yeast AMPK directly phosphorylates Tda1 to govern its activity, while CK2 regulates Tda1 nuclear localization, thus linking glucose stress to chromatin regulation.","method":"In vitro kinase assay with Tda1 and histone H3, phosphorylation site identification (H3pT11), genetic epistasis in yeast (AMPK and CK2 mutants), nuclear localization analysis","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct in vitro kinase assay identifying histone substrate, yeast ortholog with genetic epistasis, single lab but multiple orthogonal methods","pmids":["33372657"],"is_preprint":false},{"year":2013,"finding":"miR-211 targets NUAK1 directly, reducing NUAK1 expression and promoting melanoma cell adhesion; inhibition of miR-211 increases NUAK1 expression and decreases melanoma adhesion, while upregulation of miR-211 restores adhesion through NUAK1 repression. This defines the MITF/miR-211/NUAK1 axis as an inhibitor of the melanoma invasive program.","method":"miR-211 gain/loss-of-function, luciferase reporter assay for NUAK1 3'UTR targeting, adhesion assays, NUAK1 knockdown","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter validating direct miRNA targeting, functional phenotypic rescue, single lab","pmids":["23934065"],"is_preprint":false},{"year":2024,"finding":"NUAK1 phosphorylates PSD3 (Pleckstrin Homology and Sec7-domain containing protein 3) at Ser476; phospho-deficient PSD3 leads to aberrant ARF6 activation and PI(4,5)P2 accumulation in intracellular vesicles, and in neurons leads to enhanced spine maturation in an ARF6-dependent fashion.","method":"ATP-analog sensitive NUAK1 chemical genetics screen, direct phosphorylation assay of PSD3, phospho-deficient mutant PSD3 (S476A), ARF6 activation assays, PI(4,5)P2 imaging, dendritic spine analysis in neurons","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — chemical genetics with ATP-analog sensitive kinase identifying direct substrate, specific phosphorylation site mutagenesis, preprint not yet peer-reviewed","pmids":["42079242"],"is_preprint":true},{"year":2025,"finding":"NUAK1 regulates alternative splicing in developing cortical neurons through phosphorylation of the splicing co-factor SON, controlling conserved splicing events in genes crucial for neurodevelopment; this NUAK1-SON pathway is required for proper neuronal development.","method":"NUAK1 knockout in cortical neurons, phosphorylation assays for SON, alternative splicing analysis (RNA-seq), SON knockdown phenocopy experiments","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct phosphorylation of SON demonstrated, alternative splicing genome-wide analysis, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.10.10.681550"],"is_preprint":true},{"year":2024,"finding":"NUAK1 is present in human erythrocytes, undergoes increased phosphorylation in P. falciparum-infected cells, and is required for parasite invasion; pharmacological NUAK1 inhibition reduces MYPT1 phosphorylation in erythroid cells and inhibits parasite growth; NUAK1 overexpression partially rescues invasion phenotypes caused by inhibitors.","method":"NUAK1 inhibitors (HTH-01-015, WZ4003) with chemoproteomic selectivity profiling, MYPT1 phosphorylation assays, NUAK1 overexpression rescue, parasite invasion assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemoproteomic selectivity profiling, substrate (MYPT1) phosphorylation readout, genetic rescue experiment, preprint","pmids":["41278793"],"is_preprint":true},{"year":2024,"finding":"NUAK1 crystal structure obtained using a chimeric protein; structure-guided drug design exploiting the unique Glu139 residue of NUAK1 enabled development of highly selective inhibitors with subnanomolar potency.","method":"X-ray crystallography of NUAK1 chimeric protein, structure-activity relationship, co-crystal structures of inhibitor-NUAK1 complexes","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — first crystal structure of NUAK1 with functional validation of Glu139 as selectivity determinant, single lab, primarily medicinal chemistry focus","pmids":["39588908"],"is_preprint":false}],"current_model":"NUAK1 is an AMPK-related serine/threonine kinase activated by LKB1 (via T-loop phosphorylation at Thr211) and alternatively by calcium/PKCα, that phosphorylates multiple substrates including PP1β-MYPT1 (inhibiting the phosphatase to regulate PLK1, myosin light chain, and NRF2 nuclear import), tau at Ser356 (stabilizing it), caspase-6 at Ser257 (inhibiting its activation), LATS1 at Ser464 (destabilizing it to promote senescence), p53, IRS1 at Ser1097 (suppressing insulin signaling), NADK at Ser64 (mitigating ROS), hnRNP A1 (controlling its localization), PNUTS (regulating spliceosome-RNAPII coupling), Akt at Ser473, PSD3 at Ser476 (regulating ARF6 and dendritic spine maturation), and SON (regulating alternative splicing in neurons); its own stability is controlled by CDK→PLK1→SCFβTrCP-mediated ubiquitylation and by USP9X-mediated deubiquitylation, and it shuttles between nucleus (via importin-β/IPO7/IPO9-dependent NLS) and cytoplasm in response to oxidative stress."},"narrative":{"mechanistic_narrative":"NUAK1 (ARK5) is an AMPK-related serine/threonine kinase that couples upstream growth-factor and energy-stress signaling to control of cell survival, metabolism, the cytoskeleton, mitochondrial behavior, and gene expression, with prominent roles in both neuronal development and tumor biology [PMID:23791179, PMID:29500295]. It is activated by T-loop phosphorylation at Thr211 by LKB1 and by NDR2 during IGF-1 signaling, with AKT phosphorylating a separate regulatory-domain site (Ser600); in LKB1-null tumor cells a calcium/PKCα route maintains NUAK1 activity to engage the AMPK-TORC1 metabolic checkpoint [PMID:21317932, PMID:16488889, PMID:29106388]. A recurring effector mechanism is NUAK1 inhibition of the PP1β-MYPT1 phosphatase, which it exploits to activate PLK1 and PLK4 in centrosome duplication and to promote GSK3β-dependent nuclear import of the antioxidant regulator NRF2, linking the kinase to genomic stability and redox control [PMID:24785407, PMID:29500295, PMID:36975767]. Through direct substrate phosphorylation NUAK1 acts on diverse targets: tau at Ser356 to stabilize it and drive tauopathy [PMID:27720485], caspase-6 at Ser257 to block apoptosis [PMID:15273717], LATS1 at Ser464 to promote senescence [PMID:19927127], IRS1 at Ser1097 to suppress insulin signaling in muscle [PMID:22418434], NADK at Ser64 to mitigate ROS [PMID:39159134], and the RNA-processing factors PNUTS and hnRNP A1 to control splicing and stress-dependent relocalization [PMID:32006464, PMID:35963429]. In neurons the LKB1-NUAK1 pathway controls cortical axon branching by immobilizing mitochondria at presynaptic sites and by regulating mitochondrial metabolism via the microprotein BRAWNIN [PMID:23791179, PMID:38514619]. In cancer NUAK1 promotes invasion, fibronectin-dependent spheroid integrity, and chemoresistance, and is a TGF-β-inducible profibrotic kinase that sustains YAP and TGF-β/SMAD signaling in a positive feedback loop driving organ fibrosis [PMID:15060171, PMID:35320001, PMID:32429240]. NUAK1 itself is regulated by a CDK→PLK→SCFβTrCP degradation cascade and by USP9X-mediated deubiquitylation, and shuttles between nucleus and cytoplasm via importin-β/IPO7/IPO9-dependent nuclear import that is blocked by oxidative stress [PMID:24785407, PMID:31090959, PMID:40310323].","teleology":[{"year":2003,"claim":"Established NUAK1/ARK5 as an anti-apoptotic kinase, defining its first cellular role in protecting cells from death-receptor and metabolic stress.","evidence":"ARK5 overexpression in HepG2 cells with Bid/FLIP/caspase-8 immunoblotting and cell death assays under multiple stimuli","pmids":["13679856"],"confidence":"Medium","gaps":["Direct substrate in the caspase-8 axis not identified here","Overexpression-only; loss-of-function not tested"]},{"year":2004,"claim":"Identified the first direct NUAK1 substrate mediating apoptosis resistance, showing it phosphorylates procaspase-6 at Ser257 to block its activation.","evidence":"Antisense knockdown, caspase-6 S257A mutagenesis and in vitro kinase assay in colorectal cancer cells","pmids":["15273717"],"confidence":"High","gaps":["In vivo relevance of the phospho-site not established","Did not address kinase activation requirements"]},{"year":2004,"claim":"Placed NUAK1 downstream of Akt as a driver of tumor invasion via MMP induction, linking the kinase to metastatic phenotypes.","evidence":"Matrigel invasion, MMP activity assays, rapamycin treatment and nude mouse tumor model","pmids":["15060171"],"confidence":"Medium","gaps":["Direct kinase substrate driving MMP expression unknown","Single lab, overexpression-based"]},{"year":2005,"claim":"Defined transcriptional control of NUAK1, showing Large-MAF factors drive its expression to mediate IGF-1-induced myeloma invasion.","evidence":"Promoter MARE analysis, luciferase reporter mutagenesis, ChIP and invasion assays","pmids":["16044163"],"confidence":"Medium","gaps":["MAF regulation not shown in other tissue contexts"]},{"year":2006,"claim":"Resolved how NUAK1 is activated, identifying NDR2 as the Thr211 T-loop kinase during IGF-1 signaling and AKT as a separate Ser600 activator.","evidence":"In vitro kinase assays with NDR2/ARK5, Thr211 mutagenesis, co-IP and IGF-1 stimulation","pmids":["16488889"],"confidence":"High","gaps":["Relative contributions of NDR2 versus LKB1 to T211 phosphorylation not delineated"]},{"year":2009,"claim":"Connected NUAK1 to senescence and genome instability, showing it phosphorylates and destabilizes LATS1 at Ser464.","evidence":"Loss-of-function fibroblast screen, shRNA/overexpression, LATS1 phospho-assay and dominant-negative epistasis","pmids":["19927127"],"confidence":"Medium","gaps":["Mechanism linking LATS1 loss to aneuploidy not fully resolved","Single lab"]},{"year":2011,"claim":"Linked LKB1-NUAK1 to p53-dependent cell-cycle arrest, showing NUAK1 binds and phosphorylates p53 and occupies the p21 promoter.","evidence":"Co-IP, in vitro kinase assay, ChIP on p21/WAF1 promoter and cell-cycle analysis with kinase-dead mutants","pmids":["21317932"],"confidence":"Medium","gaps":["p53 phospho-site not mapped","Direct DNA binding by NUAK1 vs. recruitment unclear"]},{"year":2012,"claim":"Established NUAK1 as a negative regulator of insulin signaling in muscle via IRS1 Ser1097 phosphorylation.","evidence":"Muscle-specific knockout mice, quantitative phosphoproteomics of soleus, insulin signaling and glucose tolerance assays","pmids":["22418434"],"confidence":"High","gaps":["Direct vs. indirect IRS1 phosphorylation not separated","Whole-body metabolic consequences limited"]},{"year":2012,"claim":"Revealed a developmental cytoskeletal role, showing NUAK1/NUAK2 redundantly drive apical constriction during neural plate hinge-point formation.","evidence":"NUAK1/NUAK2 double-mutant mice with immunostaining for phospho-MLC2, F-actin, cortactin and acetylated tubulin","pmids":["22689267"],"confidence":"Medium","gaps":["Direct cytoskeletal substrate not identified","Redundancy obscures NUAK1-specific function"]},{"year":2013,"claim":"Defined the canonical neuronal function, showing the LKB1-NUAK1 pathway promotes axon branching by immobilizing presynaptic mitochondria.","evidence":"Conditional KO, in vivo KD/OE, live mitochondrial imaging and Syntaphilin genetic epistasis","pmids":["23791179"],"confidence":"High","gaps":["Direct substrate controlling mitochondrial arrest not identified at this stage"]},{"year":2013,"claim":"Identified upstream miRNA control, placing NUAK1 in a MITF/miR-211 axis that governs melanoma adhesion.","evidence":"miR-211 gain/loss-of-function, NUAK1 3'UTR luciferase reporter and adhesion assays","pmids":["23934065"],"confidence":"Medium","gaps":["Downstream NUAK1 substrate in adhesion not defined"]},{"year":2014,"claim":"Solved NUAK1 protein turnover and a key effector node, defining a CDK→PLK→SCFβTrCP degradation cascade and NUAK1 activation of PLK1 through PP1β-MYPT1 inhibition.","evidence":"Co-IP, phospho-site mutagenesis (Ser445/476/480), ubiquitylation assays, NUAK1 inhibitors and cell-cycle synchronization","pmids":["24785407"],"confidence":"High","gaps":["Physiological triggers of CDK-driven degradation not mapped"]},{"year":2017,"claim":"Identified an LKB1-independent activation route, showing calcium/PKCα sustains NUAK1 activity in LKB1-null tumors to support AMPK-TORC1 and MYC cell survival.","evidence":"Calcium manipulation, PKCα inhibition/knockdown, NUAK1 activity and MYC-dependent viability assays","pmids":["29106388"],"confidence":"Medium","gaps":["PKCα phospho-site on NUAK1 not mapped"]},{"year":2018,"claim":"Connected NUAK1 to redox-driven oncogenesis, showing it promotes NRF2 nuclear import via PP1β/AKT/GSK3β and is required for colorectal tumor maintenance.","evidence":"Genetic NUAK1 deletion in autochthonous colorectal cancer model, PP1β/GSK3β assays, NRF2 fractionation and pharmacological inhibition","pmids":["29500295"],"confidence":"High","gaps":["Direct NUAK1 substrate within the NRF2 import machinery not resolved beyond PP1β"]},{"year":2019,"claim":"Established the basis of NUAK1 nucleocytoplasmic shuttling, identifying a bipartite NLS and importin-β/IPO7/IPO9-dependent import inhibited by oxidative stress.","evidence":"NLS prediction/deletion mutants, importin knockdown, importazole, MS of NUAK1-importin interactions and immunofluorescence","pmids":["31090959"],"confidence":"Medium","gaps":["Mechanism by which oxidative stress blocks import not defined"]},{"year":2020,"claim":"Defined a nuclear transcriptional-coupling function, showing NUAK1 phosphorylates the PP1 subunit PNUTS to sustain spliceosome activity and productive RNAPII elongation in MYC-driven cells.","evidence":"Nuclear fractionation, proximity proteomics, in vitro PNUTS phosphorylation, spliceosome and nascent RNA assays, RNAPII ChIP-seq and inhibitors","pmids":["32006464"],"confidence":"High","gaps":["PNUTS phospho-sites not mapped","Generality beyond MYC-transformed cells untested"]},{"year":2020,"claim":"Extended NUAK1 into mTORC2/Akt signaling, showing it directly phosphorylates Akt Ser473 and regulates mTOR lysosome positioning.","evidence":"Co-IP with mTORC2 components, in vitro Akt phosphorylation, lysosome positioning and endosome fractionation","pmids":["38135881"],"confidence":"Medium","gaps":["Reconciliation with NUAK1 being downstream of Akt elsewhere unresolved"]},{"year":2020,"claim":"Began dissecting compartment-specific metabolic roles, linking cytosolic NUAK1 to respiration/glycolysis and mitochondrial morphology.","evidence":"Subcellular fractionation, Seahorse respiration, ATP measurement and mitochondrial morphology imaging","pmids":["32754444"],"confidence":"Medium","gaps":["Molecular substrate controlling mitochondrial morphology not identified"]},{"year":2020,"claim":"Showed NUAK1 maintains fibronectin-dependent ovarian cancer spheroid integrity downstream of LKB1.","evidence":"CRISPR NUAK1 KO, LKB1-NUAK1 phospho-assays, transcriptomics, fibronectin rescue and xenograft metastasis","pmids":["32429240"],"confidence":"Medium","gaps":["Mechanism linking NUAK1 kinase activity to FN1 transcription unknown"]},{"year":2020,"claim":"Connected NUAK1 inhibition to immunogenic cell death via NRF2/ROS, revealing a mevalonate-pathway negative-feedback brake.","evidence":"Kinome-wide CRISPR screen, NRF2 reporters, ROS and ICD markers, simvastatin and cholesterol rescue","pmids":["39824180"],"confidence":"Medium","gaps":["Direct NUAK1 substrate in this axis beyond NRF2 regulation not defined"]},{"year":2016,"claim":"Identified NUAK1 as a tau-stabilizing kinase, defining direct Ser356 phosphorylation as a therapeutic node in tauopathy.","evidence":"Cell and Drosophila genetic screens, in vitro/in vivo phospho-assays and mouse tauopathy haploinsufficiency","pmids":["27720485"],"confidence":"High","gaps":["Mechanism by which Ser356 phosphorylation stabilizes tau not fully resolved"]},{"year":2022,"claim":"Established NUAK1 as a core profibrotic kinase, defining a TGF-β→NUAK1→YAP/SMAD positive feedback loop driving fibrosis across organs.","evidence":"Fibroblast-specific conditional KO, pharmacological inhibition and kidney/lung/liver fibrosis models","pmids":["35320001"],"confidence":"High","gaps":["Direct NUAK1 substrate in the YAP/SMAD circuit not identified"]},{"year":2022,"claim":"Defined NUAK1 control of hnRNP A1 stress relocalization through phosphorylation in the F-peptide/M9 region.","evidence":"Co-IP, in vitro kinase assay, M9-motif mutagenesis, fractionation and caspase activation assays","pmids":["35963429"],"confidence":"High","gaps":["Functional consequences for specific mRNA targets not mapped"]},{"year":2022,"claim":"Identified USP9X as the deubiquitinase that stabilizes and activates NUAK1 to drive myofibroblast transformation.","evidence":"Myofibroblast-specific USP9X KO, inhibition, co-IP and deubiquitination assays with Rho-kinase readouts","pmids":["40310323"],"confidence":"Medium","gaps":["Ubiquitin-chain specificity and site on NUAK1 not defined"]},{"year":2022,"claim":"Showed NUAK1 sustains TGF-β signaling in hepatic stellate cells by suppressing Smurf2-mediated TβRI/Smad4 degradation.","evidence":"HTH-01-015 inhibition, siRNA in HSC/hepatocytes, receptor stability assays and CCl4 liver fibrosis model","pmids":["36361872"],"confidence":"Medium","gaps":["Direct NUAK1 substrate controlling Smurf2 not identified"]},{"year":2023,"claim":"Extended the PP1β effector axis to centrosome biology, showing NUAK1 governs PLK4-dependent centrosome duplication and genomic stability.","evidence":"NUAK1 inhibition/depletion in PDAC and fibroblasts, centrosome counting and MYPT1/PP1β/GSK3β/PLK4 pathway analysis","pmids":["36975767"],"confidence":"Medium","gaps":["Whether NUAK1 loss causes amplification vs. failed duplication context-dependent"]},{"year":2023,"claim":"Linked NUAK1 to ESCC metastasis through JNK/c-Jun-driven Slug transcription.","evidence":"Co-IP, Slug promoter luciferase, JNK/c-Jun inhibition and pulmonary metastasis model","pmids":["37919754"],"confidence":"Medium","gaps":["Direct kinase event upstream of JNK not defined"]},{"year":2024,"claim":"Refined the neuronal mechanism, showing NUAK1 controls axon branching through mitochondrial metabolism and the microprotein BRAWNIN, not just mitochondrial positioning.","evidence":"In vivo/in vitro NUAK1 KO neurons, mitochondrial and ATP assays, and BRAWNIN-based rescue","pmids":["38514619"],"confidence":"High","gaps":["How NUAK1 regulates BRAWNIN molecularly not resolved"]},{"year":2024,"claim":"Defined a redox-protective oncogenic substrate, showing NUAK1 phosphorylates NADK Ser64 to mitigate ROS and confer osimertinib resistance.","evidence":"Co-IP, in vitro kinase assay, NADK S64 mutagenesis, ROS measurement and xenograft","pmids":["39159134"],"confidence":"High","gaps":["Quantitative contribution of NADK phosphorylation to NADP(H) pools not measured"]},{"year":2024,"claim":"Linked NUAK1 to gastric cancer chemoresistance via a STAT5/GLI1 signaling axis.","evidence":"Depletion/inhibition, PDX and transgenic models, STAT5 activity and GLI1 stability assays with co-IP","pmids":["38996065"],"confidence":"Medium","gaps":["Direct NUAK1 phospho-target in the STAT5/GLI1 axis unknown"]},{"year":2024,"claim":"Showed NUAK1 promotes mitochondrial fission to support myeloma bioenergetics.","evidence":"Biallelic ARK5 KO, mitochondrial morphology imaging, fusion/fission protein blots and metabolic assays","pmids":["38282096"],"confidence":"Medium","gaps":["Whether NUAK1 directly phosphorylates DRP1 not established"]},{"year":2024,"claim":"Linked NUAK1 to MASH liver injury via caspase-6 activation and TAK1-RIPK1 regulation of pyroptosis.","evidence":"NUAK1 inhibition in MASH models, caspase-6 disruption and TAK1-RIPK1 co-IP/degradation assays","pmids":["38967580"],"confidence":"Medium","gaps":["Reconciliation with earlier caspase-6 inhibition finding context-dependent"]},{"year":2024,"claim":"Provided the first NUAK1 crystal structure and exploited Glu139 to develop subnanomolar selective inhibitors, enabling cleaner mechanistic dissection.","evidence":"X-ray crystallography of a NUAK1 chimera and inhibitor co-crystal structures with SAR","pmids":["39588908"],"confidence":"Medium","gaps":["Full-length, substrate-bound NUAK1 structure not obtained"]},{"year":2024,"claim":"Identified PSD3 Ser476 as a direct NUAK1 substrate controlling ARF6 activity and dendritic spine maturation.","evidence":"ATP-analog-sensitive chemical genetics, direct phospho-assay, S476A mutant, ARF6/PI(4,5)P2 imaging and spine analysis (preprint)","pmids":["42079242"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","In vivo relevance to circuit function untested"]},{"year":2025,"claim":"Defined a NUAK1-SON pathway controlling alternative splicing in developing cortical neurons.","evidence":"NUAK1 KO neurons, SON phosphorylation assays, RNA-seq splicing analysis and SON knockdown phenocopy (preprint)","pmids":["bio_10.1101_2025.10.10.681550"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","SON phospho-sites not mapped"]},{"year":2025,"claim":"Linked NUAK1 to immune evasion, showing it drives PD-L1 transcription via GSK3β/β-catenin in HCC.","evidence":"Gain/loss-of-function, p-GSK3β/β-catenin blots, nuclear fractionation and β-catenin knockdown rescue","pmids":["39901136"],"confidence":"Medium","gaps":["Direct NUAK1 substrate upstream of GSK3β not identified"]},{"year":null,"claim":"Whether NUAK1's many context-specific outputs converge on a small set of direct substrates (e.g. the PP1β-MYPT1 node) or reflect a broad, tissue-tuned substrate repertoire remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified substrate map across tissues","Direct vs. PP1β-indirect effects not systematically separated","Compartment-specific (nuclear vs. cytoplasmic) substrate sets incompletely defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,4,6,13,15,19,22,34]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[2,4,8,9,22]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,11,21]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,13,17]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[17,18,20]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[20]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,11,14,20]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,7,9,21]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,4,30]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[13,19,35]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[11,22,25]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,16]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[15,18,28]}],"complexes":[],"partners":["LKB1","NDR2","PP1Β-MYPT1","PNUTS","HNRNP A1","P53","USP9X","NADK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60285","full_name":"NUAK family SNF1-like kinase 1","aliases":["AMPK-related protein kinase 5","ARK5","Omphalocele kinase 1"],"length_aa":661,"mass_kda":74.3,"function":"Serine/threonine-protein kinase involved in various processes such as cell adhesion, regulation of cell ploidy and senescence, cell proliferation and tumor progression. Phosphorylates ATM, CASP6, LATS1, PPP1R12A and p53/TP53. Acts as a regulator of cellular senescence and cellular ploidy by mediating phosphorylation of 'Ser-464' of LATS1, thereby controlling its stability. Controls cell adhesion by regulating activity of the myosin protein phosphatase 1 (PP1) complex. Acts by mediating phosphorylation of PPP1R12A subunit of myosin PP1: phosphorylated PPP1R12A then interacts with 14-3-3, leading to reduced dephosphorylation of myosin MLC2 by myosin PP1. May be involved in DNA damage response: phosphorylates p53/TP53 at 'Ser-15' and 'Ser-392' and is recruited to the CDKN1A/WAF1 promoter to participate in transcription activation by p53/TP53. May also act as a tumor malignancy-associated factor by promoting tumor invasion and metastasis under regulation and phosphorylation by AKT1. Suppresses Fas-induced apoptosis by mediating phosphorylation of CASP6, thereby suppressing the activation of the caspase and the subsequent cleavage of CFLAR. Regulates UV radiation-induced DNA damage response mediated by CDKN1A. In association with STK11, phosphorylates CDKN1A in response to UV radiation and contributes to its degradation which is necessary for optimal DNA repair (PubMed:25329316)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O60285/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NUAK1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NUAK1","total_profiled":1310},"omim":[{"mim_id":"608130","title":"NUAK FAMILY, SNF1-LIKE KINASE, 1; NUAK1","url":"https://www.omim.org/entry/608130"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli fibrillar center","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Microtubules","reliability":"Additional"},{"location":"Mitotic spindle","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NUAK1"},"hgnc":{"alias_symbol":["ARK5","KIAA0537"],"prev_symbol":[]},"alphafold":{"accession":"O60285","domains":[{"cath_id":"3.30.200.20","chopping":"44-133","consensus_level":"high","plddt":90.9592,"start":44,"end":133},{"cath_id":"1.10.510.10","chopping":"139-315","consensus_level":"high","plddt":93.4659,"start":139,"end":315}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60285","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60285-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60285-F1-predicted_aligned_error_v6.png","plddt_mean":61.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NUAK1","jax_strain_url":"https://www.jax.org/strain/search?query=NUAK1"},"sequence":{"accession":"O60285","fasta_url":"https://rest.uniprot.org/uniprotkb/O60285.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60285/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60285"}},"corpus_meta":[{"pmid":"23791179","id":"PMC_23791179","title":"Terminal 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knockout, in vivo knockdown/overexpression, live imaging of mitochondrial transport, genetic epistasis with Syntaphilin\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vivo genetic approaches (conditional KO, KD, OE) with defined cellular phenotype, replicated with Syntaphilin epistasis experiment\",\n      \"pmids\": [\"23791179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NUAK1 deficiency impairs mitochondrial metabolism and axonal ATP concentration; upregulation of mitochondrial function rescues axonal branching in NUAK1-null neurons. NUAK1 regulates axon branching through the mitochondria-targeted microprotein BRAWNIN, exerting a dual function by controlling both mitochondrial distribution and metabolic activity.\",\n      \"method\": \"In vitro and in vivo neuronal cultures with NUAK1 knockout, mitochondrial function assays, ATP measurements, rescue experiments with mitochondrial activators, identification of BRAWNIN as downstream effector\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (metabolic assays, in vivo/in vitro KO, rescue experiments), identifies specific downstream effector BRAWNIN\",\n      \"pmids\": [\"38514619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NUAK1 stabilizes tau by direct phosphorylation specifically at Ser356; inhibition of NUAK1 reduces steady-state tau levels and suppresses neurodegeneration in tau-expressing Drosophila, and NUAK1 haploinsufficiency rescues tauopathy phenotypes in mice.\",\n      \"method\": \"Parallel cell-based and Drosophila genetic screens, in vitro/in vivo phosphorylation assays, genetic loss-of-function in mouse tauopathy model\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct phosphorylation demonstrated, replicated across Drosophila and mouse models with specific Ser356 site identified\",\n      \"pmids\": [\"27720485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ARK5 (NUAK1) suppresses cell death by glucose starvation and death receptor stimulation (TRAIL, TNF-α) by inhibiting caspase 8 activation; ARK5 overexpression delayed Bid cleavage, FLIP degradation, and caspase 8 activation. This protective effect was not observed for UV irradiation, camptothecin, or doxorubicin.\",\n      \"method\": \"ARK5 overexpression in HepG2 cells, Western blotting for Bid cleavage/FLIP degradation/caspase 8 activation, cell death assays under multiple stimuli\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, two orthogonal methods (cell death assays + western blot), mechanistically specific pathway placement\",\n      \"pmids\": [\"13679856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ARK5 (NUAK1) phosphorylates and inhibits procaspase-6 at Ser257, preventing its activation and subsequent FLIP degradation, thereby mediating resistance to FasL/Fas-induced cell death in colorectal cancer cells; in vitro kinase assay showed ARK5 phosphorylates wild-type but not caspase-6/S257A mutant.\",\n      \"method\": \"ARK5 antisense RNA knockdown, caspase-6 mutagenesis (Ser257Ala), in vitro kinase assay, Western blotting, cell death assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis confirming specific phosphorylation site, single lab\",\n      \"pmids\": [\"15273717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ARK5 (NUAK1) promotes tumor invasion downstream of Akt signaling; ARK5 expression induces activation of MMP-2, MMP-9, and new expression of MT1-MMP via rapamycin-sensitive signaling, and ARK5-overexpressing tumor cells show invasion and metastasis in nude mice.\",\n      \"method\": \"Matrigel invasion assay, MMP activity assays, rapamycin treatment, nude mouse tumor model\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro experiments, multiple readouts, single lab\",\n      \"pmids\": [\"15060171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NUAK1 promotes cellular senescence and aneuploidization by phosphorylating LATS1 at Ser464, destabilizing LATS1; ectopic NUAK1 expression triggers premature senescence with gross aneuploidies, while NUAK1 depletion extends replicative lifespan and increases LATS1 levels.\",\n      \"method\": \"Loss-of-function screen in diploid fibroblasts, shRNA depletion, ectopic overexpression, Western blotting, LATS1 phosphorylation assay, dominant-negative LATS1\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific phosphorylation site identified, phenotypic rescue with dominant-negative LATS1 as epistasis, single lab\",\n      \"pmids\": [\"19927127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NUAK1 directly interacts with and phosphorylates p53 in vitro and in vivo; this requires NUAK1 kinase activity and phosphorylation at Thr211 by LKB1. LKB1/NUAK1 activation leads to G1/S cell cycle arrest by inducing p21/WAF1 expression; NUAK1 binds p53-responsive elements of the p21/WAF1 promoter in the nucleus.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, ChIP on p21/WAF1 promoter, cell cycle analysis, kinase-dead mutants\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay plus co-IP plus ChIP, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"21317932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NDR2 is an upstream kinase of ARK5 (NUAK1) that directly phosphorylates the conserved Thr211 on the active T-loop of ARK5 during IGF-1 signaling, enabling full ARK5 activation; AKT phosphorylates ARK5 at Ser600 in the regulatory domain as a separate activating event.\",\n      \"method\": \"In vitro kinase assay with NDR2 and ARK5, phosphorylation site mutagenesis (Thr211), co-immunoprecipitation, IGF-1 stimulation experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis identifying specific phosphorylation site (T211), single lab\",\n      \"pmids\": [\"16488889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NUAK1 expression is controlled by CDK-PLK-SCFβTrCP E3 ubiquitin ligase complex: CDK phosphorylates NUAK1 at Ser445, triggering PLK binding, which phosphorylates NUAK1 at Ser476 and Ser480, inducing βTrCP binding, ubiquitylation and degradation. NUAK1 also activates PLK1 via inhibition of the PP1β-MYPT1 phosphatase that dephosphorylates PLK1 Thr210.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation site mutagenesis (Ser445, Ser476, Ser480), ubiquitylation assays, NUAK1 inhibitors (WZ4003, HTH-01-015), cell cycle synchronization, rescue with phospho-mutant NUAK1\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including mutagenesis, Co-IP, ubiquitylation assays and inhibitor pharmacology, single lab with comprehensive mechanistic dissection\",\n      \"pmids\": [\"24785407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ARK5 (NUAK1) is a transcriptional target of the Large-MAF family (c-MAF, MAFB) via MAF-recognition element (MARE) sequences in its promoter; ARK5 mediates IGF-1-induced cell invasion in multiple myeloma downstream of MAF transcription factors.\",\n      \"method\": \"Gene expression profiling, promoter sequence analysis with MARE identification, luciferase reporter with MARE deletion/mutation, chromatin immunoprecipitation (ChIP), ARK5 overexpression in non-expressing cell lines, invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assays plus mutagenesis, single lab, two orthogonal methods for transcriptional regulation\",\n      \"pmids\": [\"16044163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NUAK1 is activated by oxidative stress and facilitates nuclear import of the antioxidant master regulator NRF2: activated NUAK1 inhibits PP1β, which cooperates with AKT activation to suppress GSK3β-dependent phosphorylation that normally prevents NRF2 nuclear import; deletion of NUAK1 suppresses colorectal tumor formation and induces regression of preexisting autochthonous tumors.\",\n      \"method\": \"Genetic NUAK1 deletion in autochthonous mouse colorectal cancer model, PP1β inhibition assays, GSK3β phosphorylation analysis, NRF2 nuclear fractionation, pharmacological NUAK1 inhibition\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods in vivo and in vitro, specific pathway dissection (PP1β/AKT/GSK3β/NRF2), autochthonous tumor models\",\n      \"pmids\": [\"29500295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NUAK1 is a TGF-β-inducible profibrotic kinase; TGF-β rapidly induces NUAK1 in fibroblasts, which in turn promotes profibrotic YAP and TGF-β/SMAD signaling; activated YAP/TAZ further induces NUAK1 expression, creating a positive feedback loop. Fibroblast-specific NUAK1 loss or pharmacologic NUAK1 inhibition attenuates fibrosis in kidney, lung, and liver mouse models.\",\n      \"method\": \"Fibroblast-specific conditional NUAK1 knockout mice, pharmacological NUAK1 inhibition, multiple organ fibrosis mouse models, YAP/SMAD signaling assays\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO in multiple in vivo fibrosis models, pharmacological validation, mechanistic pathway dissection with positive feedback loop\",\n      \"pmids\": [\"35320001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NUAK1 is a predominantly nuclear protein that associates with nuclear PP1 interactors including PNUTS (a nuclear regulatory subunit of PP1) and phosphorylates PNUTS; both NUAK1 and PNUTS associate with the splicing machinery. NUAK1 inhibition abolishes chromatin association of PNUTS, reduces spliceosome activity, suppresses nascent RNA synthesis, and in MYC-transformed cells traps non-productive RNAPII at the pause site and first exon-intron boundary.\",\n      \"method\": \"Nuclear fractionation, Co-IP/proximity proteomics, in vitro phosphorylation of PNUTS, spliceosome activity assays, nascent RNA synthesis measurement, RNAPII ChIP-seq, NUAK1 inhibitors\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including Co-IP, phosphorylation assays, spliceosome activity and genome-wide RNAPII mapping, single lab with comprehensive mechanism\",\n      \"pmids\": [\"32006464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In tumor cells lacking LKB1, NUAK1 activity is maintained by an alternative pathway: calcium-dependent activation of PKCα phosphorylates and activates NUAK1, supporting AMPK-TORC1 metabolic checkpoint engagement and protecting MYC-overexpressing tumor cells from cell death.\",\n      \"method\": \"Pharmacological calcium manipulation, PKCα inhibition/knockdown, NUAK1 activity assays, AMPK-TORC1 signaling readouts, MYC-dependent cell viability assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific pathway dissection with pharmacological and genetic approaches, single lab\",\n      \"pmids\": [\"29106388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NUAK1-deficient muscle shows decreased phosphorylation of IRS1 at Ser1097, leading to enhanced insulin signaling (increased phosphorylation of IRS1 Tyr608, AKT Thr308, TBC1D4 Thr649), suggesting NUAK1 negatively regulates insulin signaling in oxidative muscle through IRS1 Ser1097 phosphorylation.\",\n      \"method\": \"Muscle-specific NUAK1 knockout mice, quantitative phosphoproteome analysis of soleus muscle, insulin signaling assays, glucose tolerance tests\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — quantitative phosphoproteomics plus in vivo knockout with specific phosphorylation site (IRS1 Ser1097) identified, single lab\",\n      \"pmids\": [\"22418434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NUAK1 and NUAK2 complementarily function in apical constriction and apico-basal elongation during dorsolateral hinge point formation in cephalic neural plate; NUAK1/NUAK2 double mutants show reduced apical concentration of phosphorylated myosin light chain 2, F-actin, and cortactin, and impaired development of acetylated α-tubulin-positive microtubules.\",\n      \"method\": \"NUAK1/NUAK2 double mutant mouse analysis, immunostaining for phospho-MLC2, F-actin, cortactin, acetylated α-tubulin\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic double-mutant epistasis with specific cellular phenotype (apical constriction), single lab\",\n      \"pmids\": [\"22689267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NUAK1 contains a conserved bipartite nuclear localization signal (NLS) at its N-terminal domain and is actively imported into the nucleus by importin-β members KPNB1 (importin-β1), IPO7 (importin-7), and IPO9 (importin-9); oxidative stress induces NUAK1 cytoplasmic accumulation by inhibiting this nuclear transport.\",\n      \"method\": \"Bioinformatics NLS prediction, subcellular fractionation, NLS deletion mutants, importin knockdown (IPO7, IPO9 siRNA), importazole treatment, mass spectrometry identification of NUAK1-importin interactions, immunofluorescence\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (MS, mutagenesis, knockdown, pharmacological), single lab\",\n      \"pmids\": [\"31090959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cytosolic NUAK1 increases ATP levels via increased mitochondrial respiration and maintains glycolytic capacity under mitochondrial inhibition; NUAK1 inhibition leads to 'donut-like' mitochondrial morphology changes indicating NUAK1-dependent mitochondrial morphology regulation. Nuclear NUAK1 appears involved in the metabolic switch to glycolysis.\",\n      \"method\": \"Subcellular fractionation, mitochondrial respiration assays (Seahorse), ATP measurement, NUAK1 inhibition, mitochondrial morphology imaging\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple metabolic assays plus imaging with compartment-specific NUAK1 variants, single lab\",\n      \"pmids\": [\"32754444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ARK5 (NUAK1) directly interacts with and phosphorylates hnRNP A1 on serine residues within the F-peptide region; the M9 motif of hnRNP A1 is essential for this interaction and phosphorylation. ARK5-mediated phosphorylation of hnRNP A1 controls its cytoplasmic relocalization during hypertonic stress; ARK5 silencing increases Bcl-xL expression and delays caspase activation.\",\n      \"method\": \"Immunoprecipitation, in vitro kinase assay, hnRNP A1 domain mutagenesis (M9 motif deletion), subcellular fractionation, siRNA knockdown, caspase activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus Co-IP plus mutagenesis identifying the interaction domain, single lab\",\n      \"pmids\": [\"35963429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NUAK1 coordinates growth factor-dependent mTORC2 and Akt activation by two mechanisms: (1) interacting with mTORC2 components and regulating mTOR lysosome positioning; (2) directly phosphorylating Akt at Ser473. NUAK1 selectively promotes Akt-dependent phosphorylation of FOXO1/3a but not TSC2, and is associated with early endosomes.\",\n      \"method\": \"Co-immunoprecipitation with mTORC2 components, in vitro Akt phosphorylation assays, lysosome positioning analysis, subcellular fractionation (early endosome), NUAK1 inhibitors, specific substrate phosphorylation analysis\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, in vitro kinase assay, organelle positioning), single lab\",\n      \"pmids\": [\"38135881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NUAK1 governs centrosome duplication in pancreatic cancer via MYPT1/PP1β and GSK3β-dependent regulation of PLK4; loss of NUAK1 triggers genomic instability through inaccurate centrosome duplication, an effect conserved in primary fibroblasts.\",\n      \"method\": \"NUAK1 inhibition and depletion in PDAC cells, centrosome counting, genomic instability assays, MYPT1/PP1β and GSK3β-PLK4 pathway analysis\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific molecular pathway placement (MYPT1/PP1β/GSK3β/PLK4), multiple cell systems, single lab\",\n      \"pmids\": [\"36975767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NUAK1 directly phosphorylates NADK (nicotinamide adenine dinucleotide kinase) at Ser64, which mitigates osimertinib-induced ROS accumulation and confers osimertinib resistance in NSCLC; NUAK1-NADK interaction was confirmed by co-immunoprecipitation and in vitro kinase assay.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, phosphorylation site mutagenesis (NADK Ser64), ROS measurement, genetic/pharmacological NUAK1 blockade, in vivo xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with specific phosphorylation site, Co-IP, in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39159134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NUAK1 activates STAT5-mediated transcription and stabilizes GLI1 protein in gastric cancer, promoting cancer cell expansion and chemotherapy resistance through the NUAK1/STAT5/GLI1 signaling axis.\",\n      \"method\": \"NUAK1 depletion/inhibition, patient-derived xenograft and transgenic mouse models, STAT5 transcriptional activity assays, GLI1 protein stability assays, co-immunoprecipitation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vivo models (PDX, transgenic), pathway dissection, single lab\",\n      \"pmids\": [\"38996065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NUAK1 loss in ovarian cancer spheroids dramatically reduces FN1 gene expression (fibronectin), which is required for spheroid integrity; LKB1 maintains NUAK1 phosphorylation and promotes its stabilization; NUAK1KO spheroids show reduced integrity and increased cell death, rescued by co-incubation with soluble fibronectin.\",\n      \"method\": \"CRISPR NUAK1 KO in EOC cells, LKB1-NUAK1 phosphorylation assays, transcriptome analysis, fibronectin rescue experiments, xenograft metastasis model\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with transcriptomics, fibronectin rescue, xenograft, single lab\",\n      \"pmids\": [\"32429240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NUAK1 inhibition increases ROS via downregulation of NRF2-mediated antioxidant gene expression, triggering immunogenic cell death (ICD); XBP1s downstream of ICD-induced ER stress activates the mevalonate/cholesterol pathway as a negative feedback mechanism that dampens ROS and ICD.\",\n      \"method\": \"Kinome-wide CRISPR-Cas9 screen, NRF2 reporter assays, ROS measurement, ICD markers, HMGCR inhibition with simvastatin, cholesterol supplementation experiments\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus mechanistic validation with multiple pathway components, single lab\",\n      \"pmids\": [\"39824180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NUAK1 promotes ESCC metastasis by enhancing Slug transcription through activation of the JNK/c-Jun pathway; silencing Slug completely abolishes migration and invasion of NUAK1-overexpressing ESCC cells; NUAK1 and Slug interact as shown by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation, dual-luciferase reporter assay for Slug promoter, JNK/c-Jun inhibition, NUAK1 overexpression/knockdown, in vivo pulmonary metastasis model\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, reporter assay, in vivo rescue/epistasis, single lab\",\n      \"pmids\": [\"37919754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP9X deubiquitinates and activates ARK5 (NUAK1), promoting TGF-β1-induced myofibroblast transformation via the Rho kinase pathway; USP9X-ARK5 interaction demonstrated by binding and deubiquitination assays.\",\n      \"method\": \"Myofibroblast-specific USP9X knockout, pharmacological USP9X inhibition, co-immunoprecipitation, deubiquitination assay, ARK5 activation assays, Rho kinase pathway analysis\",\n      \"journal\": \"JACC. Basic to translational science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific enzyme-substrate relationship (USP9X-ARK5 deubiquitination) with Co-IP and in vivo KO, single lab\",\n      \"pmids\": [\"40310323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ARK5 (NUAK1) enhances mitochondrial fission in multiple myeloma; ARK5 knockout leads to enhanced mitochondrial fusion (increased MFN1, MFN2, OPA1), reduced phospho-DRP1 (Ser616), lower ATP levels, higher lactate and ROS, showing ARK5 promotes mitochondrial fission for bioenergetic support.\",\n      \"method\": \"Biallelic ARK5 knockout in MM cell lines, mitochondrial morphology imaging, Western blotting for fusion/fission proteins, ATP measurement, ROS and lactate assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic KO clones with multiple molecular readouts for mitochondrial dynamics, single lab\",\n      \"pmids\": [\"38282096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In hepatic stellate cells, ARK5 (NUAK1) prevents degradation of TGF-β type I receptor (TβRI) and Smad4 by inhibiting Smurf2 expression, maintaining continuous TGF-β signaling; in hepatocytes, ARK5 induces EMT and promotes secretion of inflammatory factors that further activate HSCs.\",\n      \"method\": \"ARK5 inhibition with HTH-01-015, siRNA knockdown in HSC and hepatocyte cell lines, TβRI/Smad4 stability assays, Smurf2 expression analysis, CCl4-induced liver fibrosis mouse model\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic inhibition in multiple cell types plus in vivo model, mechanistic pathway dissection, single lab\",\n      \"pmids\": [\"36361872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NUAK1 promotes MASH-related liver injury by facilitating Caspase 6 activation and triggering pyroptosis; NUAK1/Caspase 6 axis inhibition accelerates interaction between TAK1 and RIPK1, leading to RIPK1 degradation and reduced inflammation.\",\n      \"method\": \"NUAK1 inhibition in MASH mouse models, Caspase 6 disruption, TAK1-RIPK1 co-immunoprecipitation, RIPK1 degradation assays\",\n      \"journal\": \"Hepatology communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro experiments with specific pathway placement (Caspase 6-TAK1-RIPK1), single lab\",\n      \"pmids\": [\"38967580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NUAK1 promotes PD-L1 transcriptional expression in hepatocellular carcinoma by activating GSK3β Ser9 phosphorylation, leading to β-catenin nuclear accumulation and transcriptional activation of PD-L1; knockdown of β-catenin reverses NUAK1-mediated PD-L1 upregulation.\",\n      \"method\": \"NUAK1 gain/loss-of-function, Western blotting for p-GSK3β/β-catenin, nuclear fractionation, β-catenin knockdown rescue, immunohistochemistry on patient samples\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple molecular readouts, epistasis with β-catenin knockdown, single lab\",\n      \"pmids\": [\"39901136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Yeast Tda1, the ortholog of human NUAK1, is a direct kinase for histone H3 threonine 11 (H3pT11) upon low glucose stress; yeast AMPK directly phosphorylates Tda1 to govern its activity, while CK2 regulates Tda1 nuclear localization, thus linking glucose stress to chromatin regulation.\",\n      \"method\": \"In vitro kinase assay with Tda1 and histone H3, phosphorylation site identification (H3pT11), genetic epistasis in yeast (AMPK and CK2 mutants), nuclear localization analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro kinase assay identifying histone substrate, yeast ortholog with genetic epistasis, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33372657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"miR-211 targets NUAK1 directly, reducing NUAK1 expression and promoting melanoma cell adhesion; inhibition of miR-211 increases NUAK1 expression and decreases melanoma adhesion, while upregulation of miR-211 restores adhesion through NUAK1 repression. This defines the MITF/miR-211/NUAK1 axis as an inhibitor of the melanoma invasive program.\",\n      \"method\": \"miR-211 gain/loss-of-function, luciferase reporter assay for NUAK1 3'UTR targeting, adhesion assays, NUAK1 knockdown\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter validating direct miRNA targeting, functional phenotypic rescue, single lab\",\n      \"pmids\": [\"23934065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NUAK1 phosphorylates PSD3 (Pleckstrin Homology and Sec7-domain containing protein 3) at Ser476; phospho-deficient PSD3 leads to aberrant ARF6 activation and PI(4,5)P2 accumulation in intracellular vesicles, and in neurons leads to enhanced spine maturation in an ARF6-dependent fashion.\",\n      \"method\": \"ATP-analog sensitive NUAK1 chemical genetics screen, direct phosphorylation assay of PSD3, phospho-deficient mutant PSD3 (S476A), ARF6 activation assays, PI(4,5)P2 imaging, dendritic spine analysis in neurons\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — chemical genetics with ATP-analog sensitive kinase identifying direct substrate, specific phosphorylation site mutagenesis, preprint not yet peer-reviewed\",\n      \"pmids\": [\"42079242\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NUAK1 regulates alternative splicing in developing cortical neurons through phosphorylation of the splicing co-factor SON, controlling conserved splicing events in genes crucial for neurodevelopment; this NUAK1-SON pathway is required for proper neuronal development.\",\n      \"method\": \"NUAK1 knockout in cortical neurons, phosphorylation assays for SON, alternative splicing analysis (RNA-seq), SON knockdown phenocopy experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phosphorylation of SON demonstrated, alternative splicing genome-wide analysis, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.10.10.681550\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NUAK1 is present in human erythrocytes, undergoes increased phosphorylation in P. falciparum-infected cells, and is required for parasite invasion; pharmacological NUAK1 inhibition reduces MYPT1 phosphorylation in erythroid cells and inhibits parasite growth; NUAK1 overexpression partially rescues invasion phenotypes caused by inhibitors.\",\n      \"method\": \"NUAK1 inhibitors (HTH-01-015, WZ4003) with chemoproteomic selectivity profiling, MYPT1 phosphorylation assays, NUAK1 overexpression rescue, parasite invasion assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemoproteomic selectivity profiling, substrate (MYPT1) phosphorylation readout, genetic rescue experiment, preprint\",\n      \"pmids\": [\"41278793\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NUAK1 crystal structure obtained using a chimeric protein; structure-guided drug design exploiting the unique Glu139 residue of NUAK1 enabled development of highly selective inhibitors with subnanomolar potency.\",\n      \"method\": \"X-ray crystallography of NUAK1 chimeric protein, structure-activity relationship, co-crystal structures of inhibitor-NUAK1 complexes\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — first crystal structure of NUAK1 with functional validation of Glu139 as selectivity determinant, single lab, primarily medicinal chemistry focus\",\n      \"pmids\": [\"39588908\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUAK1 is an AMPK-related serine/threonine kinase activated by LKB1 (via T-loop phosphorylation at Thr211) and alternatively by calcium/PKCα, that phosphorylates multiple substrates including PP1β-MYPT1 (inhibiting the phosphatase to regulate PLK1, myosin light chain, and NRF2 nuclear import), tau at Ser356 (stabilizing it), caspase-6 at Ser257 (inhibiting its activation), LATS1 at Ser464 (destabilizing it to promote senescence), p53, IRS1 at Ser1097 (suppressing insulin signaling), NADK at Ser64 (mitigating ROS), hnRNP A1 (controlling its localization), PNUTS (regulating spliceosome-RNAPII coupling), Akt at Ser473, PSD3 at Ser476 (regulating ARF6 and dendritic spine maturation), and SON (regulating alternative splicing in neurons); its own stability is controlled by CDK→PLK1→SCFβTrCP-mediated ubiquitylation and by USP9X-mediated deubiquitylation, and it shuttles between nucleus (via importin-β/IPO7/IPO9-dependent NLS) and cytoplasm in response to oxidative stress.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NUAK1 (ARK5) is an AMPK-related serine/threonine kinase that couples upstream growth-factor and energy-stress signaling to control of cell survival, metabolism, the cytoskeleton, mitochondrial behavior, and gene expression, with prominent roles in both neuronal development and tumor biology [#0, #11]. It is activated by T-loop phosphorylation at Thr211 by LKB1 and by NDR2 during IGF-1 signaling, with AKT phosphorylating a separate regulatory-domain site (Ser600); in LKB1-null tumor cells a calcium/PKC\\u03b1 route maintains NUAK1 activity to engage the AMPK-TORC1 metabolic checkpoint [#7, #8, #14]. A recurring effector mechanism is NUAK1 inhibition of the PP1\\u03b2-MYPT1 phosphatase, which it exploits to activate PLK1 and PLK4 in centrosome duplication and to promote GSK3\\u03b2-dependent nuclear import of the antioxidant regulator NRF2, linking the kinase to genomic stability and redox control [#9, #11, #21]. Through direct substrate phosphorylation NUAK1 acts on diverse targets: tau at Ser356 to stabilize it and drive tauopathy [#2], caspase-6 at Ser257 to block apoptosis [#4], LATS1 at Ser464 to promote senescence [#6], IRS1 at Ser1097 to suppress insulin signaling in muscle [#15], NADK at Ser64 to mitigate ROS [#22], and the RNA-processing factors PNUTS and hnRNP A1 to control splicing and stress-dependent relocalization [#13, #19]. In neurons the LKB1-NUAK1 pathway controls cortical axon branching by immobilizing mitochondria at presynaptic sites and by regulating mitochondrial metabolism via the microprotein BRAWNIN [#0, #1]. In cancer NUAK1 promotes invasion, fibronectin-dependent spheroid integrity, and chemoresistance, and is a TGF-\\u03b2-inducible profibrotic kinase that sustains YAP and TGF-\\u03b2/SMAD signaling in a positive feedback loop driving organ fibrosis [#5, #12, #24]. NUAK1 itself is regulated by a CDK\\u2192PLK\\u2192SCF\\u03b2TrCP degradation cascade and by USP9X-mediated deubiquitylation, and shuttles between nucleus and cytoplasm via importin-\\u03b2/IPO7/IPO9-dependent nuclear import that is blocked by oxidative stress [#9, #17, #27].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established NUAK1/ARK5 as an anti-apoptotic kinase, defining its first cellular role in protecting cells from death-receptor and metabolic stress.\",\n      \"evidence\": \"ARK5 overexpression in HepG2 cells with Bid/FLIP/caspase-8 immunoblotting and cell death assays under multiple stimuli\",\n      \"pmids\": [\"13679856\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate in the caspase-8 axis not identified here\", \"Overexpression-only; loss-of-function not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified the first direct NUAK1 substrate mediating apoptosis resistance, showing it phosphorylates procaspase-6 at Ser257 to block its activation.\",\n      \"evidence\": \"Antisense knockdown, caspase-6 S257A mutagenesis and in vitro kinase assay in colorectal cancer cells\",\n      \"pmids\": [\"15273717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of the phospho-site not established\", \"Did not address kinase activation requirements\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Placed NUAK1 downstream of Akt as a driver of tumor invasion via MMP induction, linking the kinase to metastatic phenotypes.\",\n      \"evidence\": \"Matrigel invasion, MMP activity assays, rapamycin treatment and nude mouse tumor model\",\n      \"pmids\": [\"15060171\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase substrate driving MMP expression unknown\", \"Single lab, overexpression-based\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined transcriptional control of NUAK1, showing Large-MAF factors drive its expression to mediate IGF-1-induced myeloma invasion.\",\n      \"evidence\": \"Promoter MARE analysis, luciferase reporter mutagenesis, ChIP and invasion assays\",\n      \"pmids\": [\"16044163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MAF regulation not shown in other tissue contexts\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved how NUAK1 is activated, identifying NDR2 as the Thr211 T-loop kinase during IGF-1 signaling and AKT as a separate Ser600 activator.\",\n      \"evidence\": \"In vitro kinase assays with NDR2/ARK5, Thr211 mutagenesis, co-IP and IGF-1 stimulation\",\n      \"pmids\": [\"16488889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of NDR2 versus LKB1 to T211 phosphorylation not delineated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected NUAK1 to senescence and genome instability, showing it phosphorylates and destabilizes LATS1 at Ser464.\",\n      \"evidence\": \"Loss-of-function fibroblast screen, shRNA/overexpression, LATS1 phospho-assay and dominant-negative epistasis\",\n      \"pmids\": [\"19927127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking LATS1 loss to aneuploidy not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked LKB1-NUAK1 to p53-dependent cell-cycle arrest, showing NUAK1 binds and phosphorylates p53 and occupies the p21 promoter.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, ChIP on p21/WAF1 promoter and cell-cycle analysis with kinase-dead mutants\",\n      \"pmids\": [\"21317932\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"p53 phospho-site not mapped\", \"Direct DNA binding by NUAK1 vs. recruitment unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established NUAK1 as a negative regulator of insulin signaling in muscle via IRS1 Ser1097 phosphorylation.\",\n      \"evidence\": \"Muscle-specific knockout mice, quantitative phosphoproteomics of soleus, insulin signaling and glucose tolerance assays\",\n      \"pmids\": [\"22418434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. indirect IRS1 phosphorylation not separated\", \"Whole-body metabolic consequences limited\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed a developmental cytoskeletal role, showing NUAK1/NUAK2 redundantly drive apical constriction during neural plate hinge-point formation.\",\n      \"evidence\": \"NUAK1/NUAK2 double-mutant mice with immunostaining for phospho-MLC2, F-actin, cortactin and acetylated tubulin\",\n      \"pmids\": [\"22689267\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cytoskeletal substrate not identified\", \"Redundancy obscures NUAK1-specific function\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the canonical neuronal function, showing the LKB1-NUAK1 pathway promotes axon branching by immobilizing presynaptic mitochondria.\",\n      \"evidence\": \"Conditional KO, in vivo KD/OE, live mitochondrial imaging and Syntaphilin genetic epistasis\",\n      \"pmids\": [\"23791179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate controlling mitochondrial arrest not identified at this stage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified upstream miRNA control, placing NUAK1 in a MITF/miR-211 axis that governs melanoma adhesion.\",\n      \"evidence\": \"miR-211 gain/loss-of-function, NUAK1 3'UTR luciferase reporter and adhesion assays\",\n      \"pmids\": [\"23934065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream NUAK1 substrate in adhesion not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Solved NUAK1 protein turnover and a key effector node, defining a CDK\\u2192PLK\\u2192SCF\\u03b2TrCP degradation cascade and NUAK1 activation of PLK1 through PP1\\u03b2-MYPT1 inhibition.\",\n      \"evidence\": \"Co-IP, phospho-site mutagenesis (Ser445/476/480), ubiquitylation assays, NUAK1 inhibitors and cell-cycle synchronization\",\n      \"pmids\": [\"24785407\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological triggers of CDK-driven degradation not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified an LKB1-independent activation route, showing calcium/PKC\\u03b1 sustains NUAK1 activity in LKB1-null tumors to support AMPK-TORC1 and MYC cell survival.\",\n      \"evidence\": \"Calcium manipulation, PKC\\u03b1 inhibition/knockdown, NUAK1 activity and MYC-dependent viability assays\",\n      \"pmids\": [\"29106388\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PKC\\u03b1 phospho-site on NUAK1 not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected NUAK1 to redox-driven oncogenesis, showing it promotes NRF2 nuclear import via PP1\\u03b2/AKT/GSK3\\u03b2 and is required for colorectal tumor maintenance.\",\n      \"evidence\": \"Genetic NUAK1 deletion in autochthonous colorectal cancer model, PP1\\u03b2/GSK3\\u03b2 assays, NRF2 fractionation and pharmacological inhibition\",\n      \"pmids\": [\"29500295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct NUAK1 substrate within the NRF2 import machinery not resolved beyond PP1\\u03b2\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established the basis of NUAK1 nucleocytoplasmic shuttling, identifying a bipartite NLS and importin-\\u03b2/IPO7/IPO9-dependent import inhibited by oxidative stress.\",\n      \"evidence\": \"NLS prediction/deletion mutants, importin knockdown, importazole, MS of NUAK1-importin interactions and immunofluorescence\",\n      \"pmids\": [\"31090959\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which oxidative stress blocks import not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a nuclear transcriptional-coupling function, showing NUAK1 phosphorylates the PP1 subunit PNUTS to sustain spliceosome activity and productive RNAPII elongation in MYC-driven cells.\",\n      \"evidence\": \"Nuclear fractionation, proximity proteomics, in vitro PNUTS phosphorylation, spliceosome and nascent RNA assays, RNAPII ChIP-seq and inhibitors\",\n      \"pmids\": [\"32006464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PNUTS phospho-sites not mapped\", \"Generality beyond MYC-transformed cells untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended NUAK1 into mTORC2/Akt signaling, showing it directly phosphorylates Akt Ser473 and regulates mTOR lysosome positioning.\",\n      \"evidence\": \"Co-IP with mTORC2 components, in vitro Akt phosphorylation, lysosome positioning and endosome fractionation\",\n      \"pmids\": [\"38135881\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with NUAK1 being downstream of Akt elsewhere unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Began dissecting compartment-specific metabolic roles, linking cytosolic NUAK1 to respiration/glycolysis and mitochondrial morphology.\",\n      \"evidence\": \"Subcellular fractionation, Seahorse respiration, ATP measurement and mitochondrial morphology imaging\",\n      \"pmids\": [\"32754444\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular substrate controlling mitochondrial morphology not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed NUAK1 maintains fibronectin-dependent ovarian cancer spheroid integrity downstream of LKB1.\",\n      \"evidence\": \"CRISPR NUAK1 KO, LKB1-NUAK1 phospho-assays, transcriptomics, fibronectin rescue and xenograft metastasis\",\n      \"pmids\": [\"32429240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking NUAK1 kinase activity to FN1 transcription unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected NUAK1 inhibition to immunogenic cell death via NRF2/ROS, revealing a mevalonate-pathway negative-feedback brake.\",\n      \"evidence\": \"Kinome-wide CRISPR screen, NRF2 reporters, ROS and ICD markers, simvastatin and cholesterol rescue\",\n      \"pmids\": [\"39824180\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NUAK1 substrate in this axis beyond NRF2 regulation not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified NUAK1 as a tau-stabilizing kinase, defining direct Ser356 phosphorylation as a therapeutic node in tauopathy.\",\n      \"evidence\": \"Cell and Drosophila genetic screens, in vitro/in vivo phospho-assays and mouse tauopathy haploinsufficiency\",\n      \"pmids\": [\"27720485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Ser356 phosphorylation stabilizes tau not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established NUAK1 as a core profibrotic kinase, defining a TGF-\\u03b2\\u2192NUAK1\\u2192YAP/SMAD positive feedback loop driving fibrosis across organs.\",\n      \"evidence\": \"Fibroblast-specific conditional KO, pharmacological inhibition and kidney/lung/liver fibrosis models\",\n      \"pmids\": [\"35320001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct NUAK1 substrate in the YAP/SMAD circuit not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined NUAK1 control of hnRNP A1 stress relocalization through phosphorylation in the F-peptide/M9 region.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, M9-motif mutagenesis, fractionation and caspase activation assays\",\n      \"pmids\": [\"35963429\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequences for specific mRNA targets not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified USP9X as the deubiquitinase that stabilizes and activates NUAK1 to drive myofibroblast transformation.\",\n      \"evidence\": \"Myofibroblast-specific USP9X KO, inhibition, co-IP and deubiquitination assays with Rho-kinase readouts\",\n      \"pmids\": [\"40310323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin-chain specificity and site on NUAK1 not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed NUAK1 sustains TGF-\\u03b2 signaling in hepatic stellate cells by suppressing Smurf2-mediated T\\u03b2RI/Smad4 degradation.\",\n      \"evidence\": \"HTH-01-015 inhibition, siRNA in HSC/hepatocytes, receptor stability assays and CCl4 liver fibrosis model\",\n      \"pmids\": [\"36361872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NUAK1 substrate controlling Smurf2 not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the PP1\\u03b2 effector axis to centrosome biology, showing NUAK1 governs PLK4-dependent centrosome duplication and genomic stability.\",\n      \"evidence\": \"NUAK1 inhibition/depletion in PDAC and fibroblasts, centrosome counting and MYPT1/PP1\\u03b2/GSK3\\u03b2/PLK4 pathway analysis\",\n      \"pmids\": [\"36975767\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NUAK1 loss causes amplification vs. failed duplication context-dependent\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked NUAK1 to ESCC metastasis through JNK/c-Jun-driven Slug transcription.\",\n      \"evidence\": \"Co-IP, Slug promoter luciferase, JNK/c-Jun inhibition and pulmonary metastasis model\",\n      \"pmids\": [\"37919754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase event upstream of JNK not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined the neuronal mechanism, showing NUAK1 controls axon branching through mitochondrial metabolism and the microprotein BRAWNIN, not just mitochondrial positioning.\",\n      \"evidence\": \"In vivo/in vitro NUAK1 KO neurons, mitochondrial and ATP assays, and BRAWNIN-based rescue\",\n      \"pmids\": [\"38514619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NUAK1 regulates BRAWNIN molecularly not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a redox-protective oncogenic substrate, showing NUAK1 phosphorylates NADK Ser64 to mitigate ROS and confer osimertinib resistance.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, NADK S64 mutagenesis, ROS measurement and xenograft\",\n      \"pmids\": [\"39159134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of NADK phosphorylation to NADP(H) pools not measured\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked NUAK1 to gastric cancer chemoresistance via a STAT5/GLI1 signaling axis.\",\n      \"evidence\": \"Depletion/inhibition, PDX and transgenic models, STAT5 activity and GLI1 stability assays with co-IP\",\n      \"pmids\": [\"38996065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NUAK1 phospho-target in the STAT5/GLI1 axis unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed NUAK1 promotes mitochondrial fission to support myeloma bioenergetics.\",\n      \"evidence\": \"Biallelic ARK5 KO, mitochondrial morphology imaging, fusion/fission protein blots and metabolic assays\",\n      \"pmids\": [\"38282096\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NUAK1 directly phosphorylates DRP1 not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked NUAK1 to MASH liver injury via caspase-6 activation and TAK1-RIPK1 regulation of pyroptosis.\",\n      \"evidence\": \"NUAK1 inhibition in MASH models, caspase-6 disruption and TAK1-RIPK1 co-IP/degradation assays\",\n      \"pmids\": [\"38967580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with earlier caspase-6 inhibition finding context-dependent\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the first NUAK1 crystal structure and exploited Glu139 to develop subnanomolar selective inhibitors, enabling cleaner mechanistic dissection.\",\n      \"evidence\": \"X-ray crystallography of a NUAK1 chimera and inhibitor co-crystal structures with SAR\",\n      \"pmids\": [\"39588908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Full-length, substrate-bound NUAK1 structure not obtained\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified PSD3 Ser476 as a direct NUAK1 substrate controlling ARF6 activity and dendritic spine maturation.\",\n      \"evidence\": \"ATP-analog-sensitive chemical genetics, direct phospho-assay, S476A mutant, ARF6/PI(4,5)P2 imaging and spine analysis (preprint)\",\n      \"pmids\": [\"42079242\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"In vivo relevance to circuit function untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a NUAK1-SON pathway controlling alternative splicing in developing cortical neurons.\",\n      \"evidence\": \"NUAK1 KO neurons, SON phosphorylation assays, RNA-seq splicing analysis and SON knockdown phenocopy (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.10.10.681550\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"SON phospho-sites not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked NUAK1 to immune evasion, showing it drives PD-L1 transcription via GSK3\\u03b2/\\u03b2-catenin in HCC.\",\n      \"evidence\": \"Gain/loss-of-function, p-GSK3\\u03b2/\\u03b2-catenin blots, nuclear fractionation and \\u03b2-catenin knockdown rescue\",\n      \"pmids\": [\"39901136\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NUAK1 substrate upstream of GSK3\\u03b2 not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether NUAK1's many context-specific outputs converge on a small set of direct substrates (e.g. the PP1\\u03b2-MYPT1 node) or reflect a broad, tissue-tuned substrate repertoire remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified substrate map across tissues\", \"Direct vs. PP1\\u03b2-indirect effects not systematically separated\", \"Compartment-specific (nuclear vs. cytoplasmic) substrate sets incompletely defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 4, 6, 13, 15, 19, 22, 34]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [2, 4, 8, 9, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 11, 21]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 13, 17]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [17, 18, 20]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 11, 14, 20]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 7, 9, 21]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 4, 30]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [13, 19, 35]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [11, 22, 25]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 16]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [15, 18, 28]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LKB1\", \"NDR2\", \"PP1\\u03b2-MYPT1\", \"PNUTS\", \"hnRNP A1\", \"p53\", \"USP9X\", \"NADK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}