| 2013 |
LKB1 directly activates NUAK1 kinase, and the LKB1-NUAK1 pathway controls axon branching in cortical neurons by promoting mitochondria immobilization at nascent presynaptic sites; conditional deletion of LKB1 or NUAK1 knockdown drastically reduces axon branching in vivo, while overexpression increases branching, and manipulation of Syntaphilin (a mitochondrial anchor) phenocopies NUAK1 effects. |
Conditional knockout, in utero knockdown/overexpression, live imaging, Syntaphilin genetic manipulation in mouse cortical neurons |
Cell |
High |
23791179
|
| 2016 |
NUAK1 phosphorylates tau at Ser356, stabilizing tau protein levels; inhibition of NUAK1 in Drosophila suppresses neurodegeneration in tau-expressing flies, and NUAK1 haploinsufficiency rescues tauopathy phenotypes in a mouse model. |
Cell-based and Drosophila genetic screens, in vitro phosphorylation assay, tauopathy mouse model |
Neuron |
High |
27720485
|
| 2003 |
ARK5/NUAK1 suppresses cell death (induced by nutrient starvation, TRAIL, and TNF-α) by inhibiting caspase 8 activation, delaying Bid cleavage and FLIP degradation. |
Overexpression in HepG2 cells, Western blot for caspase 8 activation, Bid cleavage, FLIP degradation |
Oncogene |
Medium |
13679856
|
| 2004 |
ARK5/NUAK1 directly phosphorylates caspase-6 at Ser257 in vitro, preventing procaspase-6 activation and thereby suppressing Fas-mediated cell death in colorectal cancer cells; mutation of Ser257 to Ala abolishes this protection. |
In vitro kinase assay with wild-type and S257A mutant caspase-6, antisense RNA knockdown, Western blot |
Oncogene |
High |
15273717
|
| 2004 |
ARK5/NUAK1 is activated downstream of Akt and promotes tumor invasion by inducing activation of MMP-2, MMP-9, and MT1-MMP via rapamycin-sensitive signaling; ARK5 overexpression in PANC-1 cells leads to invasion and metastasis in nude mice. |
Matrigel invasion assay, nude mouse xenograft, Western blot for MMP activation, pharmacological inhibition |
Molecular and cellular biology |
Medium |
15060171
|
| 2006 |
NDR2 kinase phosphorylates ARK5/NUAK1 at Thr211 on the T-loop during IGF-1 signaling, providing full kinase activation; Akt phosphorylates ARK5 at Ser600 in the regulatory domain, and combined phosphorylation at T211 (by NDR2) and S600 (by Akt) is required for full ARK5 activity. |
In vitro kinase assay, mutant constructs, co-immunoprecipitation, IGF-1 stimulation in colorectal cancer cells |
The Journal of biological chemistry |
High |
16488889
|
| 2005 |
ARK5/NUAK1 is transcriptionally regulated by the Large-MAF family transcription factors (c-MAF and MAFB) through MAF-recognition element (MARE) sequences in the ARK5 promoter; ARK5 mediates IGF-1-induced cell invasion in multiple myeloma. |
Chromatin immunoprecipitation, promoter reporter assay with MARE deletion/mutation, gene expression profiling |
Oncogene |
High |
16044163
|
| 2009 |
NUAK1 phosphorylates LATS1 at Ser464, promoting its degradation and thereby controlling cellular ploidy and senescence; NUAK1 overexpression triggers premature senescence and aneuploidies, while a dominant-negative LATS1 phenocopies NUAK1 effects. |
Loss-of-function screen, shRNA depletion, overexpression, in vitro kinase assay for LATS1 phosphorylation |
The EMBO journal |
High |
19927127
|
| 2011 |
NUAK1 directly interacts with and phosphorylates p53 in vitro and in vivo in a LKB1-dependent manner; phosphorylation of NUAK1 at Thr211 by LKB1 is required for NUAK1 kinase activity; the LKB1/NUAK1/p53 axis induces G1/S cell cycle arrest via p21/WAF1 and NUAK1 associates with p53 in the nucleus at the p21 promoter. |
Co-immunoprecipitation, in vitro kinase assay, chromatin immunoprecipitation, cell cycle analysis |
Oncogene |
High |
21317932
|
| 2012 |
Muscle-specific knockout of NUAK1 prevents high-fat diet-induced glucose intolerance; NUAK1 suppresses insulin signaling by promoting phosphorylation of IRS1 at Ser1097; loss of NUAK1 enhances phosphorylation of IRS1 Tyr608, AKT Thr308, and TBC1D4 Thr649, improving glucose uptake. |
Muscle-specific knockout mice, glucose tolerance test, quantitative phosphoproteomics of soleus muscle |
The Journal of biological chemistry |
High |
22418434
|
| 2012 |
NUAK1 and NUAK2 together (but not individually) are required for apical constriction and apico-basal elongation during dorsolateral hinge point formation in neural plate; double mutants show defective apical concentration of phosphorylated myosin light chain 2, F-actin, and cortactin, causing neural tube defects. |
Double knockout mouse model, immunofluorescence for cytoskeletal markers |
Developmental dynamics |
Medium |
22689267
|
| 2014 |
NUAK1 expression is controlled through the cell cycle by CDK phosphorylation at Ser445, which triggers PLK1 binding; PLK1 then phosphorylates NUAK1 at Ser476 and Ser480, promoting binding to βTrCP and SCFβTrCP-mediated ubiquitylation and degradation; NUAK1 inhibits the PP1β-MYPT1 phosphatase complex and thereby promotes PLK1 T-loop phosphorylation at Thr210, establishing a reciprocal regulatory loop. |
Biochemical fractionation, co-immunoprecipitation, in vitro phosphorylation, ubiquitylation assay, NUAK1 inhibitors (WZ4003, HTH-01-015), site-directed mutagenesis |
The Biochemical journal |
High |
24785407
|
| 2013 |
NUAK1 is a direct target of miR-211, which is regulated by the MITF transcription factor; miR-211 suppresses NUAK1 expression and promotes melanoma cell adhesion, thereby inhibiting the invasive program. |
miRNA overexpression/inhibition, luciferase reporter assay for 3'UTR targeting, adhesion assays |
The Journal of investigative dermatology |
Medium |
23934065
|
| 2018 |
NUAK1 is activated by oxidative stress and facilitates nuclear import of the antioxidant master regulator NRF2 by coordinating PP1β inhibition with AKT activation to suppress GSK3β-dependent inhibition of NRF2 nuclear import; deletion of NUAK1 suppresses colorectal tumor formation and causes regression of established tumors. |
NUAK1 conditional knockout, autochthonous colorectal tumor models, Western blot for PP1β, AKT, GSK3β, NRF2 nuclear fractionation |
Cancer discovery |
High |
29500295
|
| 2020 |
NUAK1 is a predominantly nuclear kinase that phosphorylates PNUTS (a nuclear regulatory subunit of PP1) to locally inhibit PP1 activity; NUAK1-PNUTS interaction is required for chromatin association of PNUTS, spliceosome activity, and nascent RNA synthesis; in MYC-overexpressing cells, NUAK1 inhibition causes global RNAPII accumulation at the pause site and first exon-intron boundary without increasing mRNA synthesis. |
Nuclear/cytoplasmic fractionation, co-immunoprecipitation of PP1 interactor network, in vitro kinase assay of PNUTS, NUAK1 inhibition, RNAPII ChIP, nascent RNA synthesis assay |
Molecular cell |
High |
32006464
|
| 2022 |
TGF-β induces rapid NUAK1 upregulation in fibroblasts; NUAK1 in turn promotes YAP/TAZ and TGF-β/SMAD profibrotic signaling; activated YAP/TAZ further induces NUAK1 expression, creating a positive feedback loop; fibroblast-specific loss or pharmacological inhibition of NUAK1 markedly attenuates kidney, lung, and liver fibrosis in mouse models. |
Fibroblast-specific NUAK1 knockout, mouse models of organ fibrosis, Western blot for SMAD/YAP signaling, pharmacological inhibition |
Science translational medicine |
High |
35320001
|
| 2019 |
NUAK1 nuclear import is mediated by a bipartite nuclear localization signal at its N-terminal domain and requires importin-β members KPNB1, IPO7, and IPO9; oxidative stress induces NUAK1 cytoplasmic accumulation by affecting its nuclear transport. |
Cell fractionation, mass spectrometry identification of importin interactors, importin-β knockdown, Importazole treatment, NLS mutant constructs |
Journal of cellular biochemistry |
Medium |
31090959
|
| 2017 |
In tumor cells lacking LKB1, NUAK1 kinase activity is maintained by an alternative calcium-dependent pathway involving PKCα activation; calcium/PKCα-dependent NUAK1 activation supports AMPK-TORC1 metabolic checkpoint engagement, protecting tumor cells from MYC-driven cell death; MYC transcriptionally regulates PKCα and ITPR to promote this pathway. |
LKB1-null cell models, PKCα knockdown/inhibition, calcium manipulation, MYC transcriptomics, TORC1 signaling assays |
Oncogene |
Medium |
29106388
|
| 2020 |
Cytosolic NUAK1 increases ATP production by enhancing mitochondrial respiration; NUAK1 inhibition leads to mitochondrial morphology changes ('donut-like' structures); nuclear NUAK1 is involved in the metabolic switch to glycolysis; NUAK1 subcellular localization differentially affects metabolic outcomes in cancer cells. |
Subcellular fractionation, mitochondrial respiration assays, ATP measurements, live-cell imaging of mitochondrial morphology, NUAK1 inhibition |
Frontiers in oncology |
Medium |
32754444
|
| 2024 |
NUAK1 deficiency significantly impairs mitochondrial metabolism and axonal ATP concentration in cortical neurons; upregulation of mitochondrial function rescues axon branching defects in NUAK1-null neurons in vitro and in vivo; NUAK1 regulates axon branching through the mitochondria-targeted microprotein BRAWNIN, demonstrating a dual function controlling both mitochondrial distribution and metabolic activity. |
NUAK1 conditional knockout, mitochondrial function assays, ATP biosensors, BRAWNIN knockdown/overexpression, in vivo axon branching quantification |
Nature communications |
High |
38514619
|
| 2020 |
LKB1 phosphorylates and stabilizes NUAK1 in ovarian cancer spheroids; NUAK1 loss reduces spheroid integrity and fibronectin (FN1) expression (745-fold decrease); fibronectin is required for compact spheroid formation and metastasis; NUAK1 loss extends survival in a xenograft model of intraperitoneal metastasis. |
NUAK1 knockout, transcriptome analysis, fibronectin rescue experiments, xenograft metastasis model |
Cancers |
Medium |
32429240
|
| 2022 |
ARK5/NUAK1 directly interacts with and phosphorylates hnRNP A1 on serine residues within the F-peptide region; the M9 motif of hnRNP A1 is required for ARK5 interaction and phosphorylation; ARK5-mediated phosphorylation controls hnRNP A1 cytoplasmic relocalization during hypertonic stress; ARK5 silencing increases Bcl-xL expression and delays caspase activation. |
Co-immunoprecipitation, in vitro kinase assay, RNAi-based kinome screen, flow cytometry for caspase activation |
The Journal of biological chemistry |
High |
35963429
|
| 2023 |
NUAK1 governs accurate centrosome duplication via MYPT1/PP1β and GSK3β-dependent regulation of PLK4; loss of NUAK1 triggers genomic instability in both pancreatic cancer cells and primary fibroblasts. |
NUAK1 inhibition/depletion, centrosome counting, genomic instability assays, pathway analysis in PDAC cells |
Molecular oncology |
Medium |
36975767
|
| 2023 |
NUAK1 promotes metastasis in esophageal squamous cell carcinoma by activating the JNK/c-Jun pathway, which upregulates Slug transcription; silencing Slug completely abolishes NUAK1-overexpression-driven migration and invasion. |
Co-immunoprecipitation, immunofluorescence, dual-luciferase reporter gene assay for Slug promoter, in vivo pulmonary metastasis model |
Cancer cell international |
Medium |
37919754
|
| 2024 |
NUAK1 directly phosphorylates NADK (nicotinamide adenine dinucleotide kinase) at Ser64, reducing ROS accumulation and thereby conferring osimertinib resistance in NSCLC; genetic or pharmacological blockade of NUAK1 restores osimertinib sensitivity. |
In vitro kinase assay identifying NADK S64 phosphorylation, NUAK1 knockdown/overexpression, ROS measurements, in vitro and in vivo drug sensitivity assays |
Cancer research |
High |
39159134
|
| 2023 |
NUAK1 interacts with mTORC2 components and regulates mTORC2-dependent Akt activation by controlling lysosome positioning and mTOR association with lysosomes; NUAK1 also directly phosphorylates Akt at Ser473; NUAK1 is associated with early endosomes and selectively promotes Akt/FOXO1/3a signaling but not Akt/TSC2 signaling. |
Co-immunoprecipitation of mTORC2 components, in vitro kinase assay for Akt S473, lysosome positioning assay, subcellular fractionation, Akt substrate phosphorylation analysis |
Cell & bioscience |
Medium |
38135881
|
| 2024 |
NUAK1 upregulates GLI1 expression by activating STAT5-mediated transcription and stabilizing GLI1 protein; depletion or inhibition of NUAK1 impairs cancer cell expansion and tumor formation via the NUAK1/STAT5/GLI1 axis in gastric cancer. |
Patient-derived xenograft, transgenic mouse model, siRNA knockdown, pharmacological inhibition, Western blot and reporter assays for STAT5/GLI1 |
Cell reports |
Medium |
38996065
|
| 2020 |
In yeast, Tda1 (the ortholog of human NUAK1) directly phosphorylates histone H3 at Thr11 upon low glucose stress; yeast AMPK (Snf1) phosphorylates Tda1 to govern its activity, while CK2 regulates Tda1 nuclear localization; AMPK and CK2 signaling converge on histone kinase Tda1 to link glucose stress to chromatin regulation. |
In vitro kinase assay, H3pT11 ChIP, mutant analysis, epistasis in budding yeast |
eLife |
High |
33372657
|
| 2025 |
USP9X deubiquitinates and thereby activates ARK5/NUAK1; USP9X-activated NUAK1 promotes TGF-β1-induced myofibroblast transformation via the Rho kinase pathway; myofibroblast-specific USP9X knockout or pharmacological inhibition reduces NUAK1 activity and attenuates cardiac fibrosis. |
Co-immunoprecipitation, USP9X knockout (myofibroblast-specific), in vivo myocardial infarction model, Western blot for NUAK1 ubiquitination/activation and Rho kinase pathway |
JACC. Basic to translational science |
Medium |
40310323
|
| 2024 |
ARK5/NUAK1 regulates mitochondrial morphological dynamics, promoting fission over fusion in multiple myeloma cells; ARK5 knockout cells show enhanced mitochondrial fusion, reduced phosphorylation of DRP1 at Ser616, higher MFN1/MFN2 expression, lower ATP, higher lactate, and higher ROS levels. |
Biallelic ARK5 knockout in myeloma cell lines, mitochondrial morphology imaging, Western blot for DRP1/MFN1/MFN2, ATP and lactate measurements |
Cell death discovery |
Medium |
38282096
|
| 2021 |
NUAK1 facilitates nuclear import of NRF2 by inhibiting PP1β, which leads to AKT activation and suppression of GSK3β-dependent phosphorylation of NRF2, thus reducing GSK3β-mediated inhibition of NRF2 nuclear import; silencing NUAK1 upregulates PP1β and downregulates phospho-GSK3βSer9, suppressing NRF2 nuclear accumulation and GPX4 expression. |
siRNA knockdown, Western blot for PP1β, p-GSK3βSer9, NRF2 nuclear fractionation, NUAK1 agonist rescue experiment |
Aging |
Medium |
33819186
|
| 2018 |
Haploinsufficiency of NUAK1 in mice impairs cortical axon branching and leads to behavioral deficits including defective spatial memory consolidation, impaired social novelty, and abnormal sensorimotor gating, confirming NUAK1 as a haploinsufficient autism spectrum disorder candidate gene. |
NUAK1 heterozygous knockout mice, cortical connectivity analysis, behavioral test battery |
Nature communications |
High |
30327473
|
| 2024 |
NUAK1 promotes PD-L1 transcription in hepatocellular carcinoma by phosphorylating GSK3β at Ser9, which activates β-catenin nuclear accumulation and PD-L1 gene expression; knockdown of β-catenin reverses NUAK1-mediated PD-L1 upregulation. |
Gain and loss of function experiments, Western blot and immunofluorescence for GSK3β/β-catenin/PD-L1, β-catenin knockdown rescue, IHC of patient samples |
Molecular medicine (Cambridge, Mass.) |
Medium |
39901136
|
| 2025 |
NUAK1 is present in human erythrocytes and undergoes increased phosphorylation in P. falciparum-infected cells; NUAK1 inhibition reduces MYPT1 phosphorylation in erythroid cells; genetic overexpression of NUAK1 in erythroid cells partially rescues both signaling and parasite invasion phenotypes caused by NUAK1 inhibitors. |
Chemoproteomic profiling confirming inhibitor selectivity, phosphoproteomic analysis, NUAK1 overexpression in erythroid cells, P. falciparum invasion assays |
bioRxiv (PMID available: 41278793)preprint |
Medium |
41278793
|
| 2025 |
NUAK1 phosphorylates the splicing co-factor SON, regulating a conserved set of alternative splicing events in genes crucial for neurodevelopment in cortical neurons; SON is required for proper cortical neuron development consistent with ZTTK syndrome phenotypes. |
NUAK1 conditional knockout in cortical neurons, RNA splicing analysis, identification of SON as phosphorylation substrate, SON knockdown |
bioRxivpreprint |
Medium |
|
| 2024 |
NUAK1 kinase activity correlates with MYPT1 phosphorylation at Ser445 and Ser910 in vascular smooth muscle cells; NUAK1 knockdown decreases myosin light chain phosphorylation, potentially by increasing MYPT1 phosphatase activity, reducing contractility and altering F-actin cytoskeletal organization. |
Phosphoproteomic analysis, NUAK1 knockdown, pMLC and MYPT1 phosphorylation Western blot, impedance-based contraction assay |
bioRxivpreprint |
Low |
|
| 2024 |
First crystal structures of a NUAK1 chimeric protein were determined, providing structural insights into inhibitor binding modes and identifying a unique glutamate residue (Glu139) that can be exploited for selective NUAK1 targeting. |
X-ray crystallography of NUAK1 chimeric protein with bound inhibitors |
Journal of medicinal chemistry |
Medium |
39588908
|
| 2022 |
ARK5/NUAK1 prevents degradation of TGF-β type I receptor (TβRI) and Smad4 proteins by inhibiting Smurf2 expression in hepatic stellate cells, thereby maintaining TGF-β signaling; in hepatocytes, ARK5 induces EMT and promotes inflammatory cytokine secretion, synergistically driving liver fibrosis. |
ARK5 knockdown in HSCs and hepatocytes, Western blot for TβRI/Smad4/Smurf2, mouse CCl4-fibrosis model with HTH-01-015 inhibitor |
International journal of molecular sciences |
Medium |
36361872
|
| 2024 |
NUAK1 promotes pyroptosis and inflammation in MASH by activating Caspase 6; NUAK1/Caspase 6 axis inhibition accelerates the interaction between TAK1 and RIPK1, leading to RIPK1 degradation and suppression of hepatic inflammation. |
NUAK1 inhibition in vivo and in vitro MASH models, Western blot for Caspase 6, TAK1, RIPK1, caspase 6 disruption experiments |
Hepatology communications |
Medium |
38967580
|