NUAK1

Official Full Name

NUAK family kinase 1

Organism

Homo sapiens

GeneID

9891

Background

Enables p53 binding activity and protein serine/threonine kinase activity. Involved in protein phosphorylation; regulation of cell adhesion; and regulation of cellular senescence. Located in cytoplasm; microtubule cytoskeleton; and nuclear lumen. Implicated in uterine fibroid. Biomarker of uterine fibroid. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

ARK5;

Bio Chemical Class

Kinase

Protein Sequence

MEGAAAPVAGDRPDLGLGAPGSPREAVAGATAALEPRKPHGVKRHHHKHNLKHRYELQETLGKGTYGKVKRATERFSGRVVAIKSIRKDKIKDEQDMVHIRREIEIMSSLNHPHIISIYEVFENKDKIVIIMEYASKGELYDYISERRRLSERETRHFFRQIVSAVHYCHKNGVVHRDLKLENILLDDNCNIKIADFGLSNLYQKDKFLQTFCGSPLYASPEIVNGRPYRGPEVDSWALGVLLYTLVYGTMPFDGFDHKNLIRQISSGEYREPTQPSDARGLIRWMLMVNPDRRATIEDIANHWWVNWGYKSSVCDCDALHDSESPLLARIIDWHHRSTGLQADTEAKMKGLAKPTTSEVMLERQRSLKKSKKENDFAQSGQDAVPESPSKLSSKRPKGILKKRSNSEHRSHSTGFIEGVVGPALPSTFKMEQDLCRTGVLLPSSPEAEVPGKLSPKQSATMPKKGILKKTQQRESGYYSSPERSESSELLDSNDVMGSSIPSPSPPDPARVTSHSLSCRRKGILKHSSKYSAGTMDPALVSPEMPTLESLSEPGVPAEGLSRSYSRPSSVISDDSVLSSDSFDLLDLQENRPARQRIRSCVSAENFLQIQDFEGLQNRPRPQYLKRYRNRLADSSFSLLTDMDDVTQVYKQALEICSKLN

Open

Approved Drug

Clinical Trial Drug

Discontinued Drug

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Detailed Information

The NUAK1 (NUAK Family Kinase 1) gene is located at chromosome 12q23.3 in humans and encodes a serine/threonine kinase consisting of 661 amino acids. It belongs to the AMP-activated protein kinase (AMPK)-related kinase family. Its structure comprises a kinase domain (which mediates phosphorylation) and a C-terminal regulatory domain (which binds to the MYPT1-PP1 complex). Activation of NUAK1 depends on upstream kinases such as AKT1 and LKB1, which phosphorylate the Thr211 residue, thereby regulating multiple downstream pathways:

Cell Cycle and Apoptosis: NUAK1 phosphorylates p53 at Ser15 and Ser392, thereby enhancing p53-mediated transcription of CDKN1A (p21), which leads to G1-phase arrest. It also phosphorylates CASP6, inhibiting its activation and antagonizing Fas-dependent apoptosis.
Energy Stress Response: Under glucose deprivation, NUAK1 suppresses the Hippo pathway by inhibiting LATS1 kinase (phosphorylated at Ser464), promoting YAP nuclear translocation and glycolytic gene expression, thus driving the Warburg effect.
DNA Damage Repair: In response to UV irradiation, NUAK1 cooperates with STK11 to activate CDKN1A phosphorylation, promoting its degradation to release DNA repair factors.

Figure 1. Structural alignment of NUAK1 and NUAK2. (Skalka GL, et al., 2024)

Physiological and Pathological Significance

NUAK1 displays dual roles in tumor progression:

Oncogenic Effects:

Gastric Cancer: In a study of 117 gastric adenocarcinoma samples, NUAK1 expression was significantly higher in tumor tissues compared to adjacent normal tissues and positively correlated with TNM stage. High NUAK1 expression was associated with a 5-year overall survival rate of only 19%, serving as an independent prognostic factor. Mechanistically, NUAK1 enhances tumor cell migration by phosphorylating PPP1R12A (a subunit of myosin phosphatase), thereby inhibiting MLC2 dephosphorylation.

Endometrial Cancer: NUAK1 is overexpressed in poorly differentiated endometrial carcinomas and promotes epithelial–mesenchymal transition (EMT) and lymph node metastasis through the ERK/STAT3 pathway.

Tumor-Suppressive Potential:In high-grade chondrosarcomas, NUAK1 is activated by the JAK3/STAT1 axis and induces caspase-dependent apoptosis, indicating a tissue-specific functional divergence.

Clinical Applications and Challenges

Induction of Immunogenic Cell Death (ICD): A genome-wide CRISPR-Cas9 kinase screen revealed that NUAK1 inhibition downregulates NRF2-mediated antioxidant genes, leading to reactive oxygen species (ROS) accumulation and endoplasmic reticulum (ER) stress. This triggers the release of damage-associated molecular patterns (DAMPs) such as HMGB1 and ATP, activating the dendritic cell–T cell antitumor immune axis.

Cholesterol Metabolism Feedback:ER stress triggered by ICD activates XBP1s, which upregulates the mevalonate pathway and enhances cholesterol synthesis. Due to its antioxidant properties, cholesterol neutralizes ROS, reducing the efficacy of NUAK1 inhibitors.

Combination Therapy Strategy: Co-administration of NUAK1 inhibitors with statins (e.g., simvastatin) blocks compensatory cholesterol synthesis, significantly enhancing CD8⁺ T cell and NK cell infiltration. In mouse models, a triple combination therapy (NUAK1 inhibitor + simvastatin + anti-PD-1 antibody) resulted in a tumor regression rate of 70%. Notably, this effect was reversed by a high-cholesterol diet.

Challenges in clinical translation include the potential of statins to inhibit T cell proliferation, as cholesterol is essential for membrane biosynthesis, necessitating optimized dosing schedules. Additionally, NUAK1's role in normal metabolic regulation—such as hepatic gluconeogenesis—may pose risks of off-target toxicity.

Future Directions

Key areas of focus in NUAK1 research include:

Tissue-Specific Delivery Systems:Development of GalNAc-conjugated NUAK1 siRNAs to enable liver-targeted gene silencing while avoiding systemic side effects.
Biomarker Development: Single-cell sequencing has identified a NUAK1^high/TREM2⁺ macrophage subset associated with chemotherapy resistance in gastric cancer (hazard ratio HR = 2.31), which may serve as a predictive biomarker for personalized therapy.
Novel Allosteric Inhibitors: The compound MTX-115, targeting the C-terminal regulatory domain of NUAK1, has demonstrated blood–brain barrier permeability in animal models, offering therapeutic potential for glioblastoma.

References:

van de Vis RAJ, Moustakas A, van der Heide LP. NUAK1 and NUAK2 Fine-Tune TGF-β Signaling. Cancers (Basel). 2021 Jul 5;13(13):3377.
Skalka GL, Whyte D, Lubawska D, et al. NUAK: never underestimate a kinase. Essays Biochem. 2024 Nov 18;68(3):295-307.

Quick Inquiry

Interested in learning more?

Contact us today for a free consultation with the scientific team and discover how Creative Biogene can be a valuable resource and partner for your organization.

Request a quote today!

Inquiry