{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNUAK1, an AMPK‐related kinase also known as ARK5, is a critical regulator of cellular metabolic homeostasis and survival. It is activated downstream of LKB1 and Akt signaling and functions to limit mTORC1‐mediated protein synthesis while preserving mitochondrial respiratory complex expression and efficient glutamine metabolism. These actions help maintain ATP levels during nutrient deprivation and oncogenic stress (for example, MYC deregulation), and NUAK1 can be further activated by upstream factors such as IGF‐1 through NDR2‐mediated phosphorylation as well as via calcium‐dependent pathways involving PKCα."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its metabolic functions, NUAK1 plays a pivotal role in regulating cancer cell adhesion, migration, and invasion. Post‐translational modifications, such as atypical polyubiquitination (which is counteracted by the deubiquitinating enzyme USP9X), and direct interactions with myosin phosphatase complexes allow NUAK1 to modulate cell detachment and cytoskeletal dynamics. NUAK1 also phosphorylates substrates like procaspase‐6—thereby inhibiting cell death signaling—and is subject to regulation by several microRNAs (for example, miR‐211 in melanoma, miR‐203 in head and neck cancer, and miR‐145‐5p in nasopharyngeal carcinoma). In diverse tumor types including colorectal, non‐small cell lung, gastric, breast cancer, multiple myeloma, and hepatocellular carcinoma, elevated NUAK1 expression correlates with enhanced invasive behavior and poorer clinical outcome, highlighting its potential as a prognostic biomarker and therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNUAK1 also contributes to cell cycle regulation and stress responses. It promotes cellular senescence through phosphorylation of targets such as LATS1, thereby affecting genomic stability and ploidy, and it can interact with p53 to induce cell cycle arrest via p21 upregulation. In neuronal contexts, NUAK1 phosphorylates tau at Ser356 to enhance its stability, implicating it in tau‐associated neurodegeneration. Furthermore, upon oxidative stress, NUAK1 facilitates the nuclear import of the antioxidant regulator NRF2, which in turn activates protective transcriptional programs against oxidative damage."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Atsushi Suzuki, Gen-Ichi Kusakai, Atsuhiro Kishimoto, et al. 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