{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNUAK2, also known as SNARK, is an AMP‐activated protein kinase–related kinase that is rapidly induced in response to diverse metabolic stressors. It is activated by stimuli such as glucose deprivation, muscle contraction, and even ultraviolet irradiation, thereby promoting insulin‐independent glucose transport and enhancing cellular survival. In addition, NUAK2 upregulation by death receptor (CD95) and inflammatory signals like TNFα contributes to its anti‐apoptotic and stress‐adaptation roles, with effects that extend to modulation of viral replication."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in metabolic homeostasis, NUAK2 plays a key part in regulating cytoskeletal dynamics and cell shape. It achieves this by interacting with cytoskeletal regulators—such as MRIP—to promote myosin regulatory light chain phosphorylation and maintain actin stress fiber assembly. Furthermore, a conserved nuclear localization signal enables NUAK2 to modulate gene transcription, and its proper activity is essential for developmental processes including neural tube closure, where it appears to influence Hippo signaling and the organization of the actomyosin network."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDeregulation of NUAK2 is increasingly recognized as an important factor in oncogenesis and tumor progression. Its genomic amplification in melanomas and acral tumors has been linked to enhanced cell proliferation, migration, and resistance to apoptosis, while aberrant NUAK2 expression in glioblastoma, cervical cancer, and breast cancer—often mediated by disruptions in microRNA or circular RNA regulatory networks—further underscores its oncogenic potential. In some tumor cells, upregulation of NUAK2 in response to viral proteins (e.g. EBV LMP1) also confers drug resistance, and recent findings indicate that NUAK2 influences immune cell differentiation by restricting T‐cell effector responses. 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"}, {"type": "b", "children": [{"type": "t", "text": "Identification of SNF1/AMP kinase-related kinase as an NF-kappaB-regulated anti-apoptotic kinase involved in CD95-induced motility and invasiveness."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M404334200"}], "href": "https://doi.org/10.1074/jbc.M404334200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15345718"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15345718"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Hiroyuki Yamamoto, Seiji Takashima, Yasunori Shintani, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Regulation of skeletal muscle sucrose, non-fermenting 1/AMP-activated protein kinase-related kinase (SNARK) by metabolic stress and diabetes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetologia (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00125-009-1465-x"}], "href": "https://doi.org/10.1007/s00125-009-1465-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19652946"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19652946"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Ho-Jin Koh, Taro Toyoda, Nobuharu Fujii, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sucrose nonfermenting AMPK-related kinase (SNARK) mediates contraction-stimulated glucose transport in mouse skeletal muscle."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1008131107"}], "href": "https://doi.org/10.1073/pnas.1008131107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20713714"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20713714"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Kaku Goto, Wenyu Lin, Leiliang Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The AMPK-related kinase SNARK regulates hepatitis C virus replication and pathogenesis through enhancement of TGF-β signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hepatol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jhep.2013.06.025"}], "href": "https://doi.org/10.1016/j.jhep.2013.06.025"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23831117"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23831117"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Wataru Kuga, Katsuya Tsuchihara, Tsutomu Ogura, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nuclear localization of SNARK; its impact on gene expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2008.10.143"}], "href": "https://doi.org/10.1016/j.bbrc.2008.10.143"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18992219"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18992219"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Tea Vallenius, Kari Vaahtomeri, Bianca Kovac, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "NUAK2 silencing inhibits the proliferation, migration and epithelial‑to‑mesenchymal transition of cervical cancer cells via upregulating CYFIP2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Med Rep (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/mmr.2021.12457"}], "href": "https://doi.org/10.3892/mmr.2021.12457"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34558636"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34558636"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Ritian Lin, Wei Wu, Huimin Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "GPR65 promotes intestinal mucosal Th1 and Th17 cell differentiation and gut inflammation through downregulating NUAK2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Transl Med (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ctm2.771"}], "href": "https://doi.org/10.1002/ctm2.771"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35343079"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35343079"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Yijun Dai, Wenjian Shi, Yanru Qiu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Circ_0000033 up-regulates NUAK2 by sequestering miR-378a-3p to promote breast tumorigenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Environ Mol Mutagen (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/em.22558"}], "href": "https://doi.org/10.1002/em.22558"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37357410"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37357410"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Vibhu Prasad, Berati Cerikan, Yannick Stahl, et al. 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