Alternative titles; symbols
HGNC Approved Gene Symbol: NUAK1
Cytogenetic location: 12q23.3 Genomic coordinates (GRCh38) : 12:106,063,345-106,138,954 (from NCBI)
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1998) cloned KIAA0537. The deduced 661-amino acid protein shares about 52% identity over 252 amino acids with plant SNF1-related protein kinase (605705). The KIAA0537 protein had an apparent molecular mass of about 75 kD by SDS-PAGE. RT-PCR detected highest expression in heart and brain, followed by skeletal muscle, kidney, ovary, placenta, lung, and liver. Little to no expression was detected in other tissues examined.
Suzuki et al. (2003) found that an antibody directed against SNARK (608131) cross-reacted with a 74-kD protein that they called ARK5. By screening databases, they determined that KIAA0537 and ARK5 are identical. Overall, SNARK and ARK5 share 55% amino acid homology, including 84% similarity within the N-terminal catalytic domains. ARK5 also shares significant homology with several other AMP-activated protein kinases, including AMPK-alpha-1 (PRKAA1; 602739), AMPK-alpha-2 (PRKAA2; 600497), and MELK (607025).
By in vitro assay of ARK5 expressed by transfected HepG2 colon cancer cells, Suzuki et al. (2003) demonstrated phosphorylation of a synthetic test peptide. The phosphorylation was stimulated by AMP and did not require accessory binding proteins. Transfection of ARK5 also increased the survival of HepG2 cells exposed to glucose starvation and reduced oxygen tension. Increased cell survival was accompanied by phosphorylation of ARK5 on ser600 by AKT (see 164730), which activated ARK5 kinase activity. Activated ARK5 phosphorylated ATM (607585), which led to phosphorylation of p53 (191170). The authors proposed that ARK5 is a tumor cell survival factor that is activated by AKT and acts as an ATM kinase under conditions of nutrient starvation.
Liu et al. (2012) showed in human and murine cell lines that oncogenic levels of MYC (190080) establish a dependence on ARK5 for maintaining metabolic homeostasis and for cell survival. ARK5 is an upstream regulator of AMPK and limits protein synthesis via the mTOR complex-1 (see 601231) signaling pathway. ARK5 also maintains expression of mitochondrial respiratory chain complexes and respiratory capacity, which is required for efficient glutamine metabolism. Inhibition of ARK5 leads to a collapse of cellular ATP levels in cells expressing deregulated MYC, inducing multiple proapoptotic responses as a secondary consequence. Depletion of ARK5 prolonged survival in MYC-driven mouse models of hepatocellular carcinoma, demonstrating that targeting cellular energy homeostasis is a valid therapeutic strategy to eliminate tumor cells that express deregulated MYC.
By radiation hybrid analysis, Nagase et al. (1998) mapped the NUAK1 gene to chromosome 12.
Liu, L., Ulbrich, J., Muller, J., Wustefeld, T., Aeberhard, L., Kress, T. R., Muthalagu, N., Rycak, L., Rudalska, R., Mull, R., Kempa S., Zender, L., Eilers, M., Murphy, D. J. Deregulated MYC expression induces dependence upon AMPK-related kinase 5. Nature 483: 608-612, 2012. [PubMed: 22460906] [Full Text: https://doi.org/10.1038/nature10927]
Nagase, T., Ishikawa, K., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 5: 31-39, 1998. [PubMed: 9628581] [Full Text: https://doi.org/10.1093/dnares/5.1.31]
Suzuki, A., Kusakai, G., Kishimoto, A., Lu, J., Ogura, T., Lavin, M. F., Esumi, H. Identification of a novel protein kinase mediating Akt survival signaling to the ATM protein. J. Biol. Chem. 278: 48-53, 2003. [PubMed: 12409306] [Full Text: https://doi.org/10.1074/jbc.M206025200]