The human NUAK1 gene is composed of seven exons and spans approximately 76.7 kbp of genomic DNA.

The human NUAK1 gene encodes a 6828-bp mRNA. The coding region contains 1986 bp. Three short splice variants (547-569 bp) have been reported.

No pseudogenes are known.

NUAK1 protein consists of 661 amino acids and has a molecular weight of 74 kDa (Nagase et al., 1998). NUAK1 contains a serine/threonine-protein kinase domain at its N-terminus that is conserved among AMPKalphas and AMPK-related kinases (AMPK-RKs) (Manning et al., 2002). The same as the AMPKalphas and most other AMPK-RKs, NUAK1 can be phosphorylated by tumor suppressor LKB1 at a conserved threonine residue (corresponding to Thr-211 in NUAK1) in the T-loop of the catalytic domain, which activates the kinase activity of NUAK1 (Lizcano et al., 2004). The phosphorylation at Thr-211 is prevented by atypical Lys29/ Lys33-linked polyubiquitin chains, which can be removed by the de-ubiquitinating enzyme USP9X (Al-Hakim et al., 2008).

NUAK1 is preferentially expressed in highly oxidative tissues such as cerebrum, heart, and soleus muscle in human and mouse (Nagase et al., 1998; Inazuka et al., 2012). In mouse embryogenesis, NUAK1 is prominently expressed in the neuroectoderm during neurulation, and in the cerebral cortex after the late embryonic stage (Ohmura et al., 2012; Courchet et al., 2013). In C2C12 mouse myoblasts, NUAK1 is increasingly expressed as the cells differentiate into myotubes (Niesler et al., 2007). The elevated expression of NUAK1 has been observed in clinical samples obtained from colorectal cancers, pancreatic cancers, hepatocellular carcinomas, gliomas, and angioimmunoblastic T-cell lymphomas (Kusakai et al., 2004a; Morito et al., 2006; Liu et al., 2012; Cui et al., 2013).

NUAK1 is found in both the cytoplasm and nucleus.

In HEK293 cells NUAK1 phosphorylates myosin phosphatase regulator MYPT1, which inhibits the activity of a MYPT1-PPP1CB phosphatase complex, enhancing cell detachment (Zagorska et al., 2010). In WI-38 fetal lung fibroblasts and MCF10A immortalized mammary epithelial cells NUAK1 phosphorylates the cyclin-dependent protein kinase regulator LATS1, which leads to destabilization of LATS1 and induces aneuploidy, resulting in cellular senescence in a cellular context-dependent manner (Humbert et al., 2010). In A549 lung adenocarcinoma cells NUAK1 acts as a transcriptional coactivator in a complex with LKB1 and a tumor suppressor p53, which induces cell cycle G1 arrest (Hou et al., 2011).
In mice, NUAK1 is essential for closure of the ventral body wall in developing embryos (Hirano et al., 2006). NUAK1 and NUAK2 function in a complementary manner in the apical constriction and apico-basal elongation during early embryogenesis (Ohmura et al., 2012). The LKB1-NUAK1 pathway regulates cortical axon branching by immobilizing mitochondria at nascent presynaptic sites during postnatal neuronal development (Courchet et al., 2013). NUAK1 has a role in the negative feedback regulation of insulin signaling, which is involved in glucose intolerance under high-fat diet conditions (Inazuka et al., 2012).
In Caenorhabditis elegans, UNC-82, an ortholog of NUAK1 and NUAK2, maintains the organization of cytoskeletal structure during cell-shape change presumably through phosphorylation of myosin and paramyosin (Hoppe et al., 2010).

NUAK1 has the highest homology to NUAK2, whose similarity in the protein as a whole is 58%, and 82% in the kinase domain in human. Homo sapiens NUAK1 is 91% similar to Mus musculus NUAK1, 75% similar to Xenopus tropicalis NUAK1, and 65% similar to Caenorhabditis elegans UNC-82.

A C-to-T transition at residues 661 in the NUAK1 gene that results in a Pro-to-Ser substitution at codon 221 (P221S) has been found in tissue samples from human colorectal carcinomas and melanomas (Cancer Genome Atlas Network, 2012; Krauthammer et al., 2012).