NUAK family SNF1-like kinase 1 also known as AMPK-related protein kinase 5 (ARK5) is an enzyme that in humans is encoded by the NUAK1 gene.
AMP-activated protein kinase (AMPK) and AMPK-related kinases
Obesity and diabetes (DM) currently threaten health in almost every country in the world. Impaired energy balance is considered a major cause of obesity and type 2 diabetes. AMP-activated protein kinase (AMPK) is a highly conserved serine/threonine protein kinase (PK) with multiple substrates and has been developed. It is called energy steady state main sensor and regulator. AMPK acts as a heterotrimer consisting of one catalytic subunit (a) and two regulatory subunits (b and g), as its activity is regulated by an increase in the intracellular AMP: ATP ratio in cells under metabolic stress (Eg hypoxia, heat shock and ischemia). It is reported that AMPK plays a key role in regulating glucose and cholesterol metabolism and cell proliferation, cell polarity, and tumorigenesis by responding to metabolic stress. In addition, AMPK activity may also be regulated by hormones and cytokines, leading to changes in metabolism, which may in turn promote tumor progression.
Structure and expression
Members of the NUAK family (including NUAK1 (ARK5) and NUAK2 (SNARK)) contain a ubiquitin-related domain located near the C-terminus of their catalytic domain, which is required for LKB1 phosphorylation and activation. A homology search analysis of the amino acid sequence of ARK5 revealed that the overall homology with human SNARK was 55.0%. Although AMPK has a heterotrimer function, it is unclear whether ARK5 and SNARK also serve as heterotrimers. The human ARK5 protein consists of 661 amino acids (about 76 kDa). The mouse ARK5 protein is expected to contain 658 amino acids, while the rat ARK5 protein is a polypeptide containing 660 amino acids. ARK5 mRNA and protein are detected in the heart, kidney, brain, liver and skeletal muscle. Interestingly, Fisher et al. According to reports, Western blot analysis using home-made antibodies showed that there were two prominent ARK5 bands in skeletal muscle, and the lower of the two bands showed the same molecular weight as AMPK, indicating the potential interaction of ARK5 with new AMPK family kinases. ARK5 expression is closely related to matrix metalloproteinase 2 (MMP2), MMP9, and S100 calcium-binding protein A4 (S100A4), and is closely related to the poor prognosis of multiple myeloma. In addition, ARK5 expression is also related to the v-raf murine sarcoma virus oncogene B1 (BRAF) -mediated pathway. BRAF is considered to be a new indicator of papillary thyroid carcinoma progression and aggressiveness. The expression of ARK5 mRNA in colon cancer is related to the stage, and the expression level of ARK5 mRNA in liver metastases of colon cancer is high. Colorectal cancer cell lines DLD-1, WiDr, HCT-15, SW620, LoVo, SW480 and SW1116. However, ARK5 is higher expressed in differentiated C2C12 myotubes than undifferentiated myoblasts, suggesting that NAUK / ARK proteins have multiple roles in different cell types.
Function and regulation of ARK5
Similar to other members of the AMPK family, ARK5 contains a highly conserved active T loop, suggesting the presence of upstream kinases that phosphorylate threonine residues in the catalytic domain. LKB1 and Akt kinase modified serine 600 modified ARK5 phosphate on threonine 211, which can activate its kinase activity. Like most AMPK-regulated kinases, ARK5 activity is increased 10- to 20-fold by LKB1 phosphorylation of its T-cyclothreonine. A recent study showed that ARK5 / SNARK immune complex activity was significantly reduced in skeletal muscle from muscle-specific Lkb1 knockout mice using antibodies that did not distinguish between the two proteins using basic and contractile stimulation. This suggests that SNARK and ARK5 may be important regulators of LKB1 in skeletal muscle. Recently, Matrigel invasion tests have shown that both overexpression and endogenous ARK5 show strong Akt-mediated activity. Importantly, ARK5 is the only AMPK family member to date regulated by Akt.
Conclusions
The NUAK family is essential for malignancy and energy metabolism. Further work is needed to elucidate the regulatory mechanism and function of NUAK family proteins. Although the functions of the NUAK family are not fully understood, ARK5 and SNARK are expected to be potential therapeutic targets for the treatment of human cancer and metabolic diseases such as obesity and DM.
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