Adenylate kinase 6 (AK6) is present in a variety of organisms, and human AK6 is also known as human coilin-interacting nuclear ATPase protein (hCINAP). AK6 is a single α/β structural ribozyme, an atypical ribozyme. AK6 is similar in structure to other AKs. However it is located in the nucleus and is expressed in the nuclear AK6 of human Hela cells and lung adenocarcinoma tumor cells. The AK6 gene is located at 12p11 of the chromosome and contains 1119 bases, including 4 exons and 3 introns. AK6 binds to the motif structure and has ATPase activity, including three functional subdomains: core domain, containing ATP junction sites; NMP linkage domain; cap-like domain.
Studies have shown that different species of AK6 have more than 86% identical amino acid sequences. However, AK6 has less than 18% identical amino acid sequences compared to other AK family members such as AK1 - AK5. The enzymatic properties of AK6 have many similarities to AK5. AMP and dAMP are the preferred substrates for AK6, followed by CMP and dCMP. All NTPs and dNTPs are available as AK6 phosphate donors, and CTP and UTP are the preferred phosphate donors for AK6. Members of the AKs family have a GXPGXGKGT sequence in the P loop, while the last Gly of AK6 is replaced by Thr-17.AK6 differs from other AKs in its capping domain and NMP-related domain.
AK6 is a highly conserved and widely expressed protein in eukaryotes. AK6 mRNA is an alternative splicing from the TAF9 site and is also labeled with the transcriptional factor TAF‖D32. In addition to AK enzyme activity, AK6 also has ATPase/GTPase protein properties, as well as persistent atypical AK and ATPase activities.
Cajal bodies (CBs) are nuclear organelles involved in ribonucleoprotein function and RNA maturation, and CB is assembled on helix proteins during the cell cycle. AK6 Post-translational modification, such as phosphorylation and methylation, affects the assembly of CBs. The CB is involved in RTPs splicing, histone mRNA processing, and telomerase formation. In neuronal and tumor cells, such as transcriptionally active cells that require high levels of RNPs, CB is required for modification. Hebert et al. found that the CB decomposed during mitosis and recombined in the G1 phase of the cell cycle. Transcriptional inhibitors, translational inhibitors, nuclear export inhibitors, phosphatase inhibitors, kinase inhibitors, etc. can cause CB breakdown and/or spiral protein localization errors. AK6 can form a biological interaction with the carboxy terminal of the helix protein. The carboxy terminus of the helix protein can also down-regulate the number of CB in the nucleus in combination with the CB. Yeast two-hybrid experiments showed that AK6 can regulate the cell cycle by binding to the carboxy terminus of CB. It has been found that overexpression of AK6 in Hela cells leads to a decrease in Cajal in each nucleus, affecting the stability and/or assembly rate of CB, further affecting the proliferation, differentiation and metastasis of Hela cells themselves.
NF-κB controls a variety of cellular functions, including immune response, cell proliferation, and apoptosis. NF-κB must be controlled by the correct time and space to prevent its abnormal activation. NF-κB dysregulation can promote tumor growth, tumor cell proliferation, invasion and metastasis through transcriptional regulation of the corresponding genes. At present, non-physiological high expression and constitutive activation of NF-κB have been found in various tumors. Qu et al. found that AK6 negatively regulates NF-κB by reducing the action of the IκB kinase (IKK) complex. Under NF-κB stimulation, AK6 interacts with IKKα and IKKβ and inhibits IKK phosphorylation. AK6 interacts with the catalytic subunit of PP1 (protein phosphatase), and aggregates PP1 in dephosphorylated IKK and regulates the formation of the IKK-AK6-PP1 complex. In NF-κB extremely active inflammatory diseases, AK6 expression levels are decreased. Therefore, AK6 may be involved in the development of inflammation-related tumors.
Ji et al studied the overexpression of adenylate kinase AK6 in CRC (colorectal cancer) tissues. Consumption of AK6 can cause CRCSCs (colorectal cancer stem cells) to lose mesenchymal characteristics, thereby inhibiting their invasion, self-renewal, tumorigenesis and chemical resistance. Mechanistically, it binds to the C-terminal domain of LDHA, a key regulator of glycolysis, and AK6 is dependent on its adenylate kinase activity to promote LDHA phosphorylation at tyrosine 10, and then leads to Warburg Over-effect and lower levels of cellular ROS. Furthermore, AK6 expression is positively correlated with the level of Y10-phosphorylated LDHA in CRC patients. This study will identify effective modulators of metabolic reprogramming in CRCSCs, and AK6 is a promising drug target for CRC invasion and metastasis.
Figure 1. AK6(hCINAP)depends on its adenylate kinase activity to promote CRCs growth and invasion. (Ji, et al. 2017).
The wild-type p53 gene encodes a nuclear phosphorylating protein consisting of 393 amino acids, which encodes a product that monitors cellular gene integrity, promotes DNA repair of damage, and eliminates cancerous cells by inducing apoptosis. HDM2 is a major regulator of p53 discovered in recent years. It participates in the degradation of p53 by regulating p53 ribosome stress response , and inhibits the transcriptional activity of p53 to play a negative role in the regulation of p53. In addition, RPS14 induces p53 arrest in the G1 and G2 phases of the cell cycle. Zhang et al. have shown that both Increased and decreased RPS14 expression can activate p53. When RPS14 is expressed at a higher level, it binds to HDM2 and inhibits p53 degradation and ubiquitination. NEDD8 is a ubiquitin-like modified protein encoded by 81 amino acids and is highly expressed in the nucleus and relatively weakly expressed in the cytoplasm. The modification process in which NEDD8 specifically binds to a substrate protein is called Neddylation. AK6 is a novel regulator of the RPS14-HDM2-p53 pathway. By controlling Neddylation, AK6 inhibits the interaction between RPS14 and HDM2, negatively regulating the effect of RPS14 on HDM2-p53 and promoting the degradation of p53 and promoting tumor growth.
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