Ak6, also known as human coilin-interacting nuclear ATPase protein (hCINAP), is an atypical adenylate kinase. It plays critical roles in multiple biological processes such as gene transcription, ribosome synthesis, cell metabolism, proliferation, apoptosis, DNA damage responses, and genome stability [1]. It is involved in maintaining the homeostasis of cellular adenine nucleotide composition and is thought to contribute to the energetic communication between mitochondria and nucleus through phosphotransfer networks [4,5].

Knockdown of Ak6 in human testicular carcinoma (NT2 cells) inhibits cell proliferation and promotes apoptosis. Ak6 was found to regulate the phosphorylation states of WNK1 (Thr60) and affect the phosphorylation level of Akt (Ser473) under hypotonic conditions, likely influencing chloride channel, ion transport, and homeostasis in NT2 cells [2]. In a Drosophila model, knockdown of Ak6 improved locomotor dysfunction, rescued neurodegeneration, and increased brain adenosine levels, suggesting that glial adenosine metabolism related to Ak6 could be a therapeutic target in Parkinson's disease [3].

In conclusion, Ak6 is essential for multiple cellular processes and is associated with cancer and neurodegenerative diseases. The studies on Ak6 knockdown in NT2 cells and Drosophila models have revealed its role in cell proliferation, apoptosis, ion homeostasis, and adenosine metabolism, providing insights into potential therapeutic strategies for related diseases.

References:

1. Xu, Ruidan, Yang, Yongfeng, Zheng, Xiaofeng. 2021. Unique structural features of the adenylate kinase hCINAP/AK6 and its multifaceted functions in carcinogenesis and tumor progression. In FEBS letters, 595, 2071-2084. doi:10.1002/1873-3468.14158. https://pubmed.ncbi.nlm.nih.gov/34245011/

2. Ke, Shengwei, Zhang, Ran, He, Yaohui, Li, Jianyuan, Song, Xiaoyuan. 2021. Human adenylate kinase 6 regulates WNK1 (with no lysine kinase-1) phosphorylation states and affects ion homeostasis in NT2 cells. In Experimental cell research, 402, 112565. doi:10.1016/j.yexcr.2021.112565. https://pubmed.ncbi.nlm.nih.gov/33744230/

3. Sodders, Maggie J, Avila-Pacheco, Julian, Okorie, Ernest C, Clish, Clary, Olsen, Abby L. 2024. Genetic screening and metabolomics identify glial adenosine metabolism as a therapeutic target in Parkinson's disease. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.05.15.594309. https://pubmed.ncbi.nlm.nih.gov/38798570/

4. Ren, Hui, Wang, Liya, Bennett, Matthew, Zhang, Chuanmao, Su, Xiao-Dong. 2005. The crystal structure of human adenylate kinase 6: An adenylate kinase localized to the cell nucleus. In Proceedings of the National Academy of Sciences of the United States of America, 102, 303-8. doi:. https://pubmed.ncbi.nlm.nih.gov/15630091/

5. Noma, Takafumi. . Dynamics of nucleotide metabolism as a supporter of life phenomena. In The journal of medical investigation : JMI, 52, 127-36. doi:. https://pubmed.ncbi.nlm.nih.gov/16167529/