Eef2k, also known as eukaryotic elongation factor 2 kinase, is a member of the α -kinase family. It phosphorylates the threonine 56 residue of eEF2 to inhibit global peptide elongation, thus negatively regulating the elongation step of protein synthesis. Its activity is controlled by multiple regulatory inputs, including inhibition by mTORC1 signaling, and is activated under stress conditions. It is associated with the calmodulin-induced signaling pathway and is often overexpressed in malignant cells [1,3,4,5,7].

In male mice, Eef2k-knockout mice were generated using Nuclease technology. These mice exhibited normal fertility and development, with no differences in spermatogenesis, sperm counts, or germ cell apoptosis compared to wild-type mice, suggesting Eef2k is dispensable for male fertility [5]. In melanoma, high Eef2k expression correlated with better response and longer survival in patients treated with PD-1 mAb. Mechanistically, Eef2k bound to and inactivated GSK3β, leading to PD-1 upregulation and tumor immune evasion. Knockdown of Eef2k enhanced CD8+ T cell activity and decreased tumor growth [2]. Also, in doxorubicin-induced cardiotoxicity, overexpression of Eef2k alleviated cardiomyocyte death and autophagy blockade, while knockdown aggravated the injury, indicating its protective role [6].

In conclusion, Eef2k plays a crucial role in regulating protein synthesis and is involved in various biological processes and disease conditions. Gene-knockout mouse models have been valuable in revealing its functions, such as its non-essential role in male fertility, its impact on the tumor immune microenvironment in melanoma, and its protective role in doxorubicin-induced cardiotoxicity. Understanding Eef2k may provide potential therapeutic strategies for cancer and other diseases [2,5,6].

References:

1. Klupt, Kody A, Jia, Zongchao. 2023. eEF2K Inhibitor Design: The Progression of Exemplary Structure-Based Drug Design. In Molecules (Basel, Switzerland), 28, . doi:10.3390/molecules28031095. https://pubmed.ncbi.nlm.nih.gov/36770760/

2. Chen, Xisha, Wang, Kuansong, Jiang, Shilong, Yin, Mingzhu, Cheng, Yan. . eEF2K promotes PD-L1 stabilization through inactivating GSK3β in melanoma. In Journal for immunotherapy of cancer, 10, . doi:10.1136/jitc-2021-004026. https://pubmed.ncbi.nlm.nih.gov/35347072/

3. Wang, Xuemin, Xie, Jianling, Proud, Christopher G.. 2017. Eukaryotic Elongation Factor 2 Kinase (eEF2K) in Cancer. In Cancers, 9, . doi:10.3390/cancers9120162. https://pubmed.ncbi.nlm.nih.gov/29186827/

4. Wang, Huiping, Jin, Wenke, Li, Zixiang, Zhang, Lan, Fu, Leilei. 2024. Targeting eukaryotic elongation factor 2 kinase (eEF2K) with small-molecule inhibitors for cancer therapy. In Drug discovery today, 29, 104155. doi:10.1016/j.drudis.2024.104155. https://pubmed.ncbi.nlm.nih.gov/39214495/

5. Feng, Tianhao, Zhou, Shushu, Shi, Xiaodan, Meng, Xuhui, Liu, Mingxi. . Eef2k is not required for fertility in male mice. In Translational andrology and urology, 10, 1988-1999. doi:10.21037/tau-21-18. https://pubmed.ncbi.nlm.nih.gov/34159079/

6. Guan, Junjie, Mo, Hongwei, Virak, Vicheth, Zhong, Chongbin, Yang, Pingzhen. 2024. eEF2K alleviates doxorubicin-induced cardiotoxicity by inhibiting GSK3β and improving autophagy dysfunction. In Cell biology and toxicology, 41, 15. doi:10.1007/s10565-024-09966-2. https://pubmed.ncbi.nlm.nih.gov/39708064/

7. Karakas, Didem, Ozpolat, Bulent. 2020. Eukaryotic elongation factor-2 kinase (eEF2K) signaling in tumor and microenvironment as a novel molecular target. In Journal of molecular medicine (Berlin, Germany), 98, 775-787. doi:10.1007/s00109-020-01917-8. https://pubmed.ncbi.nlm.nih.gov/32377852/