Traf2- and Nck-interacting kinase (TNIK) is a key regulator of pathological metabolic signaling in several diseases, making it a promising drug target [1]. It is involved in cell migration, proliferation, and differentiation, and participates in various biological processes. TNIK is a regulatory component of the transcriptional complex composed of β -catenin and T -cell factor 4 (TCF4), playing a role in the Wnt/β -catenin signaling pathway [3].

TNIK knockout mice exhibited hyperlocomotor activity and were protected against diet-induced fat expansion, insulin resistance, and hepatic steatosis. This shows that TNIK governs lipid and glucose homeostasis [2]. In injured renal proximal tubule epithelial cells, depletion of TNIK led to inflammation and apoptosis, indicating that TNIK acts to suppress inflammatory signaling and apoptosis to promote cell survival [4]. In castration-resistant prostate cancer, TNIK was found to drive cancer progression by phosphorylating EGFR [5].

In conclusion, TNIK plays essential roles in multiple biological processes such as glucose and lipid metabolism, cell survival in the context of renal injury, and cancer progression. The use of TNIK knockout mouse models has been crucial in revealing its functions in these disease-related areas, providing insights into potential therapeutic strategies for metabolic disorders, acute kidney injury, and certain cancers [2,4,5].

References:

1. Ewald, Collin Y, Pulous, Fadi E, Lok, Sarah Wing Yan, Ren, Feng, Zhavoronkov, Alex. 2024. TNIK's emerging role in cancer, metabolism, and age-related diseases. In Trends in pharmacological sciences, 45, 478-489. doi:10.1016/j.tips.2024.04.010. https://pubmed.ncbi.nlm.nih.gov/38777670/

2. Pham, T C Phung, Dollet, Lucile, Ali, Mona S, Havula, Essi, Sylow, Lykke. 2023. TNIK is a conserved regulator of glucose and lipid metabolism in obesity. In Science advances, 9, eadf7119. doi:10.1126/sciadv.adf7119. https://pubmed.ncbi.nlm.nih.gov/37556547/

3. Kukimoto-Niino, Mutsuko, Shirouzu, Mikako, Yamada, Tesshi. 2022. Structural Insight into TNIK Inhibition. In International journal of molecular sciences, 23, . doi:10.3390/ijms232113010. https://pubmed.ncbi.nlm.nih.gov/36361804/

4. Bradford, Shayna T J, Wu, Haojia, Kirita, Yuhei, Muto, Yoshiharu, Humphreys, Benjamin D. 2024. TNIK depletion induces inflammation and apoptosis in injured renal proximal tubule epithelial cells. In American journal of physiology. Renal physiology, 326, F827-F838. doi:10.1152/ajprenal.00262.2023. https://pubmed.ncbi.nlm.nih.gov/38482555/

5. Guo, Jianing, Liang, Jiaming, Wang, Youzhi, Niu, Yuanjie, Jiang, Ning. 2023. TNIK drives castration-resistant prostate cancer via phosphorylating EGFR. In iScience, 27, 108713. doi:10.1016/j.isci.2023.108713. https://pubmed.ncbi.nlm.nih.gov/38226156/