Stk3, also known as Mammalian STE20-like protein kinase 2 (MST2), is a core kinase of the Hippo pathway. The Hippo pathway is an evolutionarily conserved signaling cascade that regulates numerous biological processes such as cell growth, fate decision, organ size control, and regeneration [1]. Stk3 plays a crucial role in immunomodulation, organ development, cellular differentiation, and cancer suppression [3]. Genetic models, like KO or CKO mouse models, are valuable for studying its functions.

In adipocytes, genetic inactivation of Stk3 and Stk4 increases mitochondrial mass and function, stabilizes uncoupling protein 1 in beige adipose tissue, and confers resistance to metabolic dysfunction induced by high-fat diet feeding. This reveals that Stk3 and Stk4 are key physiological suppressors of mitochondrial capacity in adipose tissues [2]. In ovarian cancer, low Stk3 expression was correlated with a poor prognosis, and overexpression of Stk3 significantly inhibited cell proliferation, apoptosis, and migration of ovarian cancer cells in vitro and tumor growth in vivo, suggesting its role in suppressing ovarian cancer progression [4]. In pancreatic cancer, Stk3 was found to be reduced, and it promoted apoptosis, inhibited cell migration, invasion, and proliferation by suppressing the PI3K/AKT/mTOR pathway with the assistance of RASSF1 [5].

In conclusion, Stk3, as a key component of the Hippo pathway, is involved in multiple biological processes. Studies using KO/CKO mouse models have revealed its important roles in metabolic regulation and cancer suppression, especially in obesity-related diseases, ovarian cancer, and pancreatic cancer. These findings provide valuable insights into the underlying mechanisms of these diseases and potential therapeutic targets.

References:

1. Ma, Shenghong, Meng, Zhipeng, Chen, Rui, Guan, Kun-Liang. 2019. The Hippo Pathway: Biology and Pathophysiology. In Annual review of biochemistry, 88, 577-604. doi:10.1146/annurev-biochem-013118-111829. https://pubmed.ncbi.nlm.nih.gov/30566373/

2. Cho, Yoon Keun, Son, Yeonho, Saha, Abhirup, Granneman, James G, Lee, Yun-Hee. 2021. STK3/STK4 signalling in adipocytes regulates mitophagy and energy expenditure. In Nature metabolism, 3, 428-441. doi:10.1038/s42255-021-00362-2. https://pubmed.ncbi.nlm.nih.gov/33758424/

3. Zhao, Ziying, Chu, Yuan, Feng, Anqi, Chen, Tao, Xu, Meidong. 2024. STK3 kinase activation inhibits tumor proliferation through FOXO1-TP53INP1/P21 pathway in esophageal squamous cell carcinoma. In Cellular oncology (Dordrecht, Netherlands), 47, 1295-1314. doi:10.1007/s13402-024-00928-8. https://pubmed.ncbi.nlm.nih.gov/38436783/

4. Wang, Xiangyu, Wang, Fengmian, Zhang, Zhi-Gang, Yang, Xiao-Mei, Zhang, Rong. 2020. STK3 Suppresses Ovarian Cancer Progression by Activating NF-κB Signaling to Recruit CD8+ T-Cells. In Journal of immunology research, 2020, 7263602. doi:10.1155/2020/7263602. https://pubmed.ncbi.nlm.nih.gov/33062724/

5. Chen, Jun, Liu, Fuqiang, Wu, Jiao, Jiang, Zhongxiang, Jiang, Zheng. 2023. Effect of STK3 on proliferation and apoptosis of pancreatic cancer cells via PI3K/AKT/mTOR pathway. In Cellular signalling, 106, 110642. doi:10.1016/j.cellsig.2023.110642. https://pubmed.ncbi.nlm.nih.gov/36871796/