Dstyk, a dual serine/threonine and tyrosine non-receptor protein kinase, is involved in multiple cellular functions and signaling pathways. It is located in late endosomal/lysosomal compartments and is associated with pathways such as mTOR-dependent autophagy, lysosomal biogenesis, and Wnt/β-catenin signaling [1,2,5]. It plays a significant role in various biological processes and disease conditions, making it an important target for research. Genetic models, like gene knockout mouse models, have been crucial in understanding its functions.

In zebrafish, dstyk mutation leads to congenital scoliosis-like vertebral malformations due to dysregulated mTORC1/TFEB pathway, affecting notochord vacuole biogenesis and spine development [2]. In lung cancer, Dstyk inhibition prevents mTOR-dependent cytoprotective autophagy, impairs lysosomal biogenesis, and sensitizes cancer cells to T cell-mediated cytotoxicity and anti-PD-1 treatment. Also, its copy number gain predicts lack of response to immunotherapy [1]. In triple-negative breast cancer and colorectal cancer, Dstyk enhances chemoresistance and promotes metastasis via epithelial-mesenchymal transition (EMT) [3,4]. Loss of Dstyk in lung adenocarcinoma activates Wnt/β-catenin signaling and glycolysis [5]. In mice, Dstyk kinase domain ablation impairs learning and memory capabilities [6].

In conclusion, Dstyk is essential in processes like autophagy, lysosomal biogenesis, and EMT. Dstyk knockout mouse models have significantly contributed to understanding its role in diseases such as congenital scoliosis, various cancers, and potentially neurological disorders related to learning and memory. These findings highlight Dstyk as a potential therapeutic target in multiple disease areas.

References:

1. Valencia, Karmele, Echepare, Mirari, Teijeira, Álvaro, Melero, Ignacio, Montuenga, Luis M. 2022. DSTYK inhibition increases the sensitivity of lung cancer cells to T cell-mediated cytotoxicity. In The Journal of experimental medicine, 219, . doi:10.1084/jem.20220726. https://pubmed.ncbi.nlm.nih.gov/36169652/

2. Sun, Xianding, Zhou, Yang, Zhang, Ruobin, Luo, Lingfei, Chen, Lin. 2020. Dstyk mutation leads to congenital scoliosis-like vertebral malformations in zebrafish via dysregulated mTORC1/TFEB pathway. In Nature communications, 11, 479. doi:10.1038/s41467-019-14169-z. https://pubmed.ncbi.nlm.nih.gov/31980602/

3. Ogbu, Stella C, Rojas, Samuel, Weaver, John, Yao, Zhi Q, Jiang, Yong. 2021. DSTYK Enhances Chemoresistance in Triple-Negative Breast Cancer Cells. In Cells, 11, . doi:10.3390/cells11010097. https://pubmed.ncbi.nlm.nih.gov/35011659/

4. Zhang, Jinyu, Miller, Zachary, Musich, Phillip R, Howe, Philip H, Jiang, Yong. 2020. DSTYK Promotes Metastasis and Chemoresistance via EMT in Colorectal Cancer. In Frontiers in pharmacology, 11, 1250. doi:10.3389/fphar.2020.01250. https://pubmed.ncbi.nlm.nih.gov/32982725/

5. Zhong, Chenxi, Chen, Ming, Chen, Yu, Yao, Feng, Fang, Wentao. 2021. Loss of DSTYK activates Wnt/β-catenin signaling and glycolysis in lung adenocarcinoma. In Cell death & disease, 12, 1122. doi:10.1038/s41419-021-04385-1. https://pubmed.ncbi.nlm.nih.gov/34853310/

6. Li, Kui, Liu, Ji-Wei, Zhu, Zhi-Chuan, Zheng, Jing, Hu, Ze-Lan. 2014. DSTYK kinase domain ablation impaired the mice capabilities of learning and memory in water maze test. In International journal of clinical and experimental pathology, 7, 6486-92. doi:. https://pubmed.ncbi.nlm.nih.gov/25400726/