Dclk2, or doublecortin-like kinase 2, is a microtubule-associated protein kinase involved in neural development and maturation [3,4,5]. It participates in multiple biological processes and is associated with pathways related to tumorigenesis and neuronal pyroptosis [1,2]. Genetic models, such as knockout mouse models, are valuable for studying its functions.

In clear cell renal cell carcinoma (ccRCC), a kinome-wide siRNA screen identified Dclk2 as a regulator of TANK-binding kinase 1 (TBK1). Dclk2 binds to and phosphorylates TBK1 on Ser172. Depletion of Dclk2 inhibits anchorage-independent colony growth and kidney tumorigenesis in orthotopic xenograft models, while overexpression of a short isoform (DCLK2203) promotes ccRCC cell growth and tumorigenesis in vivo. This suggests Dclk2 is a TBK1 activator and a potential therapeutic target for ccRCC [1]. In breast cancer, silencing Dclk2 significantly suppresses cell migration, invasion, and lung metastasis without affecting proliferation, indicating its role in epithelial-mesenchymal transition (EMT), cell invasion, and metastasis [3]. In chronic cerebral ischemia, Cpeb4-mediated Dclk2 promotes neuronal pyroptosis by phosphorylating Ehf, a transcription factor that regulates Caspase1 and Caspase3 expression [2]. Mice lacking Dcx and Dclk2 display frequent spontaneous seizures originating from the hippocampus, along with disrupted hippocampal lamination and reduced inhibitory synaptic tone, suggesting Dclk2's role in hippocampal neuronal maturation and epilepsy [5].

In conclusion, Dclk2 plays crucial roles in neural development, tumorigenesis, and neuronal pyroptosis. Studies using gene knockout mouse models have revealed its functions in ccRCC, breast cancer, chronic cerebral ischemia-induced neuronal pyroptosis, and epilepsy. Understanding Dclk2's functions provides potential therapeutic targets for these diseases.

References:

1. Hu, Lianxin, Zhang, Yanfeng, Guo, Lei, Brugarolas, James, Zhang, Qing. 2024. Kinome-wide siRNA screen identifies a DCLK2-TBK1 oncogenic signaling axis in clear cell renal cell carcinoma. In Molecular cell, 84, 776-790.e5. doi:10.1016/j.molcel.2023.12.010. https://pubmed.ncbi.nlm.nih.gov/38211588/

2. Sun, Miao, Huang, Xin, Ruan, Xuelei, Yang, Jin, Xue, Yixue. 2024. Cpeb4-mediated Dclk2 promotes neuronal pyroptosis induced by chronic cerebral ischemia through phosphorylation of Ehf. In Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 44, 1655-1673. doi:10.1177/0271678X241240590. https://pubmed.ncbi.nlm.nih.gov/38513137/

3. He, Yanling, Dai, Xiaoqin, Li, Shengnan, Song, Kai, Shi, Jian. 2022. Doublecortin-like kinase 2 promotes breast cancer cell invasion and metastasis. In Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico, 25, 1102-1113. doi:10.1007/s12094-022-03018-z. https://pubmed.ncbi.nlm.nih.gov/36477947/

4. Tuy, Françoise Phan Dinh, Saillour, Yoann, Kappeler, Caroline, Chelly, Jamel, Francis, Fiona. . Alternative transcripts of Dclk1 and Dclk2 and their expression in doublecortin knockout mice. In Developmental neuroscience, 30, 171-86. doi:. https://pubmed.ncbi.nlm.nih.gov/18075264/

5. Kerjan, Géraldine, Koizumi, Hiroyuki, Han, Edward B, Heinemann, Stephen F, Gleeson, Joseph G. 2009. Mice lacking doublecortin and doublecortin-like kinase 2 display altered hippocampal neuronal maturation and spontaneous seizures. In Proceedings of the National Academy of Sciences of the United States of America, 106, 6766-71. doi:10.1073/pnas.0812687106. https://pubmed.ncbi.nlm.nih.gov/19342486/