Clk1, also known as Cdc2-like kinase 1, belongs to the CMGC family of dual-specificity kinases. It has the ability to phosphorylate tyrosine and serine/threonine protein residues. Clk1 plays a crucial role in regulating RNA splicing by phosphorylating members of the serine and arginine-rich (SR) family of splicing factors. It is involved in many physiological processes and has been associated with multiple pathways, such as those related to cancer development, neurodegenerative diseases, and cell cycle regulation [3]. Genetic models, like knockout mice, have been valuable in studying its functions.

In pancreatic cancer, high Clk1 expression promotes growth and metastasis by inducing aberrant exon skipping of METTL14 and Cyclin L2 through the Clk1/SRSF5 pathway [1]. In intrahepatic cholangiocarcinoma, Clk1 activates YAP to promote carcinogenesis, and in glioma, it regulates chemoresistance through the AMPK/mTOR/HIF-1α mediated glycolysis pathway [2,5]. In Trypanosoma brucei, chemical inhibition of Clk1 impairs inner kinetochore recruitment and cell cycle progression, suggesting it is part of a signaling cascade controlling kinetochore function [4].

In conclusion, Clk1 is essential for RNA splicing regulation and is involved in numerous biological processes. Its role in diseases such as cancer, neurodegenerative diseases like Alzheimer's, and infectious diseases caused by pathogens like Trypanosoma has been revealed through model-based research. The study of Clk1 knockout or conditional knockout mouse models has provided insights into its functions in these disease areas, potentially guiding the development of therapeutic strategies.

References:

1. Chen, Shi, Yang, Can, Wang, Zu-Wei, Shen, Bai-Yong, Wang, Yao-Dong. 2021. CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer. In Journal of hematology & oncology, 14, 60. doi:10.1186/s13045-021-01072-8. https://pubmed.ncbi.nlm.nih.gov/33849617/

2. Xue, Shuai, Chen, Xiangzheng, Qiu, Guoteng, Zeng, Yong, Wang, Haichuan. . CLK1 Activates YAP to Promote Intrahepatic Cholangiocarcinogenesis. In Cancer research, 85, 1035-1048. doi:10.1158/0008-5472.CAN-24-0147. https://pubmed.ncbi.nlm.nih.gov/39693605/

3. Jain, Princi, Karthikeyan, Chandrabose, Moorthy, N S Hari Narayana, Jain, Arvind Kumar, Trivedi, Piyush. . Human CDC2-like kinase 1 (CLK1): a novel target for Alzheimer's disease. In Current drug targets, 15, 539-50. doi:. https://pubmed.ncbi.nlm.nih.gov/24568585/

4. Saldivia, Manuel, Wollman, Adam J M, Carnielli, Juliana B T, Rao, Srinivasa P S, Mottram, Jeremy C. 2021. A CLK1-KKT2 Signaling Pathway Regulating Kinetochore Assembly in Trypanosoma brucei. In mBio, 12, e0068721. doi:10.1128/mBio.00687-21. https://pubmed.ncbi.nlm.nih.gov/34128702/

5. Zhang, Li, Yang, Huicui, Zhang, Wenbin, Zhen, Xuechu, Zheng, Long Tai. 2017. Clk1-regulated aerobic glycolysis is involved in glioma chemoresistance. In Journal of neurochemistry, 142, 574-588. doi:10.1111/jnc.14096. https://pubmed.ncbi.nlm.nih.gov/28581641/