Biochemical and Structural Insights into Doublecortin-like Kinase Domain 1

Abstract
Doublecortin-like kinase 1 (DCLK1) is a serine/threonine kinase and a member of the microtubule-associated protein family. Initially recognized for its essential role in neurogenesis, recent studies have revealed its involvement in biological processes beyond the central nervous system (CNS), including epithelial homeostasis, stem cell regulation, and cancer progression. Emerging evidence suggests that DCLK1 serves as a crucial regulator in the tumor microenvironment, influencing key pathways related to cell proliferation, migration, and survival.

DCLK1 is among the top 15 putative driver genes in gastric cancer and is frequently mutated across multiple malignancies, such as colorectal, pancreatic, and hepatocellular carcinomas. Its aberrant expression has been linked to cancer stem cell properties, chemoresistance, and epithelial-to-mesenchymal transition (EMT), underscoring its potential as a therapeutic target. However, the precise molecular mechanisms through which DCLK1 dysfunction contributes to tumorigenesis remain largely unknown, particularly in regard to its downstream signaling pathways.

In this study, we provide evidence that DCLK1 kinase activity negatively regulates microtubule polymerization, offering novel insights into its role in cytoskeletal organization. To further elucidate its function, we present the high-resolution crystal structure of the DCLK1 kinase domain at 1.7 Å, which reveals a well-defined ATP-binding pocket. This structural framework not only facilitates the rational design of selective kinase inhibitors but also enables precise mapping of cancer-associated mutations within the kinase domain. Our findings suggest that loss of DCLK1 kinase function may contribute to tumorigenesis by disrupting microtubule dynamics, leading to abnormal cell division, genomic instability, and enhanced tumor progression.

With growing interest in kinase-targeted therapies, the structural and functional insights presented here provide a foundation for the development of small-molecule inhibitors aimed at modulating DCLK1 activity. Further research TAE684 is needed to explore the therapeutic potential of DCLK1 inhibition in cancer treatment and to uncover its broader biological roles beyond microtubule regulation.