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Editorial

Past, Present and Future of Protein Kinase CK2 Research

Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy
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Authors to whom correspondence should be addressed.
Kinases Phosphatases 2025, 3(3), 17; https://doi.org/10.3390/kinasesphosphatases3030017
Submission received: 7 July 2025 / Accepted: 11 August 2025 / Published: 19 August 2025
(This article belongs to the Special Issue Past, Present and Future of Protein Kinase CK2 Research)
The first described instance of protein kinase activity dates back more than half a century [1] and was later identified as CK2. Since then, this enzyme has attracted enormous scientific interest, with hundreds of studies investigating its structure, function, and physiological and pathological relevance being published each year. We now know that CK2 is a constitutively active, ubiquitously expressed enzyme which is involved in a broad range of functionally diverse biological processes. Therefore, it is not surprising that its dysregulation has been linked to numerous diseases, including cancer, neurodegenerative disorders, and inflammation [2,3,4]. For this reason, CK2 is considered to be a promising drug target for various diseases, particularly for different forms of cancer. Several CK2-specific inhibitors are available [5,6,7]. However, despite decades of intensive research, this enzyme remains puzzling. Many aspects of its role in human diseases and the mechanisms that regulate its function are still not fully understood. Moreover, the recent discovery of genetic syndromes linked to mutations in the CK2α and CK2β genes [8] has opened up a new area of investigation.
This Special Issue, “Past, Present and Future of Protein Kinase CK2 Research”, comprises eight contributions, some of which are dedicated to reviewing essential features of CK2, while others showcase some of the latest advances in the field.
Niefind and his group focus on the “neglected” α’ catalytic subunit of CK2 [9]. CK2 is a tetrameric enzyme composed of two catalytic (α and/or α’) and two regulatory (β) subunits. While many crystallographic studies have focused on the α subunit, the α’ isoform has been rarely investigated, due to the poor solubility of the recombinant protein. In their work, the authors exploit the Cys336Ser CK2α’ mutant as a crystallographic tool that, along with optimized techniques, allows them to solve the structures of CK2α’ in a complex with various ligands at atomic resolution. In one of these structures, the authors highlight the N-terminal segment site, which is a ligand-binding region with the potential to develop new substrate-competitive CK2 inhibitors.
Dominguez et al. [10] address the largely overlooked issue of the transcriptional regulation of CK2α, marking an important step forward in this field of study. Despite many years of investigation, little has been published on this critical topic since the pioneering studies by Pyerin’s group [11]. By focusing on the promoter of the Csnk2a1 gene (the murine ortholog of human CSNK2A1 coding for CK2α), the authors demonstrate that the transcription factor NF-κB regulates CK2α expression. Through a combination of promoter deletions, binding assays, and functional analyses, they demonstrate that NF-κB binds to a conserved minimal promoter region. Interestingly, as CK2α itself modulates NF-κB signaling, their findings suggest a positive feedback loop in which CK2α may regulate its own expression via NF-κB.
Cesaro and colleagues [12] review the “rules” of CK2 substrate selection, emphasizing the importance of the CK2 consensus sequence in predicting phosphorylation sites, and analyzing the different experimental approaches used to confirm CK2 involvement in phosphorylation events. The authors also discuss various strategies for modulating CK2 activity, including knockdown, knockout, and inhibition by small molecules, and highlight the strengths and limitations of each method.
Tapia’s research group [13] considers the central role that CK2 plays in cancer pathogenesis and the targets involved in the CK2-dependent regulation of cell survival, proliferation, and metastasis. They identify one such target in endothelin-converting enzyme-1 (ECE1), whose isoform ECE1c is frequently overexpressed in cancer. They explore the connections between CK2, ECE1c, and cancer, focusing on the phosphorylation of the ECE1c N-terminus, which appears to protect ECE1c from degradation and activate oncogenic pathways such as Wnt/β-catenin signaling.
Pandit and colleagues [14] explore the role of CK2 in non-oncological diseases, particularly musculoskeletal disorders such as rheumatoid arthritis, osteoarthritis, bone fractures, and osteoporosis. They provide a comprehensive overview of CK2’s involvement in these conditions and discuss how targeting CK2 could help to restore biochemical imbalances, offering potential therapeutic benefits.
Quezada Meza and Ruzzene [15] evaluate CK2’s role in viral infections, with special reference to SARS-CoV-2 and other coronaviruses. Their review discusses the mechanisms by which CK2 is involved in these infections and the ways in which CK2 inhibitors are repurposed to mitigate their effects. The analysis broadens our understanding of the CK2/virus interplay and discusses how to extrapolate information that could be useful beyond the context of the recent pandemic.
Finally, two reviews provide valuable insights into the diverse strategies used for CK2 inhibition, offering complementary perspectives and highlighting promising avenues for the development of novel therapeutics targeting this kinase.
Axtman and colleagues [16], who recently discovered SGC-CK2-1, the most selective and potent CK2 inhibitor identified so far [17], review various classes of small-molecule inhibitors, including orthosteric, allosteric, and bivalent inhibitors. They also discuss the progress that has been made in developing CK2 chemical probes for in vivo studies.
Spring and coworkers [18] focus on small molecules targeting sites outside the ATP-binding site. This is an innovative strategy that, compared to the more conventional ATP-competitive inhibitors (e.g., CX-4945, SGC-CK2-1), is expected to offer higher selectivity. It includes substrate-competitive inhibitors which block CK2–substrate interactions, bi-specific inhibitors binding both ATP and substrate sites, αD site inhibitors exploiting a unique CK2 pocket, and holoenzyme disruptors preventing CK2α/β assembly. PROTACs inducing CK2 degradation are also discussed.
In summary, looking back on seven decades of research into the CK2 field, with hundreds of studies published every year, we can say that “the past” is abundant, and significant progress has been made in unraveling the physio/pathological role of this intriguing enzyme. However, “the present” is still full of surprises, and the journey is far from complete, thus making “the future” an even more exciting promise.

Author Contributions

M.S. and M.R. writing—original draft preparation; M.S. and M.R. writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflicts of interest.

References

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MDPI and ACS Style

Salvi, M.; Ruzzene, M. Past, Present and Future of Protein Kinase CK2 Research. Kinases Phosphatases 2025, 3, 17. https://doi.org/10.3390/kinasesphosphatases3030017

AMA Style

Salvi M, Ruzzene M. Past, Present and Future of Protein Kinase CK2 Research. Kinases and Phosphatases. 2025; 3(3):17. https://doi.org/10.3390/kinasesphosphatases3030017

Chicago/Turabian Style

Salvi, Mauro, and Maria Ruzzene. 2025. "Past, Present and Future of Protein Kinase CK2 Research" Kinases and Phosphatases 3, no. 3: 17. https://doi.org/10.3390/kinasesphosphatases3030017

APA Style

Salvi, M., & Ruzzene, M. (2025). Past, Present and Future of Protein Kinase CK2 Research. Kinases and Phosphatases, 3(3), 17. https://doi.org/10.3390/kinasesphosphatases3030017

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