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Kinases and Phosphatases
Special Issues
Past, Present and Future of Protein Kinase CK2 Research
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Past, Present and Future of Protein Kinase CK2 Research

A special issue of Kinases and Phosphatases (ISSN 2813-3757).

Deadline for manuscript submissions: 15 June 2024 | Viewed by 8534

Special Issue Editors

Dr. Mauro Salvi

E-Mail Website
Guest Editor
Department of Biomedical Sciences, University of Padova, Padova, Italy
Interests: protein phosphorylation; acidic protein kinases; tyrosine kinases; kinase inhibitors, signal transduction; post-translational modifications; cancer; cystic fibrosis
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Maria Ruzzene

E-Mail Website
Guest Editor
Department of Biomedical Sciences, University of Padova, Padova, Italy
Interests: signal transduction; cell signaling; signaling pathways; protein phosphorylation; protein kinases; protein phosphatases; protein kinase inhibitors; cancer biology; proteins; apoptosis; cell death; cancer research; cancer cell line
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

CK2 (formerly known as casein kinase 2) was the first protein kinase to be discovered in 1954. Since then, a huge number of studies have been published that tried to disclose its biochemical properties and its physiological and pathological roles. It is now established that CK2 is constitutively active, ubiquitously expressed, and involved in many biological processes as well as in the pathogenesis of important human diseases, including cancer, neurodegeneration and inflammation. However, despite much time and scientific effort, CK2 remains an enigmatic enzyme, as we are still far from fully understanding its actual pathophysiological roles, and the mechanisms that might modulate its functions.  Moreover, although it has long been considered a promising pharmacological target for diverse pathologies, and several inhibitors with increasing efficacy and specificity have been developed over the years, the actual value of its targeting in cancer has been recently questioned and deserves further debate. Furthermore, while its therapeutic targeting has been so far considered in terms of inhibition, the recent discovery of genetic diseases related to mutations of CK2 genes prompts the investigation of strategies to stimulate its activity, which has not been available so far.

It is, therefore, time for a Special Issue that on one hand retraces the main discoveries of CK2, and on the other, summarizes recent research and presents updates and new advances in the field.

In this Special Issue, we will, therefore, welcome original, commentary and review contributions in all areas of CK2 research and biological systems, with emphasis on works attempting to answer outstanding questions: how can a constitutive kinase be regulated? How many substrates and molecular partners does it currently count? For which human diseases does it really represent a therapeutic target, and which are the best pharmacological strategies? We look forward to contributions on these crucial issues as well as the many others that will be identified by the numerous scientists who work on CK2 or come across this fundamental enzyme.

Dr. Mauro Salvi
Prof. Dr. Maria Ruzzene
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Kinases and Phosphatases is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • CK2
  • Casein kinase 2
  • CSNK2A1
  • CSNK2A2
  • CSNK2B
  • Protein phosphorylation
  • Human diseases
  • Signal transduction

Published Papers (7 papers)

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Research

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17 pages, 4062 KiB  
Article
Discovery and Exploration of Protein Kinase CK2 Binding Sites Using CK2α′Cys336Ser as an Exquisite Crystallographic Tool
by Christian Werner, Dirk Lindenblatt, Kaido Viht, Asko Uri and Karsten Niefind
Kinases Phosphatases 2023, 1(4), 306-322; https://doi.org/10.3390/kinasesphosphatases1040018 - 25 Nov 2023
Cited by 1 | Viewed by 842
Abstract
The structural knowledge about protein kinase CK2 is dominated by crystal structures of human CK2α, the catalytic subunit of human CK2, and the product of the CSNK2A1 gene. In contrast, far fewer structures of CK2α′, its paralogous isoform and the product of the [...] Read more.
The structural knowledge about protein kinase CK2 is dominated by crystal structures of human CK2α, the catalytic subunit of human CK2, and the product of the CSNK2A1 gene. In contrast, far fewer structures of CK2α′, its paralogous isoform and the product of the CSNK2A2 gene, have been published. However, according to a PDB survey, CK2α′ is the superior alternative for crystallographic studies because of the inherent potential of the single mutant CK2α′Cys336Ser to provide crystal structures with atomic resolution. In particular, a triclinic crystal form of CK2α′Cys336Ser is a robust tool to determine high-quality enzyme-ligand complex structures via soaking. In this work, further high-resolution CK2α′Cys336Ser structures in complex with selected ligands emphasizing this trend are described. In one of these structures, the “N-terminal segment site”, a small-molecule binding region never found in any eukaryotic protein kinase and holding the potential for the development of highly selective substrate-competitive CK2 inhibitors, was discovered. In order to also address the binding site for the non-catalytic subunit CK2β, which is inaccessible in these triclinic CK2α′Cys336Ser crystals for small molecules, a reliable path to a promising monoclinic crystal form of CK2α′Cys336Ser is presented. In summary, the quality of CK2α′Cys336Ser as an exquisite crystallographic tool is solidified. Full article
(This article belongs to the Special Issue Past, Present and Future of Protein Kinase CK2 Research)
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Review

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26 pages, 8307 KiB  
Review
CK2 Inhibitors Targeting Inside and Outside the Catalytic Box
by Sophie Day-Riley, Rebekah M. West, Paul D. Brear, Marko Hyvönen and David R. Spring
Kinases Phosphatases 2024, 2(2), 110-135; https://doi.org/10.3390/kinasesphosphatases2020007 - 26 Mar 2024
Viewed by 1103
Abstract
CK2 is a protein kinase that plays an important role in numerous cellular pathways involved in cell growth, differentiation, proliferation, and death. Consequently, upregulation of CK2 is implicated in many disease types, in particular cancer. As such, CK2 has gained significant attention as [...] Read more.
CK2 is a protein kinase that plays an important role in numerous cellular pathways involved in cell growth, differentiation, proliferation, and death. Consequently, upregulation of CK2 is implicated in many disease types, in particular cancer. As such, CK2 has gained significant attention as a potential therapeutic target in cancer, and over 40 chemical probes targeting CK2 have been developed in the past decade. In this review, we highlighted several chemical probes that target sites outside the conventional ATP-binding site. These chemical probes belong to different classes of molecules, from small molecules to peptides, and possess different mechanisms of action. Many of the chemical probes discussed in this review could serve as promising new candidates for drugs selectively targeting CK2. Full article
(This article belongs to the Special Issue Past, Present and Future of Protein Kinase CK2 Research)
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24 pages, 1472 KiB  
Review
Scoping Pleiotropy of CK2 in Musculoskeletal Disorders for a Novel Targeting Approach
by Venu Pandit, Kailey DeGeorge and Anja Nohe
Kinases Phosphatases 2024, 2(1), 43-66; https://doi.org/10.3390/kinasesphosphatases2010004 - 31 Jan 2024
Viewed by 939
Abstract
Protein kinase CK2 (CK2) influences one-fifth of the cellular phosphoproteome. It regulates almost all cellular pathways and is thus a critical switch between biological processes within a cell. Inhibition of CK2 reverses oncogene addiction of tumor and alters tumor microenvironment. The success of [...] Read more.
Protein kinase CK2 (CK2) influences one-fifth of the cellular phosphoproteome. It regulates almost all cellular pathways and is thus a critical switch between biological processes within a cell. Inhibition of CK2 reverses oncogene addiction of tumor and alters tumor microenvironment. The success of this strategy and its clinical translation opens new opportunities. Targeting CK2 in musculoskeletal disorders is promising. Clinical manifestations of these disorders include dysfunctional inflammation, dysregulated cell differentiation, and senescence. Processes regulated by CK2 include all of these. Its emerging role in senescence also indicates its function’s centrality in cellular metabolism. This review summarizes considerations for targeting CK2 in musculoskeletal disorders. We have discussed the implications of CK2-regulated processes in musculoskeletal disorders. Full article
(This article belongs to the Special Issue Past, Present and Future of Protein Kinase CK2 Research)
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18 pages, 2963 KiB  
Review
CK2 Chemical Probes: Past, Present, and Future
by Han Wee Ong, David H. Drewry and Alison D. Axtman
Kinases Phosphatases 2023, 1(4), 288-305; https://doi.org/10.3390/kinasesphosphatases1040017 - 01 Nov 2023
Cited by 1 | Viewed by 1465
Abstract
Protein kinase casein kinase 2 (CK2/CSNK2) is a pleiotropic kinase involved in many cellular processes and, accordingly, has been identified as a potential target for therapeutic intervention for multiple indications. Significant research effort has been invested into identifying CK2 inhibitors as potential drug [...] Read more.
Protein kinase casein kinase 2 (CK2/CSNK2) is a pleiotropic kinase involved in many cellular processes and, accordingly, has been identified as a potential target for therapeutic intervention for multiple indications. Significant research effort has been invested into identifying CK2 inhibitors as potential drug candidates and potent and selective CK2 chemical probes to interrogate CK2 function. Here, we review the small molecule inhibitors reported for CK2 and discuss various orthosteric, allosteric, and bivalent inhibitors of CK2. We focus on the pyrazolo[1,5-a]pyrimidines and naphthyridines, two chemotypes that have been extensively explored for chemical probe development. We highlight the uptake and demonstrated utility of the pyrazolo[1,5-a]pyrimidine chemical probe SGC-CK2-1 by the scientific community in cellular studies. Finally, we propose criteria for an ideal in vivo chemical probe for investigating CK2 function in a living organism. While no compound currently meets these metrics, we discuss ongoing and future directions in the development of in vivo chemical probes for CK2. Full article
(This article belongs to the Special Issue Past, Present and Future of Protein Kinase CK2 Research)
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14 pages, 3476 KiB  
Review
Exploring Protein Kinase CK2 Substrate Recognition and the Dynamic Response of Substrate Phosphorylation to Kinase Modulation
by Luca Cesaro, Angelica Maria Zuliani, Valentina Bosello Travain and Mauro Salvi
Kinases Phosphatases 2023, 1(4), 251-264; https://doi.org/10.3390/kinasesphosphatases1040015 - 07 Oct 2023
Viewed by 1044
Abstract
Protein kinase CK2 (formerly known as casein kinase 2 or II), a ubiquitous and constitutively active enzyme, is widely recognized as one of the most pleiotropic serine/threonine kinases. It plays a critical role in numerous signaling pathways, with hundreds of bona fide substrates. [...] Read more.
Protein kinase CK2 (formerly known as casein kinase 2 or II), a ubiquitous and constitutively active enzyme, is widely recognized as one of the most pleiotropic serine/threonine kinases. It plays a critical role in numerous signaling pathways, with hundreds of bona fide substrates. However, despite considerable research efforts, our understanding of the entire CK2 substratome and its functional associations with the majority of these substrates is far from being completely deciphered. In this context, we aim to provide an overview of how CK2 recognizes its substrates. We will discuss the pros and cons of the existing methods to manipulate CK2 activity in cells, as well as exploring the dynamic response of substrate phosphorylation to CK2 modulation. Full article
(This article belongs to the Special Issue Past, Present and Future of Protein Kinase CK2 Research)
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10 pages, 1202 KiB  
Review
Protein Kinase CK2 and SARS-CoV-2: An Expected Interplay Story
by Camila Paz Quezada Meza and Maria Ruzzene
Kinases Phosphatases 2023, 1(2), 141-150; https://doi.org/10.3390/kinasesphosphatases1020009 - 16 Jun 2023
Cited by 6 | Viewed by 1768
Abstract
Protein kinase CK2 is a Ser/Thr protein kinase that phosphorylates hundreds of substrates mainly related to survival and proliferation pathways. It has long been considered an anti-cancer drug target. However, during the recent COVID-19 pandemic, CK2 inhibitors have been repurposed as anti-SARS-CoV-2 drugs. [...] Read more.
Protein kinase CK2 is a Ser/Thr protein kinase that phosphorylates hundreds of substrates mainly related to survival and proliferation pathways. It has long been considered an anti-cancer drug target. However, during the recent COVID-19 pandemic, CK2 inhibitors have been repurposed as anti-SARS-CoV-2 drugs. This was based on the initial finding of CK2 among the proteins of the host cell that interact with the viral proteins and modulate the infection. Since then, several studies have deepened our understanding of the CK2/COVID-19 connection, and we deem it is time to review all the findings. Interestingly, other coronaviruses cross-talk with CK2 as well, with similarities and differences compared to the SARS-CoV-2 case. Therefore, we believe that the analysis of the effects obtained by targeting CK2 in case of coronavirus infections, both at the molecular and phenomenological level, will help in extrapolating information that could be useful not only for COVID-19 (whose pandemic emergency is hopefully turning off) but also for other infections. Full article
(This article belongs to the Special Issue Past, Present and Future of Protein Kinase CK2 Research)
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Other

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8 pages, 1823 KiB  
Brief Report
The CK2/ECE1c Partnership: An Unveiled Pathway to Aggressiveness in Cancer
by Karla Villalobos-Nova, María de los Ángeles Toro, Pablo Pérez-Moreno, Ignacio Niechi and Julio C. Tapia
Kinases Phosphatases 2024, 2(1), 1-8; https://doi.org/10.3390/kinasesphosphatases2010001 - 19 Dec 2023
Viewed by 729
Abstract
The endothelin-1 (ET1) peptide has a pathological role in the activation of proliferation, survival and invasiveness pathways in different cancers. ET1’s effects rely on its activation by the endothelin-converting enzyme-1 (ECE1), which is expressed as four isoforms, differing only in their cytoplasmic N-terminuses. [...] Read more.
The endothelin-1 (ET1) peptide has a pathological role in the activation of proliferation, survival and invasiveness pathways in different cancers. ET1’s effects rely on its activation by the endothelin-converting enzyme-1 (ECE1), which is expressed as four isoforms, differing only in their cytoplasmic N-terminuses. We already demonstrated in colorectal cancer, glioblastoma, and preliminarily lung cancer, that the isoform ECE1c heightens aggressiveness by promoting cancer stem cell traits. This is achieved through a non-canonical ET1-independent mechanism of enhancement of ECE1c’s stability upon CK2-dependent phosphorylation at S18 and S20. Here, a K6 residue is presumably responsible for ECE1c ubiquitination as its mutation to R impairs proteasomal degradation. However, how phosphorylation enhances ECE1c’s stability and how this translates into aggressiveness are still open questions. In this brief report, by swapping residues to either phospho-mimetic or phospho-resistant amino acids, we propose that the N-terminus may also be phosphorylated at Y5 and/or T9 by an unknown kinase(s). In addition, N-terminus phosphorylation may lead to a blockage of K6 ubiquitination, increasing ECE1c’s stability and presumably activating the Wnt/β-catenin signaling pathway. Thus, a novel CK2/ECE1c partnership may be emerging to promote aggressiveness and thus become a biomarker of poor prognosis and a potential therapeutic target for several cancers. Full article
(This article belongs to the Special Issue Past, Present and Future of Protein Kinase CK2 Research)
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