70 years of CK2: still exciting, essential – and enigmatic!

In 1954, George Burnett and Eugene Kennedy were the first biochemists to report about an enzymatic activity for the phosphorylation of proteins (Burnett and Kennedy 1954). The enzyme – called “protein phosphokinase” by the authors of this pioneering work – was quite specific for casein as a substrate, i.e. for a relatively unspectacular extracellular storage and food protein. This lack of an obvious cellular function contributed to the history that Kennedy “dropped the study of protein kinases, and like the base Indian, cast a pearl away, else richer than all his tribe”, as he wrote – with reference to the tragic final scene in Shakespeare’s drama “Othello” – in an autobiographic review of his nevertheless fruitful life as a researcher (Kennedy 1992).

In the same year 1992, when Eugene Kennedy regretted his fatal decision, Edwin Krebs and Edmond Fischer received a Nobel Prize “for their discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism” (www.nobel.se). One year after Burnett and Kennedy (1954), Fischer and Krebs (1955) – as well as Sutherland and Wosilait (1955) – had presented their own first evidence pointing to an enzymatic activity for protein phosphorylation, and in 1956, they published the ultimate proof of “The phosphorylase b to a converting enzyme of rabbit skeletal muscle” (Krebs and Fischer 1956). The biological significance of this protein kinase (glycogen phosphorylase-b kinase) was clear from the beginning and it is therefore not surprising that Edwin Krebs and Edmond Fischer continued to work on the topic of protein phosphorylation and had a lasting impact on it.

Within this growing field, Burnett’s and Kennedy’s “protein phosphokinase” remained more of a niche enzyme for decades, with changing names such as phosvitin kinase (Rodnight and Lavin 1964), nuclear protein kinase NII (Thornburg and Lindell 1977) or Novicoff ascites tumour kinase (Dahmus and Natzle 1977). In the 1980s, designations such as casein kinase TS (Deana et al. 1978), G-type casein kinase (Cochet and Chambaz 1983) (referring to the fact that in addition to ATP, CK2 also accepts GTP as a cosubstrate, which distinguishes it from CK1), casein kinase II (Bidwai et al. 1993) or casein kinase 2 (Marchiori et al. 1988) began to prevail. To counteract such misleading names – based on the artificial substrate casein – the CK2 research community, which had grown in the meantime, agreed in 1994 to use the term “protein kinase CK2” in the future. This decision, communicated by Ahmed et al. (1994), was made at a first international symposium in 1994 dedicated exclusively to the enzyme, which took place in Heidelberg (Germany). On that occasion, it was also arranged to organize similar conferences about every three years in the future in order to reflect current developments in protein kinase CK2 research. In fact, follow-up conferences were held in Grenoble (France) in 1997, Santiago de Chile in 2001, London (Ontario, Canada) in 2004, Padua (Italy) in 2007, Cologne (Germany) in 2010, Lublin (Poland) in 2013 and Homburg (Germany) in 2016.

A CK2 conference planned for 2020 in Barcelona (Spain) had to be cancelled due to the coronavirus SARS-CoV-2 pandemic. Subsequently, it was questionable whether this valuable conference series could be revitalised. From a scientific point of view, there were good reasons to do this. Since the last CK2 conference in 2016, the established (dys)functions of the enzyme in cell survival, signalling, metabolism and tumourigenesis had been further substantiated which emphasized its value as a target for drug development. This has been supplemented by the appearance of Okur-Chung neurodevelopmental syndrome (OCNDS; Okur et al. 2016) and Poirier-Bienvenue syndrome (POBINDS; Poirier et al. 2017), which are rare disorders of neuronal development caused by de novo mutations in CSNK2A1 and CSNK2B, the human genes encoding the catalytic and the regulatory CK2 subunit.

In fact, the impetus for a revival of the CK2 conference series came from the CSNK2A1 foundation (San Francisco, CA, USA), an initiative of families affected by OCNDS, that supports research on the disease. So it happened that both – the historical background of 70 years of CK2 research and 30 years of CK2 conferences, but also the tragedy of a family suffering from OCNDS – dominated the opening session of the “9th International Conference on Protein Kinase CK2”, which took place from 9th to 12th of September 2024 with the motto “70 years of CK2: still exciting, essential – and enigmatic!” at the University of Münster (Germany) and was organised by Joachim Jose (Münster), Claudia Götz (Homburg) and Karsten Niefind (Cologne).

More than 80 scientists from 14 countries all over the world participated in the conference. 29 invited talks and 9 selected short presentations were given in 9 different sessions, such as “CK2 as a cellular pro-survival factor”, “CK2 in cancer biology”, “OCNDS – scientific bases”, “OCNDS – clinical and translational aspects”, “POBINDS”, “CK2 in metabolism and cellular homeostasis”, “CK2 in virus infections” and “Structure, Function and Inhibition” and finally 32 posters were presented, which led to lively discussions among the present CK2 community.

Lorenzo A. Pinna from Padua, who had already published a review of 40 years of research history after the first CK2 conference in Heidelberg (Pinna 1994), now invited the audience to “A Journey into the infancy of CK2: serendipitous findings and still open questions”, followed by Khalil Ahmed, Minneapolis, who looked back on 30 years of international CK2 conferences and the wealth of knowledge that had been accumulated during this period about the role of the protein kinase CK2 in cellular signalling. The opening session of the conference, which was officially opened by the Rector of the University of Münster, Johannes Wessels, ended with a presentation by Jennifer Sills, founder and President of the CSNK2A1 Foundation. She reported on her family’s experience with OCNDS and impressively demonstrated to the audience how important it is to intensify efforts to investigate the background and treatment options for this tragic pathology.

The morning of the following day was dedicated to the role of CK2 as pro-survival factor and its importance for tumour biology. It is long known that protein kinase CK2 is over-expressed and hyperactive in most tumours and thus, supports tumour pathogenesis. New molecular mechanisms which contribute to the tumour phenotype were presented. Some of the talks focused on CK2 as a prognostic marker or a possible target molecule for the treatment of various tumours. The current use of two CK2 inhibitors in the treatment of certain tumour types justifies further research and development of possibly even more effective CK2-inhibiting molecules. Since the immune system plays a decisive role in tumour development, the regulation of the adaptive immune cell function by CK2 was enlightened.

While the ‘tumour session’ dealt with a hyperactive CK2, the neurological diseases OCNDS and POBINDS are about low-activity or dysfunctional CK2. In OCNDS, the catalytic α subunit of CK2 is subject of de novo mutations, while in POBINDS such mutations appear in the regulatory β subunit. Both lead to a wide variety of symptoms and in particular to some degree of developmental delay and differences in brain function in the course of these diseases. The biochemical properties of some CK2 mutants were presented, as well as suitable animal models to study their impact on the whole organism. Volkan Okur, one of the two first describers and name-givers of OCNDS, gave a key lecture in which the importance of modern sequencing technologies for the diagnosis of the disease, for the detection of its clinical spectrum and for understanding of gene-disease associations as well as underlying molecular mechanisms were highlighted. The CSNK2A1 foundation (San Francisco, CA, USA), which is now an established forum for families with affected individuals, provided an insight into the problems related to the disease, as well as into the work of the foundation.

The next session was dedicated to CK2 as a regulator of a number of basic metabolic functions. Protein kinase CK2 is implicated in protein assembly, in the regulation of selective autophagy, in the controlled secretion of diverse molecules from cells and in the regulation of carbohydrate and lipid metabolism. Moreover, CK2 is ‘hijacked’ by some viruses to ensure their life cycle. It is therefore not surprising that CK2 inhibitors can also be an option for antiviral therapy.

The conference ended with a block of lectures on the latest approaches to develop such inhibitory molecules with remarkable outcomes. The aim here is not only to generate valuable tools for basic research, but also to develop potentially new, effective anti-tumour and anti-viral therapeutics. Some inhibitors have already been approved as drugs for orphan diseases by the FDA in the USA. One highlight of this session was the report on new potent bivalent CK2 inhibitors, with a benzonaphtyridine moiety addressing the ATP site and a trifluoromethoxybenzyl moiety addressing the αD pocket, that were just entering clinical trials as anti-tumour drugs.

Overall, this conference was a highly interesting forum to bring CK2 scientists from all over the world together again after the significant pandemic-related gap. New approaches and developments were presented and the breaks between the lecture blocks were characterised by lively discussions among the different groups. Finally, it was decided to keep this format of CK2 conference alive and all participants were highly delighted that Claire Coderch Boué, Beatriz de Pascual-Teresa and Irene Ortín Rémon from the University San Pablo CEU (Madrid, Spain) agreed to organize the 10th International Conference on Protein Kinase 2027 in Madrid.

This Highlight Issue in Biological Chemistry is reflecting the 9th conference on protein kinase CK2 and is mirroring as well the latest progress in CK2 research. The editors of this issue would like to express their severe thanks to all contributors; in our function as organizers of the conference, we would also like to express our special gratitude to the team of Joachim Jose from the Institute of Pharmaceutical and Medicinal Chemistry at the University of Münster, who played a key role in the organisation of the conference. In particular, the dedicated support of Eva Woltering, Dagmar Aichele, Florian Lenz and Helge Prinz is gratefully acknowledged.

The conference was supported by donations and grants of the CSNK2A1 foundation (San Francisco, CA, USA), the Fonds der Chemischen Industrie (FCI, Frankfurt, Germany), the Dr. Rolf M. Schwiete Stiftung (Mannheim, Germany), the International Office of the University of Münster, Microsynth Seqlab (Göttingen, Germany), and was sponsored by MDPI AG (Basel, Switzerland). The organizers and participants highly appreciate this support, which was crucial for convening the 9th International Conference on Protein Kinase CK2 at the PharmaCampus in Münster.