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  • Nearly years ago the first two enzymes which catalyze the

    2019-11-25

    Nearly 60years ago, the first two UNC0638 which catalyze the phosphorylation of proteins were discovered [1]. Protein phosphorylation was originally identified as a regulatory mechanism for the control of glycogen metabolism. Today it is clear that protein phosphorylation regulates most aspects of cell life, whereas, abnormal phosphorylation can be a cause of a disease. About 2% of the proteome are protein kinases, accounting for about 518 enzymes, which can phosphorylate up to 30% of all cellular proteins [2]. Substrates of protein kinases cover all aspects of the life of a cell, i.e. metabolic pathways, structural proteins, signalling pathways and DNA replication, transcription, translation and maintenance of genome stability. These pleiotropic functions make protein kinases attractive as targets for the regulation of cellular properties and for the treatment of specific diseases. The attractiveness of protein kinases as targets for regulation by inhibitors is enhanced by the fact that the activity of enzymes can be turned off or gradually regulated by these inhibitors. The link between a protein kinase and a particular disease is usually provided by the identification of some substrates which are implicated in a specific disease. However, studying protein kinases is important not only for the treatment of diseases but also for the understanding of the physiological roles of the protein kinase. All of these facts are reasons for a growing interest in developing active protein kinase inhibitors. After G-coupled receptors, protein kinases have now become the second most important group of drug targets. Some of these protein kinase inhibitors are already in clinical trials and a lot more are at preclinical stage. One of the first two kinases identified in the very early studies were the cAMP-dependent protein kinase or PKA and casein kinase II now called protein kinase CK2. Protein kinase CK2 is a tetrameric enzyme with a molecular weight of 130–150kDa. One peculiar feature of CK2 is that of using GTP almost as efficiently as ATP as a phosphate donor. The heterotetrameric enzyme is composed of two larger catalytic subunits, CK2α (44kDa) and CK2α’ (36kDa) and two smaller non-catalytic CK2β subunits (25kDa). Structural analysis revealed that the CK2α or CK2α’ subunits bind to a CK2β dimer. In earlier work on CK2, polyamines such as spermine and spermidine were found to stimulate CK2 activity [3]. Heparin on the other hand was found as an inhibitor of the kinase activity [4]. In the meantime, the number of proteins and factors that either inhibit or stimulate the enzyme activity of CK2 increased (for review see [5]). Also, the individual CK2α and CK2β subunits were shown to regulate other enzymes indicating that the subunits have additional functions other than the one known in the holoenzyme [6], [7], [8], [9], [10]. Protein kinase CK2 is different from most of the other serine/threonine kinases which UNC0638 are usually basophilic or proline dependent enzymes, whereas, CK2 recognizes acidic sites. Based on the minimum consensus site for CK2 phosphorylation S/TXXE/D, it was calculated that more than 1000 proteins in the phosphoproteome are phosphorylated by CK2. More than 400 different substrates of CK2 are known today [11], [12], in addition, there are an increasing number of binding partners for CK2. These studies revealed that CK2 plays a central role in the regulation of proliferation, apoptosis, differentiation, aging and angiogenesis (for reviews see: [8], [13], [14], [15], [16], [17], [18], [19]). Bibby and Litchfield described that high levels of CK2 have been observed in various types of cancers including breast, prostate, lung, kidney and head and neck cancer [20]. Although elevated CK2 activities have been found in organs and tissues, which are important in carbohydrate metabolism such as brain, liver and skeletal muscle [21], [22], [23], only a few CK2 substrates are already identified. A tightly controlled carbohydrate metabolism is essential for the survival and growing of cells and organs and also for a successful exercise of humans. It is striking, however, that only little is known about the role of CK2 in carbohydrate metabolism; although there was an early observation that 2,3 bisphosphoglycerate was found as an inhibitor of CK2 and that the inhibitory function can be abrogated by polyamines [24], [25]. The present review will address the role of CK2 in hormonal regulation of the carbohydrate metabolism as well as its role in the direct regulation of enzymes in the carbohydrate metabolism.