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  • An increased CK activity was found in


    An increased CK2 activity was found in septal neuronal Pacritinib structure dissected from rat embryos after hypoglycemia [36]. These data indicated that CK2 activity is not only regulated by insulin but also by the glucose concentration. One essential step in insulin action is the binding of the hormone to specific cell surface receptors. This receptor displays two functional domains, an extracellular hormone binding site and an intracellular domain processing an insulin stimulated tyrosine kinase activity [37]. It was shown that CK2 phosphorylated the intracellular domain of the insulin receptor (Fig. 2) [38]. These authors further showed that only serine and threonine residues were phosphorylated which was supported by a study with peptides derived from the insulin receptor and comprising putative CK2 phosphorylation sites [39]. The identified CK2 phosphorylation site was located in the activation site of the insulin receptor. It was further shown by Grande et al. [38] that the CK2 phosphorylation of the insulin receptor at least partially reduced its tyrosine kinase activity. One of the down-stream targets of the insulin receptor is the insulin receptor substrate 1 (IRS1), which is rapidly phosphorylated in an insulin dependent manner. One of the protein kinases phosphorylating IRS1 in addition to the insulin receptor is protein kinase CK2 [40]. These authors found some indications that CK2 phosphorylated IRS1 at least in part in an insulin dependent manner (Fig. 2). These data strongly support the idea that CK2 plays an essential role in the regulation of insulin production and release, at least in β-cells of the pancreas. It also suggests its involvement in the regulation of the insulin action and signalling in other cell types, thereby, supporting the idea that CK2 is an active member of the intracellular signalling cascade.
    CK2 and enzyme regulation of carbohydrate metabolism Only monosaccharides like glucose, fructose or galactose are taken up by active membrane transport systems [41]. Once in the cell, glucose is phosphorylated by a family of enzymes called hexokinases to form glucose-6-phosphate. For storage of glucose in a cell, glucose-6-phosphate is converted into glucose-1-phosphate by the action of phosphoglucomutase. Glucose-1-phosphate is then converted into UDP-glucose by uridyltransferase. Finally UDP-glucose is added to the non-reducing end of glycogen molecules by glycogen synthase. Glycogen synthase is one of the very early identified substrates of CK2 (Fig. 2) [42]. As in mammalian cells, glycogen synthase from yeasts exits in two forms which are interconverted by phosphorylation and dephosphorylation [43]. The phosphorylated form has little activity, whereas, the de-phosphorylated form is active. It was shown in yeast Yarrowia lipolytica that the activity of glycogen synthase was regulated by CK2 and by the phosphatase PP2a. During the early stationary phase of cell growth, an increase in CK2 activity and a decrease in the glycogen content were observed. The activity of protein phosphatase 2A on glycogen synthase however rises during the exponential growing phase [44]. These data show that CK2 is implicated in the regulation of energy storage by regulating the phosphorylation of glycogen synthase (Fig. 2). In the case of fuel requirements, glucose-6-phosphate can enter glycolysis which is a well defined sequence of reactions leading to energy production and to pyruvate as an intermediate carbohydrate metabolite. In the first step of glycolysis, glucose-6-phosphate is converted into fructose-6-phosphate by the enzyme phosphoglucose isomerase. It was reported that phosphoglucose isomerase is phosphorylated at serine 185 by CK2 (Fig. 2) [45]. Later on, it was shown that mutants of phosphoglucose isomerase mimicking CK2 phosphorylation had a decreased enzymatic activity; whereas, the alanine mutant at the CK2 site retained full activity Pacritinib structure [46]. Furthermore, it was shown that phosphoglucose isomerase wild-type and the S185A mutant protein dimerize; whereas, the mutants mimicking CK2 phosphorylation formed tetramers, demonstrating that phosphorylation affects the allosteric properties of phosphoglucose isomerase. These results demonstrate that CK2 is implicated also in the regulation of carbohydrate metabolism.