Article

Protein Kinase CK2 in Human Diseases

Institute for Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark.
Current Medicinal Chemistry (Impact Factor: 3.85). 02/2008; 15(19):1870-86. DOI: 10.2174/092986708785132933
Source: PubMed

ABSTRACT

Protein kinase CK2 (formerly referred to as casein kinase II) is an evolutionary conserved, ubiquitous protein kinase. There are two paralog catalytic subunits, i.e. alpha (A1) and alpha' (A2). The alpha and alpha' subunits are linked to two beta subunits to produce a heterotetrameric structure. The catalytic alpha subunits are distantly related to the CMGC subfamily of kinases, such as the Cdk kinases. There are some peculiarities associated with protein kinase CK2, which are not found with most other protein kinases: (i) the enzyme is constitutively active, (ii) it can use ATP and GTP and (iii) it is found elevated in most tumors investigated and rapidly proliferating tissues. With the elucidation of the structure of the catalytic subunit, it was possible to explain why the enzyme is constitutively active [1] and why it can bind GTP [2]. Considerable information on the potential roles of CK2 in various disease processes including cancer has been gained in recent years, and the present review may help to further elucidate its aberrant role in many disease states. Its peculiar structural features [3-9] may be advantageous in designing tailor-made compounds with the possibility to specifically target this protein kinase [10]. Since not all the aspects of what has been published on CK2 can be covered in this review, we would like to recommend the following reviews; (i) for general information on CK2 [11-18] and (ii) with a focus on aberrant CK2 [19-22].

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    • "CK2 is a constitutive and ubiquitous Ser/Thr protein kinase that functions as a global regulator of cell survival often found deregulated in cancer and other complex diseases [1] [2] [3] [4]. The CK2 consensus sequence, [pS/pT]-{P}-x-[E/D] or [pS/pT]-{P}-x-pS, constitutes a small motif found so far in more than 300 experimentally determined CK2 substrates among different organisms and viral proteins [3]. "
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    ABSTRACT: CK2 is a constitutively active Ser/Thr protein kinase deregulated in cancer and other pathologies, responsible for about the 20% of the human phosphoproteome. The holoenzyme is a complex composed of two catalytic (α or α´) and two regulatory (β) subunits, with individual subunits also coexisting in the cell. In the holoenzyme, CK2β is a substrate-dependent modulator of kinase activity. Therefore, a comprehensive characterization of CK2 cellular function should firstly address which substrates are phos-phorylated exclusively when CK2β is present (class-III or beta-dependent substrates). However, current experimental constrains limit this classification to a few substrates. Here, we took advantage of motif-based prediction and designed four linear patterns for predicting class-III behavior in sets of experimentally determined CK2 substrates. Integrating high-throughput substrate prediction, functional classification and network analysis, our results suggest that beta-dependent phosphorylation might exert particular regulatory roles in viral infection and biological processes/pathways like apoptosis, DNA repair and RNA metabolism. It also pointed, that human beta-dependent substrates are mainly nuclear, a few of them shuttling between nuclear and cytoplasmic compartments.
    Full-text · Article · Dec 2015
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    • "CK2 plays a key role in proliferation (Guerra and Issinger, 2008; Guerra and Issinger 1999), transformation (Ruzzene and Pinna, 2010), apoptosis (Guerra and Issinger, 2008; Ahmad et al., 2008), survival (Guerra and Issinger, 2008; Ruzzene and Pinna, 2010; Barata, 2011) and cell growth (Meggio and Pinna, 2003; Guerra and Issinger, 2008; Duncan et al., 2010). Beside the involvement CK2 in various cellular functions (Meggio and Pinna, 2003; Ahmad et al., 2008; Canton and Litchfield, 2006), overexpression of CK2 could lead to different number of cancers diseases(Faust et al., 2000; Kramerov et al., 2006; Duncan and Litchfield, 2008; Landesman-Bollag et al., 2001), including breast (Drygin et al., 2011), renal (Landesman- Bollag et al., 2001), leukemias (Piazza et al., 2013), prostate and lung cancers(Guerra and Issinger, 2008). The increased level of CK2 can also result in several central nervous system diseases such as Alzheimer, Parkinson, brain ischemia and memory impairments (Meggio and Pinna 2003; Landesman-Bollag et al., 2001; Sarno and Pinna, 2008). "
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    ABSTRACT: In this work, the quantitative structure-activity relationship models were developed for predicting activity of a series of compounds as CK2 inhibitors using multiple linear regressions and support vector machine methods. The data set consisted of 48 compounds was divided into two subsets of training and test set, randomly. The most relevant molecular descriptors were selected using the genetic algorithm as a feature selection tool. The predictive ability of the models was evaluated using Y- randomization test, cross-validation and external test set. The genetic algorithm- multiple linear regression model with six selected molecular descriptors was obtained and showed high statistical parameters (R2train=0.893, R2test=0.921, Q2LOO= 0.844, F=43.17, RMSE=0.287). Comparison of the results between GA-MLR and GA-SVM demonstrates that GA-SVM provided better results for the training set compounds, however the predictive quality for both models are acceptable. The results suggest that atomic mass and polarizabilities and also number of heteroatom in molecules are the main independent factors contributing to the CK2 inhibition activity. The predicted results of this study can be used to design of new and potent CK2 inhibitors.
    Full-text · Article · Jan 2015 · Arabian Journal of Chemistry
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    • "CK2 has been found to play a role in a vast number of normal and abnormal cell functions and has emerged as a key cellular regulator with a large number of substrates [Ahmed, 1999; Guerra and Issinger, 1999; Tawfic et al., 2001; Pinna, 2002; Meggio and Pinna, 2003; St-Denis and Litchfield, 2009]. In particular, much work has been undertaken regarding its function in cancer pathobiology and it is remarkable that CK2 has been found to be uniformly dysregulated in all cancers examined [Ahmed et al., 2000; Tawfic et al., 2001; Guerra and Issinger, 2008; Trembley et al., 2009]. "
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    ABSTRACT: CK2 (official acronym for casein kinase 2 or II) is a potent suppressor of apoptosis in response to diverse apoptotic stimuli —thus its molecular downregulation or activity inhibition results in potent induction of cell death. CK2 downregulation is known to impact mitochondrial apoptotic circuitry but the underlying mechanism(s) remain unclear. Utilizing prostate cancer cell lines subjected to CK2-specific inhibitors which cause loss of cell viability, we have found that CK2 inhibition in cells causes rapid early decrease in mitochondrial membrane potential (Δψm). Cells treated with the CK2 inhibitors TBB (4,5,6,7-tetrabromobenzotriazole) or TBCA (tetrabromocinnamic acid) demonstrate changes in Δψm which become apparent within 2 h, i.e., significantly prior to evidence of activation of other mitochondrial apoptotic signals whose temporal expression ensues subsequent to loss of Δψm. Further, we have demonstrated the presence of CK2 in purified mitochondria and it appears that the effect on Δψm evoked by inhibition of CK2 may involve mitochondrial localized CK2. Results also suggest that alterations in Ca2+ signaling may be involved in the CK2 mediated regulation of Δψm and mitochondrial permeability. Thus, we propose that a key mechanism of CK2 impact on mitochondrial apoptotic circuitry and cell death involves early loss of Δψm which may be a primary trigger for apoptotic signaling and cell death resulting from CK2 inhibition. J. Cell. Biochem. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Dec 2014 · Journal of Cellular Biochemistry
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