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PubMed2005

Salicylic acid-inducible Arabidopsis CK2-like activity phosphorylates TGA2.

We demonstrate that TGA2, TGA5 and TGA6, and TGA3 to a lesser extent, are phosphorylated by an activity in rabbit reticulocytes. Using deletion and point mutagenesis of TGA2, three amino acid (aa) residues, (11)Ser, (12)Thr and (16)Thr, were found to be critical for efficient phosphorylation by a kinase(s) in rabbit reticulocytes. These three residues also were important for phosphorylation by recombinant human Casein Kinase II (CK2) and by a CK2-like kinase in Arabidopsis leaf extracts. Salicylic acid (SA) treatment enhanced the phosphorylation of recombinant TGA2 in vitro; it also enhanced phosphorylation of a TGA2-GFP fusion protein in vivo. By contrast, in vivo phosphorylation of a TGA2-A-GFP fusion protein, in which the (11)Ser, (12)Thr and (16)Thr residues were mutated to non-phosphorylable alanine, was only poorly if at all stimulated by SA treatment. Mutation of the putative CK2 phosphorylation motif did not affect nuclear localization of TGA2. However, the DNA binding activity of TGA2 was reduced by CK2 treatment, whereas that of TGA2-A was unaffected; TGA2's DNA binding activity after incubation in a rabbit reticulocyte lysate also was substantially lower than that of comparably treated TGA2-A. Taken together, these results suggest that phosphorylation at the putative CK2 phosphorylation site negatively regulates the DNA binding activity of TGA2. Analysis of transgenic Arabidopsis overexpressing TGA2-GFP or TGA2-A-GFP, in the absence of SA treatment, revealed that they accumulated similarly elevated levels of PR-1 gene transcripts. Possible reasons why mutations in the putative CK2 phosphorylation site had little effect on PR-1 induction by TGA2 are discussed.

Amino Acid Sequence↗
PubMed2006

A CK2-dependent mechanism for degradation of the PML tumor suppressor.

The PML tumor suppressor controls key pathways for growth suppression, induction of apoptosis, and cellular senescence. PML loss occurs frequently in human tumors through unknown posttranslational mechanisms. Casein kinase 2 (CK2) is oncogenic and frequently upregulated in human tumors. Here we show that CK2 regulates PML protein levels by promoting its ubiquitin-mediated degradation dependent on direct phosphorylation at Ser517. Consequently, PML mutants that are resistant to CK2 phosphorylation display increased tumor-suppressive functions. In a faithful mouse model of lung cancer, we demonstrate that Pml inactivation leads to increased tumorigenesis. Furthermore, CK2 pharmacological inhibition enhances the PML tumor-suppressive property in vivo. Importantly, we found an inverse correlation between CK2 kinase activity and PML protein levels in human lung cancer-derived cell lines and primary specimens. These data identify a key posttranslational mechanism that controls PML protein levels and provide therapeutic means toward PML restoration through CK2 inhibition.

Amino Acid Sequence↗
PubMed2006

High phosphorylation of HBV core protein by two alpha-type CK2-activated cAMP-dependent protein kinases in vitro.

Two alpha-type CK2-activated PKAs (CK2-aPKAIalpha and CK2-aPKAIIalpha) were biochemically characterized in vitro using GST-HBV core fusion protein (GST-Hcore) and GST-Hcore157B as phosphate acceptors. It was found that (i), in the absence of cAMP, these two CK2-aPKAs phosphorylated both Ser-170 and Ser-178 on GST-Hcore and Hcore157B; (ii) this phosphorylation was approx. 4-fold higher than their phosphorylation by cAMP-activated PKAs; and (iii) suramin effectively inhibited the phosphorylation of Hcore157B by CK2-aPKAIIalpha through its direct binding to Hcore157B in vitro. These results suggest that high phosphorylation of HBV-CP by two CK2-aPKAs, in the absence of cAMP, may be involved in the pregenomic RNA (pgRNA) encapsidation and DNA-replication in HBV-infected cells.

Animals↗
PubMed2003

Inhibition of CK2 activity by TGF-beta1 promotes IkappaB-alpha protein stabilization and apoptosis of immortalized hepatocytes.

Nuclear factor kappaB (NF-kappaB) is an antiapoptotic factor involved in development, regeneration, and neoplastic progression of the liver. Previously, we have shown that stabilization of inhibitor kappaB (IkappaB)-alpha protein following treatment of hepatocytes with transforming growth factor (TGF)-beta1 promoted NF-kappaB repression, which then permitted induction of AP-1/SMAD-mediated liver cell death. Because basal IkappaB-alpha protein turnover is regulated by protein kinase CK2, here we have elucidated the regulation of CK2 kinase activity and its role in control of NF-kappaB levels following treatment with TGF-beta1. We show that both messenger RNA (mRNA) and protein levels of the CK2alpha catalytic subunit are down-regulated following TGF-beta1 stimulation in murine hepatocyte cells. The ensuing inhibition of CK2 kinase activity promotes stabilization of IkappaB protein, which is followed by the shutoff of constitutive NF-kappaB activity and induction of apoptosis. Ectopic expression of CK2alpha inhibits TGF-beta1-induced apoptosis through sustained activation of NF-kappaB. Conversely, expression of a kinase-dead mutant of CK2alpha potentiates TGF-beta1 cell killing. Importantly, we show that hepatocellular carcinomas (HCCs) derived from TGF-beta1 transgenic mice and human HCC cell lines display enhanced CK2 IkappaB kinase activity that contributes in part to an elevated NF-kappaB activity in vivo. In conclusion, inhibition of CK2 expression levels by TGF-beta1 is crucial for the induction of apoptosis of hepatocytes. Circumvention of this process by up-regulation of CK2 activity in transformed cells may contribute to the promotion of TGF-beta1-induced liver carcinogenesis.

Animals↗
PubMed2006

Drosophila CK2 regulates lateral-inhibition during eye and bristle development.

Lateral inhibition is critical for cell fate determination and involves the functions of Notch (N) and its effectors, the Enhancer of Split Complex, E(spl)C repressors. Although E(spl) proteins mediate the repressive effects of N in diverse contexts, the role of phosphorylation was unclear. The studies we describe implicate a common role for the highly conserved Ser/Thr protein kinase CK2 during eye and bristle development. Compromising the functions of the catalytic (alpha) subunit of CK2 elicits a rough eye and defects in the interommatidial bristles (IOBs). These phenotypes are exacerbated by mutations in CK2 and suppressed by an increase in the dosage of this protein kinase. The appearance of the rough eye correlates, in time and space, to the specification and refinement of the 'founding' R8 photoreceptor. Consistent with this observation, compromising CK2 elicits supernumerary R8's at the posterior margin of the morphogenetic furrow (MF), a phenotype characteristic of loss of E(spl)C and impaired lateral inhibition. We also show that compromising CK2 elicits ectopic and split bristles. The former reflects the specification of excess bristle SOPs, while the latter suggests roles during asymmetric divisions that drive morphogenesis of this sensory organ. In addition, these phenotypes are exacerbated by mutations in CK2 or E(spl), indicating genetic interactions between these two loci. Given the centrality of E(spl) to the repressive effects of N, our studies suggest conserved roles for this protein kinase during lateral inhibition. Candidates for this regulation are the E(spl) repressors, the terminal effectors of this pathway.

Amino Acid Sequence↗
PubMed2004

CK2 phosphorylation of Bdp1 executes cell cycle-specific RNA polymerase III transcription repression.

RNA polymerase III (pol III) transcription from the human U6 snRNA promoter can be reconstituted with the recombinant factors SNAPc and Brf2-TFIIIB combined with purified pol III. In this system, CK2 treatment of the pol III complex is required for transcription, whereas treatment of Brf2-TFIIIB is inhibitory. Here we show that CK2 inhibits Brf2-TFIIIB by specifically phosphorylating its Bdp1 component. Bdp1 is phosphorylated by CK2 during mitosis, and this is accompanied by Bdp1 dissociation from the U6 promoter and from chromatin in general and by transcription repression. Remarkably, whereas inhibition of CK2 in mitotic extracts restores pol III transcription, inhibition of CK2 in active S phase extracts debilitates transcription. Thus, CK2 is directed to phosphorylate different targets within the basal pol III transcription machinery at different times during the cell cycle, with opposite transcriptional effects.

Casein Kinase II↗
PubMed2006

Molecular mechanism of the neurotrophic effect of GDNF on DA neurons: role of protein kinase CK2.

Glial cell line-derived neurotrophic factor (GDNF) is suggested as a specific neurotrophic factor for midbrain dopamine (DA) neurons, but the molecular mechanism underlying the neuroprotective action of GDNF is not well known. In the present study, we have shown that GDNF increased protein kinase CK2 activity in rat substantia nigra (SN) in a dose-dependent and time-dependent manner. This effect is prevented by prior treatment of the receptor Ret blocker K-252b. Immunostaining results also revealed that CK2 is expressed in TH-positive neurons in mesencephalon culture. Transfection of the wildtype CK2alpha DNA increased, whereas transfection of the catalytically inactive CK2alphaA156 mutant DNA decreased CK2 activity in the SN. CK2alphaA156 mutant DNA also antagonized the enhancing effect of GDNF on CK2 activity. It also antagonized the enhancing effects of GDNF on tyrosine hydroxylase (TH) protein level in the SN, DA turnover in the striatum and rotarod performance in rats. Further, CK2alpha wildtype DNA increased, whereas CK2alphaA156 mutant DNA decreased TH activity in the SN without altering the TH protein level. On the other hand, the DA neuron toxin 1-methyl-4-phenylpyridinium iodide (MPP+) markedly decreased the number of TH-positive neurons and TH protein level in the SN, decreased DA level in the striatum and impaired rotarod performance in rats. Over-expression of the CK2alpha wildtype DNA partially, but significantly, prevented the deteriorating effect of MPP+ on these measures. Prior administration of MPP+ also antagonized the enhancing effect of GDNF on CK2 activity. These results together suggest that the CK2 signaling pathway contributes to the neuroprotective action of GDNF on DA neurons.

Animals↗
PubMed2003

Transcriptional activity and DNA binding of heat shock factor-1 involve phosphorylation on threonine 142 by CK2.

Heat shock factor-1 (HSF-1) is the regulator of hsp molecular chaperone transcription, although the intracellular mechanisms involved in HSF-1 activation have not been fully elucidated. As HSF1 is activated by heat shock simultaneously with the nuclear translocation of the protein kinase CK2, we have investigated the role of CK2 in HSF1 activation. We demonstrate that HSF-1 is phosphorylated by CK2 on both serine and threonine residues and has characterized a phosphorylation site at threonine 142. Mutation of Thr-142 to alanine (T142A) inhibits trans-activation of the HSP70 gene by HSF1 and in addition inhibits the accumulation of HSF-1 competent to bind heat shock elements in the nucleus. HSF1 activation by heat is correlated with the thermal activation of nuclear CK2 and overexpression of CK2 activates HSF1. Phosphorylation by CK2 on threonine 142 may therefore be an essential step in the thermal activation of latent HSF1 by stresses.

Alanine↗
PubMed2003

Selectivity of 4,5,6,7-tetrabromobenzimidazole as an ATP-competitive potent inhibitor of protein kinase CK2 from various sources.

Like the previously reported 4,5,6,7-tetrabromobenzotriazole (TBBt), the structurally related 4,5,6,7-tetrabromobenzimidazole (TBBz) is a selective ATP-competitive inhibitor of protein kinase CK2 from such divergent sources as yeast, rat liver, Neurospora crassa and Candida tropicalis, with K(i) values in the range 0.5-1 microM. It is virtually inactive vs. PKA, PKC, and a very weak inhibitor of protein kinase CK1. The corresponding tetrachlorobenzimidazole (TCBz) is a much weaker inhibitor of CK2, like tetrachlorobenzotriazole (TCBt) relative to TBBt. Bearing in mind the similarity of the van der Waals radii of Br (1.95 A) and CH(3) (2.0 A), the corresponding much less hydrophobic 4,5,6,7-tetramethylbenzotriazole (TMeBt) was prepared and found to be a very weak inhibitor of CK2, as well as of CK1. An unexpected, and significant, difference between TBBt and TBBz are their inhibitory activities vs. the yeast protein kinase PK60S, which phosphorylates, both in vitro and in intact yeast cells, three of the five pp13 kDa ribosomal surface acidic proteins in yeast cells. TBBt was previously noted to be a more effective inhibitor of PK60S than of yeast CK2; by contrast, TBBz is a relatively feeble inhibitor of PK60S, hence more selective than TBBt vs. CK2 in yeast cells. TMeBt was virtually inactive vs PK60S. Like TBBt, TBBz is an additional lead compound for development of more potent inhibitors of CK2.

Adenosine Triphosphate↗
PubMed2001

Selectivity of 4,5,6,7-tetrabromobenzotriazole, an ATP site-directed inhibitor of protein kinase CK2 ('casein kinase-2').

The specificity of 4,5,6,7-tetrabromo-2-azabenzimidazole (TBB), an ATP/GTP competitive inhibitor of protein kinase casein kinase-2 (CK2), has been examined against a panel of 33 protein kinases, either Ser/Thr- or Tyr-specific. In the presence of 10 microM TBB (and 100 microM ATP) only CK2 was drastically inhibited (>85%) whereas three kinases (phosphorylase kinase, glycogen synthase kinase 3 beta and cyclin-dependent kinase 2/cyclin A) underwent moderate inhibition, with IC(50) values one--two orders of magnitude higher than CK2 (IC(50)=0.9 microM). TBB also inhibits endogenous CK2 in cultured Jurkat cells. A CK2 mutant in which Val66 has been replaced by alanine is much less susceptible to inhibition by TBB as well as by another ATP competitive inhibitor, emodin. These data show that TBB is a quite selective inhibitor of CK2, that can be used in cell-based assays.

Adenosine Triphosphate↗
PubMed2003

Genetic interactions among ZDS1,2, CDC37, and protein kinase CK2 in Saccharomyces cerevisiae.

We report here the identification of the homologous gene pair ZDS1,2 as multicopy suppressors of a temperature-sensitive allele (cka2-13(ts)) of the CKA2 gene encoding the alpha' catalytic subunit of protein kinase CK2. Overexpression of ZDS1,2 suppressed the temperature sensitivity, geldanamycin (GA) sensitivity, slow growth, and flocculation of multiple cka2 alleles and enhanced CK2 activity in vivo toward a known physiological substrate, Fpr3. Consistent with the existence of a recently described positive feedback loop between CK2 and Cdc37, overexpression of ZDS1,2 also suppressed the temperature sensitivity, abnormal morphology, and GA sensitivity of a CK2 phosphorylation-deficient mutant of CDC37, cdc37-S14A, as well as the GA sensitivity of a cdc37-1 allele. A likely basis for all of these effects is our observation that ZDS1,2 overexpression enhances Cdc37 protein levels. Activation of the positive feedback loop between CK2 and Cdc37 likely contributes to the pleiotropic nature of ZDS1,2, as both CK2 and Cdc37 regulate diverse cellular functions.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Crystal structure of a C-terminal deletion mutant of human protein kinase CK2 catalytic subunit.

Protein kinase CK2 (formerly called: casein kinase 2) is a heterotetrameric enzyme composed of two separate catalytic chains (CK2alpha) and a stable dimer of two non-catalytic subunits (CK2beta). CK2alpha is a highly conserved member of the superfamily of eukaryotic protein kinases. The crystal structure of a C-terminal deletion mutant of human CK2alpha was solved and refined to 2.5A resolution. In the crystal the CK2alpha mutant exists as a monomer in agreement with the organization of the subunits in the CK2 holoenzyme. The refined structure shows the helix alphaC and the activation segment, two main regions of conformational plasticity and regulatory importance in eukaryotic protein kinases, in active conformations stabilized by extensive contacts to the N-terminal segment. This arrangement is in accordance with the constitutive activity of the enzyme. By structural superimposition of human CK2alpha in isolated form and embedded in the human CK2 holoenzyme the loop connecting the strands beta4 and beta5 and the ATP-binding loop were identified as elements of structural variability. This structural comparison suggests that the ATP-binding loop may be the key region by which the non-catalytic CK2beta dimer modulates the activity of CK2alpha. The beta4/beta5 loop was found in a closed conformation in contrast to the open conformation observed for the CK2alpha subunits of the CK2 holoenzyme. CK2alpha monomers with this closed beta4/beta5 loop conformation are unable to bind CK2beta dimers in the common way for sterical reasons, suggesting a mechanism to protect CK2alpha from integration into CK2 holoenzyme complexes. This observation is consistent with the growing evidence that CK2alpha monomers and CK2beta dimers can exist in vivo independently from the CK2 holoenzyme and may possess physiological roles of their own.

Adenosine Triphosphate↗
PubMed1998

The tight association of protein kinase CK2 with plasma membranes is mediated by a specific domain of its regulatory beta-subunit.

Previous immunocytochemical studies have shown that protein kinase CK2 is mostly detected both in the cytoplasm and the nucleus of most cells. In the present study, CK2 was detected in highly purified plasma membrane preparations from rat liver. The protein kinase could be released from the membranes by high salt extraction (>1 M NaCl). Plasma membranes prepared from SF9 insect cells expressing the alpha- and beta-subunits of CK2 also contained a significant amount of oligomeric CK2. Furthermore, it was demonstrated in this cell system as well as in rat liver plasma membranes, that the beta-subunit of the kinase is the targeting subunit which mediates the tight association of the enzyme to plasma membrane components. Binding studies using membranes and recombinant proteins corresponding to different regions of the beta-subunit suggest that a functional domain previously shown to be involved in the binding of polyamines may also participate to the binding of CK2 to membranes. Modification of membranes by trypsin and phospholipases indicated that the binding process may require both membrane protein(s) and phospholipids. Interestingly, it was observed that the amount of membrane-bound CK2 in liver of embryos and new born rats increases dramatically after birth and persists during the postnatal stages of development.

Animals↗
PubMed2003

Casein kinase ii (protein kinase ck2) regulates serotonin 5-ht(3) receptor channel function in ng108-15 cells.

We have used whole-cell recording techniques in the mouse neuroblastoma X rat glioma hybrid NG108-15 cell line to test whether protein kinase CK2 (CK2; also known as casein kinase II) modulates the function of the serotonin 5-HT(3) receptor (5-HT(3)R) channel. The rapid application of 5-HT (50 microM) to NG108-15 cells elicits a 5-HT(3)R-mediated inward current response that rapidly reaches peak amplitude and then desensitizes in the continued presence of agonist. Internal dialysis with CK2 (20 micrograms/ml) via the patch pipette significantly increases the amplitude and decreases the rate of desensitization of the 5-HT(3)R-mediated responses. CK2 that had been heat-inactivated has no effect on either the amplitude or the kinetics of desensitization of the 5-HT(3)R responses. These data suggest that dialysis with protein kinase CK2 significantly enhanced current through the 5-HT(3)R channel, and that CK2 may be an important regulator of 5-HT(3)R channel function in the nervous system, possibly serving to facilitate the 5-HT-induced excitation of the cells.

Animals↗
PubMed2004

Inhibition of protein kinase CK2 by condensed polyphenolic derivatives. An in vitro and in vivo study.

ATP site-directed inhibitors that can target individual kinases are powerful tools for use in signal transduction research, all the more so in the case of a pleiotropic, constitutively active protein kinase such as CK2, which is not turned on in response to specific stimuli. By screening a library of more than 200 derivatives of natural polyphenolic compounds, we have identified 16 molecules which inhibit CK2 with IC(50) values of <or=1 microM. They belong to the classes of anthraquinones (six compounds), xanthenones (two compounds), fluorenones (one compound), and coumarins (seven compounds), and their inhibitory potency correlates with the presence of nitro, amino, or halogen substituents at specific positions. Three of the most potent inhibitors, MNX (1,8-dihydroxy-4-nitroxanthen-9-one), NBC (8-hydroxy-4-methyl-9-nitrobenzo[g]chromen-2-one), and DBC (3,8-dibromo-7-hydroxy-4-methylchromen-2-one), whose IC(50) values range between 0.13 and 0.36 microM, are quite specific toward CK2 within a panel of 33 protein kinases tested. Treatment of Jurkat cells with these compounds promotes inhibition of endogenous CK2 and induction of apoptosis. A correlation is observed between their efficacy as CK2 inhibitors (as judged from IC(50) values) and their capacity to induce cell death (DC(50) values). Mutations of the unique CK2alpha residues Val66 and/or Ile174 to alanine have a detrimental effect on inhibition by these compounds with 16-67-fold increases in IC(50) values. The combined usage of these reagents can be exploited to gain information about cellular functions mediated by CK2.

Apoptosis↗
PubMed1997

Chemical features of the protein kinase CK2 polyamine binding site.

Protein kinase CK2 is a ubiquitous eukaryotic Ser/Thr kinase whose catalytic activity is enhanced several times by polyamines. We have shown previously that the regulatory beta-subunit of CK2 bears a polyamine binding site located in the region Asp51-Tyr110. In the present study, we have used spermine analogs to investigate the structural requirements of the CK2 polyamine binding site. We have observed a strong correlation between the stimulations of CK2 activity by all tested polyamines and their binding efficiencies to the enzyme. As a result, spermine was found to be the most efficient stimulator of the kinase activity and the best CK2 ligand. The effect of the pH on the stimulation of CK2 activity by spermine strongly suggests the involvement of ionic interactions between the positive charges of spermine and the negative charges of acidic amino acids of the beta-subunit. Using a fusion protein made of MBP and the beta-subunit region encompassing amino acid residues Asp51-Pro110, we have studied the binding of spermine as a function of the ionic strength. We show that this region delineates a functional and autonomous domain containing a binding site involved in the interaction with the four positive charges of spermine. Altogether, these results led to the elaboration of the first model defining the crucial structural parameters of a polyamine-protein interaction at the molecular level.

Animals↗
PubMed1997

Mutational analysis of residues implicated in the interaction between protein kinase CK2 and peptide substrates.

Sixteen derivatives of the optimal peptide substrate RRRA-DDSDDDDD in which aspartic acids were singly or multiply substituted by alanine have been assayed for their phosphorylation efficiency by either wild type protein kinase CK2 or CK2 alpha mutants defective in substrate recognition. With wild type CK2, the only detrimental single substitutions were those at positions +3 and +1. Each of these caused a 5-fold increase of Km and a 2-fold decrease of the Vmax values. If both aspartic acids at n + 1 and n + 3 were substituted however, the Km rose 24-fold and the Vmax decreased 16-fold. Multiple substitutions tend to have a more than additive effect even if they affect individually dispensable aspartic acids; thus, double, triple, and quintuple substitutions at positions n - 2 and -1, and n + 2, +4, and +5 had detrimental consequences comparable to those observed with substitutions at n + 1 and n + 3. These data indicate that additional acidic residues besides those at n + 1 and n + 3 are collectively required for efficient phosphorylation of CK2 substrates. They are also consistent with a flexible mode of binding of the substrate, where acidic residues may play interchangeable roles. Among twelve CK2 mutants in which basic residues suspected to be implicated in substrate recognition have been replaced by alanine, only K74-77A, K79R80K83A, R191,195K198A, and K198A showed substantially increased Km values with the optimal substrate RRRA-DDSDDDDD, symptomatic of a reduced ability to bind it. However, if the suboptimal substrate RRRA-AASDDDDD was used, the single mutants K49A, K71A, K77A, R80A, and H160A also exhibited Km values significantly higher than those of wild type CK2. Kinetic analysis with singly substituted derivatives of peptide RRRA-DDSDDDDD revealed that K49 is implicated in the recognition of the determinant at position n + 2, K77 cooperates with other residues nearby in the interaction with the determinants at n + 3 and n + 4, while K198 plays a prominent role in the recognition of the determinant at n + 1.

Binding Sites↗
PubMed2004

Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole.

Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and infective diseases. Thus, CK2 inhibitors designed to dissect the signaling pathways affected by this kinase, in perspective, may give rise to pharmacological tools. One of the most successful CK2 inhibitors is TBB (4,5,6,7-tetrabromobenzotriazole). Here we show that its inhibitory properties can be markedly improved by generating adducts in which N(2) is replaced by a carbon atom bound to a variety of polar functions. The most efficient inhibitor is 4,5,6,7-tetrabromo-2-(dimethylamino)benzimidazole (2c) followed by the methylsulfanyl (8), isopropylamino (2e), and amino (2a) congeners. All these compounds display K(i) values <100 nM (40 nM in the case of 2c). 2c induces apoptosis of Jurkat cells more readily than TBB (DC(50) value 2.7 vs 17 microM) and, unlike TBB, it does not display any side effect on mitochondria polarization up to 10 microM concentration. Molecular modeling of the CK2-2c complex, based on the crystal structure of the CK2-TBB complex suggests that a number of additional apolar contacts between its two methyl groups and hydrophobic residues nearby could account for its superior inhibitory properties. Consequently, 2c is even more susceptible than TBB to mutations of the unique hydrophobic residues V66 and/or I174 to alanine. We propose to adopt 2c as first choice CK2 inhibitor instead of TBB, especially for in cell studies.

Animals↗