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PubMed2002

CK2 constitutively associates with and phosphorylates chicken erythroid ankyrin and regulates its ability to bind to spectrin.

Previous analyses have shown that the phosphorylation state of chicken erythroid ankyrin regulates its association with the spectrin cytoskeleton in vivo. Treatment of erythroid cells with serine and threonine phosphatase inhibitors stimulates the hyperphosphorylation of ankyrin and its dissociation from spectrin. In this study, we demonstrate that a kinase that directs the phosphorylation of ankyrin in vivo coprecipitates with ankyrin-containing complexes and has properties identical to CK2. Studies using CK2-specific inhibitors have indicated that all of the phosphorylation events associated with erythroid ankyrin in vivo are CK2 dependent. Furthermore, inhibitor studies combined with in vitro binding analyses have indicated that the phosphorylation of erythroid ankyrin by CK2 regulates its ability to associate with spectrin. Additional analyses revealed that CK2 coprecipitates with ankyrin-3-containing complexes isolated from Madin Darby canine kidney epithelial cells and phosphorylates this epithelial ankyrin isoform in vivo. These results are the first demonstration of a kinase constitutively associating with the ankyrin-spectrin cytoskeleton in erythroid and kidney epithelial cells. This association provides a mechanism for rapidly reorganizing the membrane cytoskeleton in these cell types through the phosphorylation of ankyrin.

Animals↗
PubMed2002

Characterization of human lactoferricin as a potent protein kinase CK2 activator regulated by A-kinase in vitro.

Lactoferricin (LFcin) hydrolyzed from lactoferrin (LF), a major 80 kDa iron-binding protein in milk and other exocrine secretions, was characterized as a potent activator of protein kinase CK2 (CK2) in vitro. Human LFcin (hLFcin) at 0.5 microg stimulated approx. 5-fold CK2 activity [phosphorylation of 60S acidic ribosomal proteins (P0, P1, P2) and Hsp90 (p98)] in a manner similar to other functional proteins with oligo-Arg clusters, such as salmine A1, sperm histone H2B and HIV-1 Rev. Interestingly, this stimulatory effect of hLFcin was significantly reduced when it was phosphorylated by A-kinase in vitro. These results suggest that (i) hLFcin acts as a potent CK2 activator in vitro; and (ii) the stimulatory effect of hLFcin on CK2 activity is regulated by its phosphorylation by A-kinase in vitro.

Amino Acid Sequence↗
PubMed2006

CD5-CK2 binding/activation-deficient mice are resistant to experimental autoimmune encephalomyelitis: protection is associated with diminished populations of IL-17-expressing T cells in the central nervous system.

Regulating the differentiation and persistence of encephalitogenic T cells is critical for the development of experimental autoimmune encephalomyelitis (EAE). We reported recently that CD5 has an engagement-dependent prosurvival activity in T cells that played a direct role in the induction and progression EAE. We predicted that CD5 regulates T cell apoptosis/survival through the activation of CK2, a prosurvival serine/threonine kinase that associates with the receptor. To test this hypothesis, we generated mice expressing CD5 with the inability to bind and activate CK2 and assessed their susceptibility to EAE. We found mice deficient in CD5-CK2 signaling pathway were mostly resistant to the development of EAE. Resistance to EAE was associated with a dramatic decrease in a population of effector infiltrating Th cells that coexpress IFN-gamma and IL-17 and, to a lesser extent, cells that express IFN-gamma or IL-17 in draining lymph nodes and spinal cords. We further show that T cells deficient in CD5-CK2 signaling hyperproliferate following primary stimulation; however, following restimulation, they rapidly develop nonresponsiveness and exhibit elevated activation-induced cell death. Our results provide a direct role for CD5-CK2 pathway in T cell activation and persistence of effector T cells in neuroinflammatory disease. This study predicts that targeting of IFN-gamma(+)/IL-17(+) infiltrating Th cells will be useful for the treatment of multiple sclerosis and other systemic autoimmune diseases.

Animals↗
PubMed1999

Modulation of nuclear matrix protein phosphorylation by histones: possible involvement of NM-associated protein kinase CK2 activity.

Nuclear matrix (NM), a proteinaceous network of filaments, dictates nuclear morphology and the structure/function of DNA. Phosphorylation of NM proteins is a potential signal for regulating matrix functions. Histones also are intimately involved in DNA structure and transcription. Here, we report that various histones enhanced 32P incorporation into certain NM proteins. Modulation of NM protein phosphorylation by histones is mediated through regulation of protein kinase CK2, a messenger-independent serine/threonine kinase, which is significantly associated with the NM. The stimulatory effect of histones was mitigated by prior incubation of histones with DNA in the reaction. Phosphorylation of NM proteins was extensively reduced when an excess of the CK2-specific peptide substrate was included in the phosphorylation reaction as a competitor. Also, enhancement in the NM-associated CK2 activity by histones was blocked by inhibitors of CK2. Histone H1 effect appeared to be mediated mainly by charge effect since a stretch of polylysine induced a similar effect. Various histones also differentially affected the autophosphorylation of NM-associated CK2 subunits. This may contribute to the observed effects of histones on the NM, resulting in an enhancement and differential pattern of NM protein phosphorylation. Such a regional modification of NM protein phosphorylation might influence the nuclear functions that require histone displacement, namely, replication and transcription.

Animals↗
PubMed1999

Interactions of protein kinase CK2 subunits.

Several approaches have been used to study the interactions of the subunits of protein kinase CK2. The inactive mutant of CK2alpha that has Asp 156 mutated to Ala (CK2alphaA156) is able to bind the CK2beta subunit and to compete effectively in this binding with wild-type subunits alpha and alpha'. The interaction between CK2alphaA156 and CK2beta was also demonstrated by transfection of epitope-tagged cDNA constructs into COS-7 cells. Immunoprecipitation of epitope-tagged CK2alphaA156 coprecipitated the beta subunit and vice-versa. The assay of the CK2 activity of the extracts obtained from cells transiently transfected with these different subunits yielded some surprising results: The CK2 specific phosphorylating activity of these cells transfected with the inactive CK2alphaA156 was considerably higher than the control cells transfected with vectors alone. Assays of the immunoprecipitated CK2alphaA156 expressed in these cells, however, demonstrated that the mutant was indeed inactive. It can be concluded that transfection of the inactive CK2alphaA156 affects the endogenous activity of CK2. Transfection experiments with CK2alpha and beta subunits and CK2alphaA156 were also used to confirm the interaction of CK2 with the general CDK inhibitor p21WAF1/CIP1 co-transfected into these cells. Finally a search in the SwissProt databank for proteins with properties similar to those derived from the amino acid composition of CK2beta indicated that CK2beta is related to protein phosphatase 2A and to other phosphatases as well as to a subunit of some ion-transport ATPases.

Amino Acid Sequence↗
PubMed1999

Role of protein kinase CK2 in phosphorylation nucleosomal proteins in relation to transcriptional activity.

Protein kinase CK2 undergoes rapid translocation to nuclear matrix and nucleosomes on androgenic stimulation of growth in prostatic epithelial cells. Further, CK2 appears to be regulated differentially in the transcriptionally active and inactive nucleosomes. We have investigated the role of CK2 in phosphorylation of nucleosome-associated proteins in the transcriptionally active and inactive nucleosomes that were isolated from ventral prostate subjected to different androgenic status in vivo. Proteins associated with these nucleosomes were phosphorylated via the intrinsic protein kinase activity, using [gamma-32P]ATP in the absence and presence of GTP. Several proteins appear to be potential substrates for CK2 associated with the nucleosomes. Among them are proteins that are differentially associated with the transcriptionally active and inactive nucleosomes. Phosphorylation of several of these proteins is modulated depending not only on their sites of association (i.e., active vs. inactive nucleosomes) but also on the state of transcriptional activity. Differential phosphorylation of specific proteins by CK2 associated with the active and inactive nucleosomes may be pertinent to the process of transcription regulation.

Animals↗
PubMed2001

Roles of IKK kinases and protein kinase CK2 in activation of nuclear factor-kappaB in breast cancer.

Nuclear factor-kappaB (NF-kappaB)/Rel transcription factors regulate genes that control cell proliferation, survival, and transformation. In normal breast epithelial cells, NF-kappaB/Rel proteins are mainly sequestered in the cytoplasm bound to one of the specific inhibitory IkappaB proteins, whereas in breast cancers they are activated aberrantly. Human breast tumor cell lines, carcinogen-transformed mammary epithelial cells, and the majority of primary human or rodent breast tumor tissue samples express constitutively high levels of nuclear NF-kappaB/REL: To begin to understand the mechanism of this aberrant NF-kappaB/Rel expression, in this study we measured the activity of the major kinases implicated in regulation of IkappaB stability, namely IKKalpha, IKKbeta, and protein kinase, CK2 (formerly casein kinase II). Hs578T, D3-1, and BP-1 breast cancer cell lines displayed higher levels of IKKalpha, IKKbeta, and CK2 activity than untransformed MCF-10F mammary epithelial cells. Inhibition of IKK activity upon expression of dominant negative kinases or of CK2 activity by treatment with selective inhibitors decreased NF-kappaB/Rel activity in breast cancer cells. Inactivation of the IkappaB kinase complex in Hs578T cells via expression of a dominant negative IKKgamma/NF-kappaB essential modulator/IKK-associated protein 1 reduced soft agar colony growth. Thus, the aberrant expression of CK2 or IKK kinases promotes increased nuclear levels of NF-kappaB/Rel and transformation of breast cancer cells. Furthermore, primary human breast cancer specimens that displayed aberrant constitutive expression of NF-kappaB/Rel were found to exhibit increased CK2 and/or IKK kinase activity. These observations suggest these kinases play a similar role in an intracellular signaling pathway that leads to the elevated NF-kappaB/Rel levels seen in primary human mammary tumors and, therefore, represent potential therapeutic targets in the treatment of patients with breast cancer.

Breast Neoplasms↗
PubMed2001

HIV-1 Rev transactivator: a beta-subunit directed substrate and effector of protein kinase CK2.

The phosphorylation of HIV-1 Rev by protein kinase CK2 is strictly dependent on the regulatory beta subunit of the kinase and is deeply affected by conformational changes of the substrate outside the phosphorylation site. Here we show that Rev modulates a variety of CK2 properties, including autophosphorylation, catalytic activity toward calmodulin, and susceptibility to polycationic effectors, whose common denominator is the involvement of the beta subunit. Rev's two major CK2 sites are located at its N-terminus, immediately adjacent to a helix-loop-helix motif. By comparing the behaviour of full-size Rev with that of synthetic peptides reproducing, with suitable modifications, its N-terminal 26 amino acids including the phosphoacceptor site (Ser 5, Ser 8) and amphipathic helix-1, it appears that the functional interaction of the N-terminal portion of Rev with the N-terminal domain of the beta subunit must rely on both electrostatic and hydrophobic interactions. The former mainly involve Rev's arginine-rich domain (residues 35-50) in helix-2, while the latter are mostly mediated by residues 12-24 of helix-1. These data disclose the possibility that, besides displaying protective, regulatory and targeting properties with respect to the catalytic subunit, the CK2 beta subunit also plays a role as a docking site for a subset of CK2 substrates.

Amino Acid Motifs↗
PubMed2001

Visualization and molecular analysis of nuclear import of protein kinase CK2 subunits in living cells.

We have generated fusion proteins between the subunits of CK2 and GFP and characterized their behaviour in living cells. The expressed fusion proteins were functional and interacted with endogenous CK2. Imaging of NIH3T3 cells expressing low level of GFP-CK2alpha or GFP-CK2beta showed that both proteins were mostly nuclear in interphase. Both CK2 subunits contain nuclear localization domains that target them independently to the nucleus. Once in the nucleus, both subunits diffused rapidly in the nucleoplasm. In mitotic cells, CK2 subunits were dispersed throughout the cytoplasm and were not associated to chromatin. Our data are compatible with the idea that each subunit can translocate individually to the nucleus to interact with each other or with important cellular partners. Understanding the molecular mechanisms which regulate the dynamic localization of CK2 subunits will be of central importance.

3T3 Cells↗
PubMed2002

[Cloning, sequencing, expression, and primary identification of recombinant mouse protein kinase CK2 alpha subunit].

BACKGROUND & OBJECTIVE: Protein kinase CK2 is a highly conserved and ubiquitous eukaryotic serine/threonine kinase that is elevated and can serve as an oncogene in many tumor cells. To further research the structure and function of CK2, this study was designed to construct, express, and preliminarily identify a recombinant expression plasmid which contains the cDNA encoding mouse protein kinase CK2 alpha subunit. METHODS: The aimed cDNA was obtained from NIH 3T3 mouse fibroblasts by RT-PCR. Nde I/BamH I-digested PCR product was directly cloned into pT7-7 expression vector which had been digested by Nde I/BamH I and dephosphorylated by calf intestinal alkaline phosphatase in advance. After E. coli DH5 alpha was transformed with the recombinant DNA by CaCl2 method, transformants were obtained. The positive clones were screened out primarily by gel electrophoresis, and then analyzed by digesting with restriction enzyme. Four positive clones were selected at random and sequenced respectively. The correct recombinant plasmid was transformed into E. coli BL21(DE3) and then expressed by inducing with IPTG. The products were identified with Western blotting. RESULTS: The positive rate of transformants was 100%. The results of restriction analysis indicated that DNA band size of the insert fragment and recombinant plasmid were consistent with theoretically predicated values. The sequencing results showed one of the four clones possessed the cDNA sequence which has no mutation in the processing of PCR, which was termed as pTMCKA. One protein with molecular mass of 42 kDa was overexpressed by inducing with IPTG. The Western blot results confirmed that the recombinant product could specially react with antibody against human CK2 alpha subunit. CONCLUSIONS: The authors have successfully cloned and expressed recombinant mouse protein kinase CK2 alpha subunit in this experiment.

3T3 Cells↗
PubMed2006

Protein kinase CK2 subunits are positive regulators of AKT kinase.

Protein kinase CK2 is a highly conserved serine/threonine kinase ubiquitously distributed in all investigated eukaryotes and involved in several intracellular pathways which control, among others, cell cycle, proliferation, apoptosis and transformation. Similarly, the PI3K-AKT pathway deregulation has been shown to play an important role in tumor development and tumor response to anti-cancer treatment. In this study, it is shown that the specific inhibition of the PI3K-AKT signaling pathway in combination with depletion of CK2 subunits by antisense oligodeoxynucleotides leads to an enhanced drug-induced apoptotic response. Moreover, in vitro as well as in vivo studies show that the individual CK2 subunits interact with AKT kinase and that the complex formation is not modulated by the phosphorylation status of AKT. Furthermore, the fact that the interaction between CK2 subunits and AKT enhances AKT kinase activity identifies a novel molecular mechanism that leads to modulation of AKT activation raising the possibility that CK2 and AKT might be implicated in common pathways that control cell proliferation and survival.

Androstadienes↗
PubMed1998

Differential CD5-dependent regulation of CD5-associated CK2 activity in mature and immature T cells: implication on TCR/CD3-mediated activation.

CD5 attenuates TCR-induced signals in immature thymocytes but functions as a costimulatory molecule potentiating TCR/CD3-mediated activation in mature, peripheral T cells. We have recently shown that the serine/threonine kinase, casein kinase 2 (CK2), a major regulator of cell growth and signaling, associates with and is activated by CD5. Therefore, we tested the possibility that differential regulation of CK2 activity by CD5 may be associated with these differences in CD5 modulation of TCR signaling. Consistent with our hypothesis, CD5-specific cross-linking activated associated CK2 in thymocytes but not active in mature splenocytes. Differential regulation of CD5-associated CK2 provides, for the first time, a potential mechanism for the differential effects of CD5 signaling in immature and mature cells. We propose that CD5 modulates Ag receptor activity through developmentally regulated activation of CD5-associated CK2.

Amino Acid Sequence↗
PubMed1998

Enzymatic phosphorylation of food proteins by purified and recombinant protein kinase CK2.

Protein kinase CK2 formerly called casein kinase II is a protein kinase able to phosphorylate more than 100 proteic substrates. We have purified protein kinase CK2 from the yeast Y. lipolytica to phosphorylate milk and plant reserve proteins to a significant extent. In the case of plant reserve proteins, which are polymeric substrates, not all subunits are substrate for protein kinase CK2, even if non phosphorylated subunits contain significant potent phosphorylations sites. Best substrates were soy beta-conglycinin (0.72 P/mol) and dephosphorylated caseins (0.5 P/mol). We have studied some functional properties of phosphorylated caseins. Solubility was improved for all pH values but pI. Sensitivity to calcium has also been assessed, and it is slightly improved upon phosphorylation. We have cloned the catalytic subunit of protein kinase CK2 from yeast Y. lipolytica. The recombinant catalytic subunit expressed in E. coli was active and displayed kinetic properties similar to those of the purified enzyme. The recombinant catalytic subunit was able to phosphorylate plant reserve proteins and milk proteins to a significant extent. Best substrates were soy beta-conglycinin (1.0 P/mol), and glycinin (0.59 P/mol).

Calcium↗
PubMed2003

Dual effect of lysine-rich polypeptides on the activity of protein kinase CK2.

Protein kinase CK2 (casein kinase II) is normally a heterotetramer composed of catalytic (alpha, alpha') and regulatory subunits (beta). CK2 is able to phosphorylate a large number of protein substrates but the physiological mechanisms of its regulation are still unresolved. Lysine-rich peptides such as polylysine and histone H1 are known to stimulate the catalytic activity of the holoenzyme. This activation is mediated through the CK2beta regulatory subunit. In this communication, we report that the same concentrations of lysine-rich peptides or proteins that activate the holoenzyme cause strong inhibition of the phosphorylation of proteins catalyzed by the free catalytic CK2alpha subunit. The inhibitory effect of polylysine and histone H1 is observed with several protein substrates of CK2alpha (casein, adeno E1A, transcription factor II A, and CK2beta itself). With calmodulin, however, the inhibition of CK2alpha phosphorylation caused by polylysine is much lower while with a model peptide substrate of CK2 the inhibition caused by this polycation is negligible. The inhibition of CK2alpha by polylysine is observed only at limiting concentrations of the target substrate proteins. The dual effect of polylysine and of histone H1, which results in the inhibition of CK2alpha and stimulation of the CK2 alpha(2)beta(2) tetrameric holoenzyme, has the consequence that the addition of the CK2beta, in the presence of polylysine and low concentrations of substrate protein, can cause a 242-fold stimulation of the activity of CK2alpha. Other polycationic compounds such as polyarginine and spermine do not inhibit the phosphorylation of casein by CK2alpha, indicating that the effect is specific for lysine-rich peptides. Since there is evidence that there may be free CK2alpha subunits in the nuclei of cells, where there is abundant histone H1, the inhibition of CK2alpha by this lysine-rich protein may have physiological relevance.

Amino Acid Sequence↗
PubMed2001

Inducible expression of the regulatory protein kinase CK2beta subunit: incorporation into complexes with catalytic CK2 subunits and re-examination of the effects of CK2beta on cell proliferation.

The regulatory subunit of protein kinase CK2, designated CK2beta, exists both free in cells and in complexes with the CK2 catalytic subunits. Growing evidence suggests that CK2beta has functions dependent and independent of the CK2 catalytic subunits. There have been indications that CK2beta has functions associated with DNA damage responses and in the control of cell proliferation. For example, transient and stable constitutive overexpression of CK2beta in mammalian cells was previously shown to perturb cell cycle progression and to attenuate proliferation. To systematically investigate the molecular mechanisms responsible for these effects of CK2beta on cell proliferation, we generated human osteosarcoma U2OS cell lines with tetracycline-regulated expression of CK2beta. Increased expression of CK2beta results in increases in total cellular CK2 activity, but no changes in cell cycle profiles or proliferation. Furthermore, following exposure to ultraviolet radiation, p53 induction was identical regardless of the levels of CK2beta in cells. Mouse 3T3-L1 cells stably transfected with CK2beta also showed no alterations in cell proliferation. The differences between these results and those previously reported emphasize the complex nature of CK2beta and its cellular functions. Furthermore, these results indicate that increased expression of CK2beta is not by itself sufficient to effect alterations in cell proliferation.

3T3 Cells↗
PubMed2002

Adenovirus infection targets the cellular protein kinase CK2 and RNA-activated protein kinase (PKR) into viral inclusions of the cell nucleus.

The effects of the adenovirus infection on the distribution of the cellular protein kinase CK2 and double-stranded RNA-activated protein kinase (PKR) were examined at the ultrastructural level. Immunogold labeling revealed the redistribution of CK2 subunits and PKR to morphologically distinct structures of the cell nucleus. The electron-clear amorphous structures, designated pIX nuclear bodies in our previous work (Rosa-Calatrava et al., 2001), contained CK2 alpha and PKR. The protein crystals, which result from the regular assembly of hexon, penton base, and fiber proteins [Boulanger et al. (1970) J Gen Virol 6:329-332], contained CK2 beta and PKR. Both viral structures were devoid of viral RNA, including the PKR-inhibitor VA1 RNA generated by the RNA polymerase III. Instead, VA1 RNA accumulated in PKR-free viral compact rings in which the viral RNA generated by the RNA polymerase II was excluded.

Adenoviruses, Human↗
PubMed2007

Inhibition of protein kinase CK2 leads to a modulation of androgen receptor dependent transcription in prostate cancer cells.

BACKGROUND: The androgen receptor (AR) mediates the biological responses of androgens in the prostate gland. In prostate cancer, this pathway is often deregulated and causes an uncontrolled proliferation. METHODS: The current study focuses on the effects of an inhibition of protein kinase CK2 on the AR-mediated transcription in LNCaP prostate cancer cells. We used chemical inhibitors of CK2 as well as dominant-negative kinase mutants to downregulate the CK2 activity. We determined the effects of the inhibition by Western blot analysis of endogenous target genes of the AR as well as by reporter assays. RESULTS: We found that inhibition of CK2 led to a downregulation of the AR-dependent transcription. Moreover, the amount of the AR protein decreased significantly. CONCLUSION: According to the fact that AR pathways are involved in the development and progression of prostate cancer, the ability to modulate AR function should provide an alternative basis for the development of new cancer therapies.

Adenocarcinoma↗
PubMed1997

Protein kinase CK2 down-regulates glucose-activated expression of the acetyl-CoA carboxylase gene.

It has been suggested that, in pancreatic beta-cells, acetyl-CoA carboxylase (ACC) is a key enzyme in glucose signal transduction leading to glucose-induced insulin secretion. The PII promoter is the only active promoter for the ACC gene in the beta-cell. Here we report that, in the pancreatic beta-cell, high glucose levels (above 20 mm) activate Sp1 binding to the glucose response element of the PII promoter, which leads to a dose-dependent increase in PII transcription. The expression of a gene coding protein kinase CK2 (CK2) alpha subunit, or the presence of okadaic acid (a serine/threonine protein phosphatase inhibitor), partially blocks the glucose activation of PII transcription. The inhibitory effect of CK2 alpha, or okadaic acid, was not observed in the absence of glucose or at low glucose concentrations. Phosphorylation of Sp1 by CK2 alpha leads to the inactivation of Sp1 binding to PII. Dephosphorylation of the phosphorylated Sp1 by protein phosphatase 1 (PP1) activates the binding of Sp1 to PII. Inhibition of PP1-catalyzed Sp1 dephosphorylation by okadaic acid, or PP1 specific inhibitor 2, decreases Sp1 binding to PII. These results suggest that the phosphorylation/dephosphorylation of Sp1 by CK2/PP1 may be the underlying mechanism by which the expression of the PII promoter of ACC is controlled in the process of glucose-mediated insulin secretion in pancreatic beta-cells.

Acetyl-CoA Carboxylase↗