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PubMed1997

Two putative protein kinase CK2 phosphorylation sites are important for Myf-5 activity.

Myf-5, a member of a family of muscle-specific transcription factors, is important for myogenic cell determination and differentiation. Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity. Mutants which can no longer be phosphorylated fail to transactivate E-box-dependent reporter genes and act as trans-dominant repressors of wild-type Myf-5. Normal activity can be restored by replacing the serine residues with glutamate suggesting that a negative charge at these sites is obligatory for Myf-5 activity. Although serine133 is part of helix 2 which mediates dimerization, we find no evidence for impaired DNA-binding or heterodimerization of the Ser-Ala133 mutant. Some serine49 mutations exhibit reduced nuclear localization and/or protein stability. Our data suggest that CK2-mediated phosphorylation of Myf-5 is required for Myf-5 activity.

Animals↗
PubMed2006

Doxorubicin binds to un-phosphorylated form of hNopp140 and reduces protein kinase CK2-dependent phosphorylation of hNopp140.

Human nucleolar phosphoprotein p140 (hNopp140) is a nucleolar phosphoprotein that can bind to doxorubicin, an anti-cancer agent. We have examined the interaction between hNopp140 and doxorubicin as well as the folding property of hNopp140. Also, the effects of ATP and phosphorylation on the affinity of hNopp140 to doxorubicin are investigated by affinity dependent co-precipitation and surface plasmon resonance methods. Doxorubicin preferentially binds to un-phosphorylated form of hNopp140 with a KD value of 3.3 x 10(-7) M. Furthermore, doxorubicin reduces the protein kinase CK2-dependent phosphorylation of hNopp140, indicating that doxorubicin may perturb the cellular function of hNopp140 by reducing the protein kinase CK2-dependent phosphorylation of hNopp140. Low contents of the secondary structures of hNopp140 and the fast rate of proteolysis imply that hNopp140 has a high percentage of flexible regions or extended loop structures.

CDC2 Protein Kinase↗
PubMed1999

CK2, a protein kinase of the next millennium.

Protein kinase CK2 is a ubiquitous eukaryotic protein kinase composed of two catalytic subunits, alpha and/or alpha', and two regulatory subunits, beta. In order to define similarities and dissimilarities between the alpha and alpha' catalytic subunits, which might account for their particular cellular functions, different forms of the enzyme were expressed in Sf9 cells and their properties determined. Both catalytic subunits were expressed separately, and also along with the regulatory beta subunit, in order to obtain free alpha and alpha', as well as alpha2beta2 and alpha'2beta2 forms. Our results confirm that the beta subunit acts to stabilize the alpha and alpha' subunits and also influences the substrate specificity and kinetic properties of the enzyme. Although significant differences between the specificities of holoenzymes alpha2beta2 and alpha'2beta2 as determined using a number of substrates were not detected, autophosphorylation studies on alpha2beta2 and alpha'2beta2 revealed significant differences in this property. The regulatory subunit beta was phosphorylated less rapidly by the alpha' subunit than by the alpha subunit, and the extent of phosphorylation of beta by alpha was also greater than that of beta by alpha'. It was also noted that the thermo-stability and the extent of its activation by NaCl were greater for alpha2beta2 than for alpha'2beta2. These different properties may relate to distinct functions of the two form of CK2.

Adenosine Triphosphate↗
PubMed1999

Binding of polylysine to protein kinase CK2, measured by Surface Plasmon Resonance.

The interaction between protein kinase CK2 and polylysine has been studied by Surface Plasmon Resonance (SPR). The binding process has a very low energy of activation, it is irreversible, and too slow as to explain the enzyme activity stimulation as a direct consequence of the polylysine binding. The polylysine interaction with a peptide substrate and with casein are faster, and in agreement with a substrate-mediated mechanism of activity stimulation. After several hours of incubation, the binding of polylysine to CK2 produces the loss of enzymatic activity.

Casein Kinase II↗
PubMed1999

The binding of the alpha subunit of protein kinase CK2 and RAP74 subunit of TFIIF to protein-coding genes in living cells is DRB sensitive.

In a previous report, we documented that a major portion of the nuclear protein kinase CK2alpha (CK2alpha) subunit does not form heterooligomeric structures with the beta subunit, but it binds tightly to nuclear structures in an epithelial Chironomus cell line. We report here that the CK2alpha, but not beta, subunit is co-localized with productively transcribing RNA polymerase II (pol II) on polytene chromosomes of Chironomus salivary gland cells. Likewise, the RAP74 subunit ofTFIIF, a potential substrate for CK2, is co-localized with pol II. The occupancies of chromosomes with the CK2alpha and RAP74 subunits are sensitive to DRB, an inhibitor of pol II-based transcription and the activity of CK2 and pol II carboxyl-terminal kinases. DRB alters the chromosomal distribution of the CK2alpha and RAP74 subunits: there is a time-dependent clearance from the chromosomes of CK2alpha and RAP74 subunits, which coincides in time the completion and release of preinitiated transcripts after addition of DRB. The results suggest that both the CK2alpha and RAP74 subunits travel with the elongating pol II molecules along the DNA template during the entire transcription cycle. No detectable re-association of CK2alpha and RAP74 with the promoters takes, however, place after the completion of the preinitiated transcripts in the presence of DRB. In contrast, the binding of hypophosporylated pol II and TFIIH to the active gene loci is not abolished by the DRB regimen. Our data are consistent with the possibility that in living Chironomus salivary gland cells, DRB interferes with the recruitment of TFIIF, but not of TFIIH, to the promoter by interference with the activity of the CK2alpha subunit enzyme and phosphorylation of RAP74 and thereby DRB blocks transcription initiation.

Animals↗
PubMed2002

The plastid transcription kinase from mustard (Sinapis alba L.). A nuclear-encoded CK2-type chloroplast enzyme with redox-sensitive function.

The plastid transcription kinase (PTK), a component of the major RNA polymerase complex from mustard chloroplasts, has been implicated in redox-mediated regulation of plastid gene expression. A cloning strategy to define the PTK gene(s) resulted in the isolation of a full-length cDNA for a protein with overall high homology with the alpha subunit of cytosolic casein kinase (CK2) that contained an N-terminal extension for a putative plastid transit peptide. Using in organello chloroplast import studies, immunodetection and MS, we found that the corresponding protein, termed cpCK2alpha, is targeted to the chloroplast and is associated with the plastid RNA polymerase PEP-A. The bacterially overexpressed protein shows CK2 kinase activity and is subject to glutathione inhibition in the same way as authentic chloroplast PTK. Furthermore, it readily phosphorylates components of the plastid transcription apparatus in vitro with a substrate specificity similar to that of PTK.

Amino Acid Sequence↗
PubMed2002

[Therapeutic potential of protein kinase CK2 modulators].

Data on the nuclear cascade of signal transduction, including protein kinase CK2 (PKCK2), transcription factor HMG14 and chromatin myosin-like proteins, are generalized with regard for the modern understanding of mechanisms of synaptic plasticity. The role of the neurospecific isoform and subunit structure of PKCK2, of the individual subunit autophosphorylation of PKCK2, of phosphorylation of substrate-proteins in the enzyme activity and of conformation transformations of chromatin is examined. Data on changes in the CK2-induced cascade and synaptic plasticity in learning, on age-related amnesia and on cognitive deficits induced by ethanol and chloridine in rat embryos are presented. The prospects for using modulators PKCK2, 4,5-di(N-methylcarbamoyl)-l-alkyl-imidazoles, as potential nootropics are discussed.

Animals↗
PubMed1994

Cloning and expression of genes coding for protein kinase CK2 alpha and beta subunits in zebrafish (Danio rerio).

cDNA clones coding for the alpha and beta subunits of protein kinase 2 (CK2) in zebrafish (Danio rerio) have been isolated. Sequencing of the cDNA clones has demonstrated that one contains the complete coding sequence for the beta subunit of CK2 while the alpha clone is truncated and lacks 183 nucleotides of the 5' coding region. Comparison of the deduced amino acid sequences shows an extremely high degree of evolutionary sequence conservation of these two proteins. Northern analysis of the mRNAs coding for the alpha subunit indicates that this messenger is present in 1 h embryos as a 3.6 Kb and a 1.9 Kb species, both of which decrease in 24-h embryos. In the case of beta, the major mRNA species of approximately 1.7 Kb maintains its level during the period of embryogenesis studied. In situ hybridization of early embryos, using antisense RNAs against alpha and beta mRNAs demonstrates temporal and tissue specific expression patterns. The alpha mRNA decreases after blastula, when it is evenly distributed. The beta mRNA is maintained at high levels between 4 and 24 h of development, showing in 18 h embryos a higher concentration in the developing neural tube and in the embryonic optic and otic vesicles.

Amino Acid Sequence↗
PubMed1998

Acceleration of lpr lymphoproliferative and autoimmune disease by transgenic protein kinase CK2 alpha.

MRL-lpr/lpr mice have a Fas receptor mutation that leads to abnormalities of apoptosis, lymphoproliferation, and a lupus-like autoimmune disease associated with the production of autoantibodies. Other than Fas pathway defects, little is known about molecular abnormalities that predispose to autoimmunity. Protein kinase CK2 (also termed casein kinase II), a serine-threonine protein kinase whose targets include many critical regulators of cellular growth, is highly expressed in a lymphoproliferative disease of cattle and in many human cancers. Overexpression of the CK2alpha catalytic subunit in lymphocytes of transgenic mice leads to T cell lymphoma. We hypothesized that CK2 dysregulation and Fas mutation might cooperatively augment lymphocyte proliferation and transformation. We find that in MRL-lpr/lpr mice bearing the CK2alpha transgene, the lymphoproliferative process is dramatically exacerbated, as these mice develop massive splenomegaly and lymphadenopathy by 12 wk of age in association with increased autoantibody production and accelerated renal disease. The lymphoid organs are filled with the unusual B220+CD4-CD8- T cells typically seen in MRL-lpr/lpr mice, not the B220-CD4+CD8+ or B220-CD4-CD8+ T cells typically seen in CK2a transgenic lymphomas. The T cells do not fulfill the criteria for transformation, as they are polyclonal and not transplantable or immortal in cell culture. Thus, although the lpr lymphoproliferative and autoimmune syndrome is potentiated by the presence of the CK2a transgene, this combination of apoptotic and proliferative abnormalities appears to be insufficient to transform lymphoid cells.

Animals↗
PubMed1998

Effect of protein kinase ck2 on topoisomerase I from plasmodia of the slime mold Physarum polycephalum.

Relaxing activity of Physarum topoisomerase I was increased by calf thymus protein kinase ck2, similarly as was the activity of mammalian topoisomerase I, despite a pronounced difference between amino-acid sequences of non-conserved domains of Physarum and mammalian enzymes. This feature of Physarum topoisomerase I was cancelled in nuclear extracts isolated from dibutyryl-cAMP treated plasmodia in which the activity of protein kinase ck2 was elevated.

Amino Acid Sequence↗
PubMed1999

Protein kinase CK2 and its role in cellular proliferation, development and pathology.

Protein kinase CK2 is a pleiotropic, ubiquitous and constitutively active protein kinase that can use both ATP and GTP as phosphoryl donors with specificity for serine/threonine residues in the vicinity of acidic amino acids. Recent results show that the enzyme is involved in transcription, signaling, proliferation and in various steps of development. The tetrameric holoenzyme (alpha2beta2) consists of two catalytic alpha-subunits and two regulatory beta-subunits. The structure of the catalytic subunit with the fixed positioning of the activation segment in the active conformation through its own aminoterminal region suggests a regulation at the transcriptional level making a regulation by second messengers unlikely. The high conservation of the catalytic subunit from yeast to man and its role in the tetrameric complex supports this notion. The regulatory beta-subunit has been far less conserved throughout evolution. Furthermore the existence of different CK2beta-related proteins together with the observation of deregulated CK2beta levels in tumor cells and the reported association of CK2beta protein with key proteins in signal transduction, e.g. A-Raf, Mos, pg90rsk etc. are suggestive for an additional physiological role of CK2beta protein beside being the regulatory compound in the tetrameric holoenzyme.

Animals↗
PubMed2003

cDNA cloning, biochemical and phylogenetic characterization of beta- and beta'-subunits of Candida albicans protein kinase CK2.

We have previously reported that Candida albicans protein kinase CK2 is composed of two distinct catalytic (alpha- and alpha'-) and two distinct regulatory (beta- and beta'-) subunits. We report here the isolation of two cDNAs clones, CaCKB1 and CaCKB2, encoding C. albicans beta- and beta'-subunits, respectively. The predicted beta- and beta'-proteins have calculated molecular masses of 34 kDa and 31 kDa and show all major features conserved in beta-subunits of other organisms, including the N-terminal autophosphorylation site, the internal acidic region and a potential metal-binding motif. The deduced amino acid sequence of C. albicans beta-subunit displays 48% identity with that of Saccharomyces cerevisiae and has an unusually long C-terminal acidic region containing a putative autophosphorylation site. C. albicans beta' shows 54% sequence identity with its S. cerevisiae homologue. Semi-quantitative RT-PCR analyses indicate that the mRNAs corresponding to both subunits are present in similar amounts in the yeast and hyphal forms of the fungus. To evaluate the biochemical properties of C. albicans beta- and beta'-subunits, both proteins were expressed in Escherichia coli and purified. Experiments performed in vitro indicate that both recombinant subunits reconstitute a fully functional holoenzyme when incubated with stoichiometric amounts of human recombinant alpha-subunit, as judged by their ability to abolish basal phosphorylation of calmodulin by human recombinant alpha-subunit and the reversion of the inhibitory effect by polylysine. In addition, both regulatory subunits can be phosphorylated by human recombinant alpha subunit. Phylogenetic analysis of beta- and beta'-proteins of C. albicans and other organisms shows that the CKB gene duplication occurred before the split of the ascomycete and basidiomycete lineages.

Amino Acid Sequence↗
PubMed1999

The 37-amino-acid interdomain of dengue virus NS5 protein contains a functional NLS and inhibitory CK2 site.

The dengue virus NS5 RNA-dependent RNA polymerase has been detected in the nucleus of virus-infected mammalian cells. We demonstrate here for the first time using in vitro and in vivo assay systems that the 37-amino-acid linker interdomain of NS5 (residues 369 to 405) contains a nuclear localization sequence (NLS) which is capable of targeting b-galactosidase to the nucleus. Further, we show that the linker is recognized by subunits of the NLS-binding importin complex with an affinity similar to that of the bipartite NLS of the retinoblastoma protein and, in analogous fashion to proteins such as the SV40 large tumor antigen, contains a functional protein kinase CK2 phosphorylation site (threonine 395). Interestingly, this site appears to inhibit NS5 nuclear targeting, probably through a cytoplasmic retention mechanism. The linker may have an important role in targeting NS5 to the nucleus in a regulated manner during the dengue virus infectious cycle.

Adenosine Triphosphate↗
PubMed2000

Seasonal adaptation modulates the expression of the protein kinase CK2 beta subunit gene in the carp.

Carp fish seasonal acclimatization induces a cyclical transcriptional modulation of several genes. Its most dramatic expression results in a concomitant structural rearrangement of the nucleolar components that phenotypically represents profound shifts in the level of ribosomal RNA synthesis. In connection with the recent studies that implicate CK2 in the control of rRNA synthesis in vertebrates, we characterized the cDNA of carp protein kinase CK2beta subunit and assessed its transcriptional behavior in winter- and summer-acclimatized fish. We found a remarkable differential gene expression of CK2beta subunit between summer- and winter-acclimatized carp which correlates with the modulatory pattern observed in rRNA transcription.

Acclimatization↗
PubMed2005

Knocking out the regulatory beta subunit of protein kinase CK2 in mice: gene dosage effects in ES cells and embryos.

Knocking out the regulatory beta subunit of protein kinase CK2 in mice leads to early embryonic lethality. Heterozygous CK2beta (CK2beta+/-) knockout mice do not show an obvious phenotype. However, the number of heterozygous offsprings from CK2B+/- inter-crossings is lower than expected, meaning that some heterozygous embryos do not survive. Interestingly, CK2beta+/- ES (Embryonic Stem) cells express a considerably lower level of CK2beta than wild-type ES cells, whereas the level of CK2beta in organs from heterozygous adult mice does not significantly differ from those of wild-type mice. The data suggest a compensatory mechanism that adjusts CK2beta levels during development in the majority of, but not in all, cases (Mol Cell Biol 23: 908-915, 2003). In order to find an explanation for the gene dosage effect observed for heterozygous offsprings, we analysed embryos at mid-gestation (E10.5) as well as wild-type and CK2beta+/- ES cells for differences in growth rate and response to different stress agents. Analysis of E10.5 embryos generated from heterozygous matings revealed about 20% of smaller retarded CK2beta+/- embryos. No correlation between CK2beta levels in normal looking and retarded CK2beta+/- embryos were found. However, a different post-translational form of CK2beta protein has been detected in these retarded embryos. Cellular parameters such as growth rate and G1-, G2-checkpoints in ES cells were identical in both wild-type and CK2beta+/- cells. When ES cells were injected to induce differentiated teratocarcinoma in syngenic mice, the size of the tumours correlated with the level of CK2beta.

Animals↗
PubMed1995

Dissection of the dual function of the beta-subunit of protein kinase CK2 ('casein kinase-2'): a synthetic peptide reproducing the carboxyl-terminal domain mimicks the positive but not the negative effects of the whole protein.

The dual function of the regulatory beta-subunit of protein kinase CK2 is highlighted by its ability to abolish calmodulin phosphorylation in contrast to its stimulatory effect on the phosphorylation of peptide substrates. Here we show that a synthetic peptide reproducing the C-terminal region of the beta-subunit (beta[170-215]) stimulates to a similar extent the phosphorylation of either the peptide substrate or calmodulin and also protects the catalytic alpha-subunit against thermal inactivation as efficiently as full-length beta-subunit. These data show that the positive and negative functions of the beta-subunit reside in physically separated domains and that the elements responsible for positive regulation are located in the C-terminal region.

Amino Acid Sequence↗
PubMed1996

Identification of a cryptic protein kinase CK2 phosphorylation site in human complement protease Clr, and its use to probe intramolecular interaction.

Treatment of human (activated)C1r by CK2 resulted in the incorporation of [32P]phosphate into the N-terminal alpha region of its non-catalytic A chain. Fragmentation of 32P-labelled (activated)C1r followed by N-terminal sequence and mass spectrometry analyses allowed identification of Ser189 as the phosphorylation site. Accessibility of Ser189 was low in intact C1r, due in part to the presence of one of the oligosaccharides borne by the alpha region, further reduced in the presence of calcium, and abolished when C1r was incorporated into the C1s-C1r-C1r-C1s tetramer or the C1 complex. In contrast, phosphorylation was enhanced in the isolated alpha fragment and insensitive to calcium. Taken together, these data provide support for the occurrence of a (Ca2+)-dependent interaction between the alpha region and the remainder of the C1r molecule.

Amino Acid Sequence↗
PubMed2006

CK2-dependent C-terminal phosphorylation at T300 directs the nuclear transport of TSPY protein.

TSPY (testis-specific protein, Y-encoded) is a member of the greater SET/NAP family of molecules with various functions, e.g., in chromatin remodeling, regulation of gene expression, and has been implicated to play a role in the malignant development of gonadoblastoma, testicular and prostate cancer. Here we demonstrate that the C-terminus has a functional role for the nucleo-cytoplasmatic shuttling of the TSPY protein. Using various combinations of in vitro mutagenesis and enhanced green fluorescent protein reporter gene-expression experiments we were able to show that while the deletion of C-terminus leads to a decreased stability and enhanced degradation of the protein, the selective mutation of a C-terminal CK2 phosphorylation site (T300) prevents the TSPY protein from entering the nucleus. We conclude that phosphorylation of the (T300) residue is a necessary and functional prerequisite for TSPY's transport into the nucleus reminding of comparable data from a related Drosophila molecule, NAP1.

Amino Acid Sequence↗