Casein kinase II

DEVELOPMENTAL BIOLOGY

Embryonic

CkII is present ubiquitously throughout embryogeneis (M. Abu-Shaar and R. S. Mann, personal communication to Jaffe, 1997).

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 has been unclear. This study implicates a common role for the highly conserved Ser/Thr protein kinase CK2 during eye and bristle development. Compromising the functions of the catalytic (α) 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. 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, these 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 (Bose, 2006).

Neurogenesis reflects the outcome of a complex balance between the activities of transcription factors that favor this cell fate (ASC/Ato) and those that oppose it (E(spl)). It is increasingly apparent that formation of the eye and bristle are predicated on a similar mechanistic framework, even though the proneurals that participate in these two developmental programs are distinct. For example, the PNCs in the eye (the R8 cell) require ato, while those in the bristle (macrochaetes and IOBs) require ASC. Nevertheless, one common feature of the resolution of PNCs in the eye and the bristle is the centrality of E(spl)C, since loss of E(spl)C leads to exaggerated neurogenesis in both contexts. In the eye it leads to excess R8’s, rough eyes, and duplicated IOBs, while in the bristles this manifests as ectopic, split and missing bristles. Extensive analyses have identified the genes involved with these developmental programs, the feedback loops that reinforce proneural expression in R8’s/SOPs, and the role of E(spl)C for lateral inhibition. In contrast, it has remained unclear how phosphorylation contributes to the dynamics of this process (Bose, 2006).

It has been thought that transcription of E(spl) is, by itself, necessary and sufficient for lateral inhibition. This model emerged from studies on bristle development, where ectopic E(spl) proteins extinguished the SOPs, whereas loss of E(spl) favored this cell fate. This model needs qualification because similar outcomes have not been recapitulated in the eye. In this context, loss of E(spl) demonstrably compromises lateral inhibition and elicits excess R8’s. However, ectopic expression of E(spl) members does not block the R8 fate, and consequently the eye displays the normal hexagonal packing of the ommatidia; the only defect is loss of the IOBs whose developmental program bears similarities to that of the macrochaetes. In contrast, R8 formation is blocked by the truncated M8* protein encoded by the E(spl)D allele, or by the CK2 phophomimetic variant M8SD. It is important to note that the eye defect of E(spl)D requires N^spl, a recessive allele that attenuates ato, but not E(spl), expression. The inability of M8* to recruit Gro, which compromises repression, thus necessitates a sensitized background, one conferred by N^spl. Accordingly, M8SD (which binds Gro) elicits eye defects independent of N^spl (Karandikar, 2004). Based on the observation that both M8* and M8SD display exacerbated and equivalent interactions with Ato, it was proposed that CK2 phosphorylation switches M8 into an active repressor by uncovering the Orange domain, and it is this regulation that is bypassed by the E(spl)D mutation (Karandikar, 2004). Given that the Orange domain mediates binding to other proneurals as well, this regulation by CK2 should have been more general to lateral inhibition. These studies suggest just such a role in the eye and the bristle (Bose, 2006).

This work supports the notion that CK2 is a participant in lateral inhibition. Compromising CK2 by a number of independent routes, i.e., in wild type and backgrounds mutant for CK2 and E(spl), elicits neural defects in the eye and bristle. These include rough eyes due to the specification of excess 'founding' R8 cells, and ectopic bristles (macrochaetes and IOBs) due to the specification of excess SOP’s. These phenotypes are hallmarks of impaired lateral inhibition, and have been previously described for loss of function of the E(spl)C. Evidence is provided for genetic interactions between CK2 and E(spl). While these studies provide multiple lines of evidence, the absence of suitable antibodies have precluded a formal demonstration that E(spl) repressors are, in fact, phosphorylated in cells undergoing lateral inhibition. Nevertheless, the congruence of the results utilizing CK2-RNAi or CK2-DN in conjunction with extant mutants and cell fate in imaginal discs, together, constitute a plausible argument supporting a role for this protein kinase (Bose, 2006).

These studies also suggest secondary roles for CK2 in the bristle lineage. In contrast to R8 patterning, the roles of N and E(spl) are different during bristle morphogenesis. In the case of the macrochaete or the IOB, N and E(spl) are re-deployed following SOP selection. Specifically, the SOP gives rise to the pI neuroblast that undergoes two asymmetric divisions to generate four cell types characteristic of the sensillum; socket, shaft, sheath and neuron, and these divisions are dependent on N- and E(spl)-inhibitory signaling. Thus loss of E(spl) following SOP selection manifests as split bristles (aberrant division of the pIIa cell) or missing bristles (aberrant division of the pI cell). The split bristles described thus suggest a role for CK2 during the socket-to-shaft sister cell fate. In contrast, while the missing bristles suggest a role for CK2 during the pIIa-vs-pIIb fates, this phenotype could result from loss of the SOP itself, a possibility if CK2 levels become rate limiting for cell division. Despite the fact that the timing of the asymmetric divisions of pI, pIIa and pIIb are well known, CK2-RNAi or CK2-DN are not suitable for dissecting the roles of CK2 at these later steps of bristle development. Conditional alleles of CK2, e.g., temperature-sensitives, will be necessary to better define its roles during specification of these sister-cell fates. One major question that emerges from these studies is why is phosphorylation necessary, given that not all members of the E(spl)C are targets of CK2. It is thought that evolutionary principles, the diversities and/or affinities of interactions between E(spl)C and ASC/ato, and their spatial expression patterns, perhaps, offer insights (Bose, 2006).

Of the seven E(spl) proteins, three (M8, M5, and M7) are targeted by CK2, and these are also the most closely related. Among all E(spl) members, two regions largely account for length heterogeneity and divergence. These are sequences between HLH and Orange and those between Orange and WRPW, the CtD. However, within the CtD of M8 (and M5 and M7 as well) is a highly invariant sequence, the phosphorylation domain (P-domain) that harbors the CK2 site. Given the phylogenetic relationships of these species, it is noteworthy that over a period of ~50 million years the P-domain and the CK2 site have been remarkably conserved. For example, of all M8 homologs, only D. pseudoobscura, D. grimshawii and D. hydei harbor a Glu residue, in place of Asp, at the n + 3 position of the CK2 phosphoacceptor. While it has not been experimentally confirmed that these homologs are phosphorylated, the possibility is high because this change still conforms to the consensus (S/T-D/E-x-D/E) for recognition by CK2. The virtually identical consensus site that is present in mammalian Hes6 is targeted by CK2 (Gratton, 2003) in vivo (Bose, 2006).

The mechanisms by which E(spl) proteins mediate repression have been intensely studied. In essence, E(spl) proteins repress ASC/Ato. Repression was initially thought to involve binding to a DNA sequence, the N-box. This, however, is not the case, because E(spl) proteins neutralized for DNA-binding still function as potent repressors. Furthermore, no N-box has been found in the regulatory region of ato, while that in sc is dispensable for repression in non-SOPs. It is now thought that direct (protein–protein) interactions between E(spl) and proneurals are more critical for repression, the protein–tether model (Giagtzoglou, 2003). In this model, repression by E(spl) occurs via direct interactions with enhancer bound proneurals, rather than by activator sequestration. This model is consistent with direct interactions between E(spl) and ASC/Ato proteins. It was, in fact, the analyses of various binary combinations that were the first to suggest that these interactions are regulated and non-redundant, two aspects that appear relevant to the current findings (Bose, 2006).

Analysis of M8 and its E(spl)D encoded variant, M8* provided the first hint that these antagonistic interactions are regulated. For example, it has been reported that, in addition to Ato, M8* interacts with a much higher affinity with Ac, Sc, and Ase. A similar case is described for M8SD, which interacts with Ato or L’sc with affinities significantly higher than M8 or its non-phosphorylatable variant M8SA (Karandikar, 2004). It is noteworthy that phosphorylation of mammalian Hes6 by CK2 is also a pre-requisite for its interactions with Hes1 (Gratton, 2003). Thus CK2 phosphorylation influences antagonistic interactions between the E(spl) and the ASC/Ato. Because these studies have employed two hybrid, instead of direct protein, approaches the possibility that these are kinetic effects remains open. This interpretation is consistent with the observations that a 2× dosage of a UAS-mδ construct interferes with Ato and blocks eye development in the wild type, whereas that of m7, m5 or m8 requires N^spl. Together, these findings argue that E(spl)-ASC interactions are of variable strengths and are isoform-specific. Given that only a subset of E(spl) and ASC members are expressed in the eye and wing disc, the possibility thus arises that distinct domains of ASC define sub-regions of the proneural field. In this context, E(spl) members might have been selected based on their affinities and/or specificities for these proneural factors. Thus the type of E(spl) repressors that are deployed might reflect the combinations and levels of proneurals, with CK2 playing an integrative role. The currently available techniques preclude a distinction between these possibilities (Bose, 2006).

It is presently unclear if/how CK2 activity is modulated during neurogenesis. Expression of this enzyme appears to be constitutive in the eye and wing disc (Karandikar, 2004). Holoenzyme formation, proposed to be a dynamic process in vivo, represents an attractive regulatory mechanism, given that CK2β modulates substrate recognition and that the fly CK2β gene encodes for non-redundant isoforms of this regulatory subunit. Alternatively, CK2 might be regulated by assembly into multiprotein complexes and/or via interactions with protein phosphatases. Such a coordinated function has been described for regulation of Period, the central component of the circadian clock, by CK2 and the phosphatase PP2A. Future studies aimed at the identification of protein phosphatase(s) that counteract the phosphorylation of E(spl)m8/5/7 by CK2, or multiprotein complexes containing E(spl) and/or CK2 will be required to better define the regulatory dynamics of this process during eye and bristle development (Bose, 2006).

Effects of Mutation

The posttranslational modification of clock proteins is critical for the function of circadian oscillators. By genetic analysis of a Drosophila melanogaster circadian clock mutant known as Andante, which has abnormally long circadian periods, it has been shown that Casein kinase 2 (CK2) has a role in determining period length. Andante is a mutation of the gene encoding the ß subunit of CK2 and is predicted to perturb CK2ß subunit dimerization. It is associated with reduced ß subunit levels, indicative of a defect in alpha:ß association and production of the tetrameric alpha2:ß2 holoenzyme. Consistent with a direct action on the clock mechanism, it has been shown that CK2ß is localized within clock neurons and that the clock proteins Period (Per) and Timeless (Tim) accumulate to abnormally high levels in the Andante mutant. Furthermore, the nuclear translocation of Per and Tim is delayed in Andante, and this defect accounts for the long-period phenotype of the mutant. These results suggest a function for CK2-dependent phosphorylation in the molecular oscillator (Akten, 2003).

It is of interest that the Andante mutation affects the nuclear entry of clock proteins in the small LN_v population, but seems to have no effect on the large LN_v neurons. Such a differential effect suggests that CK2 is important for oscillator function in one population but not the other. Indeed, the small LN_v cells have been shown to be critical for the clock regulation of activity rhythms; the small cells send projections to a region of the dorsal brain implicated in clock output, and there is a circadian rhythm in the release of the clock output factor pigment dispersing factor (PDF) in these dorsal projections. Furthermore, it has been reported that the small but not the large LN_v cells show Tim rhythmicity in constant darkness (DD). Finally, there are differences between the large and small LN_v cells, with regard to the timing of Per and Tim nuclear entry. As CK2 deficits seem only to affect nuclear entry in the small LN_v neurons, it is possible that this kinase regulates differences between the two neuronal populations (Akten, 2003).

Although it is likely that CK2 acts within clock cells to help specify period length, these studies indicate neither the cellular compartment in which the kinase acts nor the molecular substrates of the enzyme that are relevant for clock function. A delay in the nuclear accumulation of clock proteins, as seen in Andante, suggests that the kinase functions in the cytoplasm to promote nuclear entry. This function might be mediated by direct phosphorylation of a clock protein (such as Per or Tim) or by activation of a second kinase such as GSK-3/Shaggy, which has been implicated in promoting the nuclear entry of Tim. The elevated levels of Per and Tim observed in Andante suggest a decreased turnover of the clock proteins, and this might arise because of a defect in the targeted degradation of one or both proteins within the nucleus. Similar to the Doubletime kinase, CK2 might act both in the cytoplasm and nucleus of clock cells to determine the timing of nuclear entry and/or stability of clock proteins (Akten, 2003).

These studies of CK2 in Drosophila suggest that this kinase might have an important role in the regulation of circadian period in other animal species. Previous studies in the plant Arabidopsis and the fungus Neurospora have also implicated CK2 activity in circadian oscillator function. The Arabidopsis study showed that overexpression of the CK2ß3 subunit is associated with a shortening of circadian period, a result similar to that obtained in this study of Drosophila CK2ß. The Neurospora study showed abnormal phosphorylation of the Frequency (Frq) protein in a Neurospora CK2alpha mutant, but circadian behavior (such as conidiation rhythms) could not be examined in that study because of reduced viability. Although neither of these previous reports characterize a mutant with decreased CK2 activity, the results are consistent with studies of Andante and indicate an evolutionarily conserved role for CK2 in circadian oscillator function (Akten, 2003).

Ackerman, P., Glover, C. V. and Osheroff, N. (1988). Phosphorylation of DNA topoisomerase II in vivo and in total homogenates of Drosophila Kc cells. The role of casein kinase II. J. Biol. Chem. 263 (25): 12653-12660. 88315066

Adler, V., et al. (1997). Conformation-dependent phosphorylation of p53. Proc. Natl. Acad. Sci. 94(5):1686-1691.

Akten, B., et al. (2003). A role for CK2 in the Drosophila circadian oscillator. Nature Neurosci. 6: 251-257. 12563262

Allende, J. E. and Allende, C. C. (1995). Protein kinase CK2: an enzyme with multiple substrates and a puzzling regulation. Faseb J. 9: 313-323

Appel, K., et al. (1995). Mapping of the interaction sites of the growth suppressor protein p53 with the regulatory beta-subunit of protein kinase CK2. Oncogene 11(10): 1971-1978.

Armstrong, S. A., et al. (1997). Casein kinase II-mediated phosphorylation of the C terminus of Sp1 decreases its DNA binding activity. J. Biol. Chem. 272 (21): 13489-13495.

Bidwai, A. P., Hanna, D. E. and Glover, C. V. (1992). Purification and characterization of casein kinase II (CkII) from delta cka1 delta cka2 Saccharomyces cerevisiae rescued by Drosophila CKII subunits. The free catalytic subunit of casein kinase II is not toxic in vivo. J. Biol. Chem. 267 (26): 18790-18796.

Birnbaum, M. J., et al. (1992). Expression and purification of the alpha and beta subunits of Drosophila casein kinase II using a baculovirus vector. Protein Expr. Purif. 3 (2): 142-150.

Boehning, D., et al. (2003). Carbon monoxide neurotransmission activated by CK2 phosphorylation of Heme Oxygenase-2. Neuron 40: 129-137. 14527438

Boldyreff, B. and Issinger, O. G. (1996). A-Raf kinase is a new interacting partner of protein kinase CK2 beta subunit. FEBS Lett. 403(2): 197-199.

Bonnet, H., et al. (1996). Fibroblast growth factor-2 binds to the regulatory beta subunit of CK2 and directly stimulates CK2 activity toward nucleolin. J. Biol. Chem. 271(40): 24781-24787.

Bose, A., et al. (2006). Drosophila CK2 regulates lateral-inhibition during eye and bristle development. Mech. Dev. 123(9): 649-64. Medline abstract: 16930955

Bourbon, H. M., et al. (1995). Phosphorylation of the Drosophila engrailed protein at a site outside its homeodomain enhances DNA binding. J Biol Chem 270 (19): 11130-11139.

Bozzetti, M. P., et al. (1995). The Ste Locus, a component of the parasitic cry-Ste System of Drosophila melanogaster, encodes a protein that forms crystals in primary spermatocytes and mimics properties of the ß subunit of Casein kinase 2. Proc. Natl. Acad. Sci. 92: 6067-6071. 7597082

Chen, M. and Cooper, J. A. (1997). The beta subunit of CKII negatively regulates xenopus oocyte maturation. Proc. Natl. Acad. Sci. 94(17): 9136-9140.

Chai, J., et al. (2001). Structural basis of Caspase-7 inhibition by XIAP. Cell 104: 769-780. 11257230

Coqueret, O., et al. (1998). DNA binding by cut homeodomain proteins is down-modulated by casein kinase II. J. Biol. Chem. 273(5): 2561-2566.

Dahmus, G. K., et al. (1984). Similarities in structure and function of calf thymus and Drosophila casein kinase II. J Biol Chem 259 (14): 9001-9006. 84264523

Dang, Q., Alghisi, G. C. and Gasser, S. M. (1994). Phosphorylation of the C-terminal domain of yeast topoisomerase II by casein kinase II affects DNA-protein interaction. J. Mol. Biol. 243 (1): 10-24.

Daniotti, J. L., et al. (1994). Cloning and expression of genes coding for protein kinase CK2 alpha and beta subunits in zebrafish (Danio rerio). Cell Mol. Biol. Res. 40 (5-6): 431-439.

Desagher, S., et al. (2001). Phosphorylation of Bid by casein kinases I and II regulates its cleavage by Caspase 8. Molec. Cell 8: 601-611. 11583622

Diaz-Nido, J., et al. (1994). Regulation of protein kinase CK2 isoform expression during rat brain development. Cell Mol. Biol. Res. 40(5-6): 581-585.

Dominguez, I., et al. (2004). Protein kinase CK2 is required for dorsal axis formation in Xenopus embryos. Dev. Biol. 274: 110-124. 15355792

Filhol, O., et al. (1996). Casein kinase 2 inhibits the renaturation of complementary DNA strands mediated by p53 protein. Biochem J 316 ( Pt 1): 331-335.

Gallant, P., et al. (1996). Myc and Max homologs in Drosophila. Science 274: 1523-1526

Gelsthorpe, M. E., et al. (2006). Regulation of the Drosophila melanogaster protein, enhancer of rudimentary, by casein kinase II. Genetics 174(1): 265-70. 16849599

Ghavidel, A. and Schultz, M. C. (1997). Casein kinase II regulation of yeast TFIIIB is mediated by the TATA-binding protein. Genes Dev. 11(21): 2780-2789

Giagtzoglou, N., et al. (2003). Two modes of recruitment of E(spl) repressors onto target genes. Development 130: 259-270. Medline abstract: 12466194

Gotz, C., et al. (1996). p21WAF1/CIP1 interacts with protein kinase CK2. Oncogene 13(2): 391-398.

Glover, C. V., et al. (1983). Purification and characterization of a type II casein kinase from Drosophila melanogaster. J Biol Chem 258 (5): 3258-3265. 83135783

Glover, C. V. (1986). A filamentous form of Drosophila casein kinase II. J. Biol. Chem. 261 (30): 14349-14354. 87033630

Gratton, M.-O. et al. (2003). Hes6 promotes cortical neurogenesis and inhibits Hes1 transcription repression activity by multiple mechanisms. Mol. Cell. Biol. 23: 6922-6935. Medline abstract: 12972610

Gruppuso, P. A. and Boylan, J. M. (1995). Developmental changes in the activity and cellular localization of hepatic casein kinase II in the rat. J. Cell. Biochem. 58(1): 65-72.

Guerra, B., et al. (1997). The carboxy terminus of p53 mimics the polylysine effect of protein kinase CK2-catalyzed MDM2 phosphorylation. Oncogene 14(22): 2683-2688.

Hagemann, C., et al. (1997). The regulatory subunit of protein kinase CK2 is a specific A-Raf activator. FEBS Lett. 403(2): 200-202

Hanna, D. E., Rethinaswamy, A. and Glover, C. V. (1995). Casein kinase II is required for cell cycle progression during G1 and G2/M in Saccharomyces cerevisiae. J. Biol. Chem. 270(43): 25905-25914.

He, Q., et al. (2006). CKI and CKII mediate the FREQUENCY-dependent phosphorylation of the WHITE COLLAR complex to close the Neurospora circadian negative feedback loop. Genes Dev. 20(18): 2552-65. Medline abstract: 16980584

Heriche, J. K., et al. (1997). Regulation of protein phosphatase 2A by direct interaction with casein kinase 2alpha. Science 276(5314): 952-955.

Hockman, D. J. and Schultz, M. C. (1996). Casein kinase II is required for efficient transcription by RNA polymerase III. Mol. Cell. Biol. 16(3): 892-898.

Hu, E. and Rubin, C. S. (1991). Casein kinase II from Caenorhabditis elegans. Cloning, characterization, and developmental regulation of the gene encoding the beta subunit. J. Biol. Chem. 266(29): 19796-19802.

Huang, G., et al. (2007). Protein kinase A and casein kinases mediate sequential phosphorylation events in the circadian negative feedback loop. Genes Dev. 21(24): 3283-95. PubMed citation: 18079175

Huang, Y., et al. (2001). Structural basis of caspase inhibition by XIAP: Differential roles of the linker versus the BIR Domain. Cell 104: 781-790. 11257231

Jaffe, L., Ryoo, H. D. and Mann, R. S. (1997). A role for phosphorylation by casein kinase II in modulating Antennapedia activity in Drosophila. Genes Dev 11 (10): 1327-1340.

Jakobi, R., Lin, W. J. and Traugh, J. A. (1994). Modes of regulation of casein kinase II. Cell. Mol. Biol. Res. 40(5-6): 421-429.

Jakobi, R. and Traugh, J. A. (1995a). Analysis of the ATP/GTP binding site of casein kinase II by site-directed mutagenesis. Physiol. Chem. Phys. Med. NMR 27(4): 293-301.

Jakobi, R. and Traugh, J. A. (1995b). Site-directed mutagenesis and structure/function studies of casein kinase II correlate stimulation of activity by the beta subunit with changes in conformation and ATP/GTP utilization. Eur. J. Biochem. 230(3): 1111-1117.

Jauch, E., Wecklein, H., Stark, F., Jauch, M. and Raabe, T. (2006). The Drosophila melanogaster DmCK2beta transcription unit encodes for functionally non-redundant protein isoforms. Gene 374: 142-52. 16530986

Karandikar, U., Trott, R. L., Yin, J., Bishop, C. P. and Bidwai, A. P. (2004). Drosophila CK2 regulates eye morphogenesis via phosphorylation of E(spl)M8. Mech. Dev. 121: 273-286. 15003630

Karandikar, U. C., Shaffer, J. Bishop, C. P. and Bidwai, A. P. (2005). Drosophila CK2 phosphorylates Deadpan, a member of the HES family of basic-helix-loop-helix (bHLH) repressors. Molec. Cell. Biochem. 274: 133-139. 16342413

Karki, S., Tokito, M. K. and Holzbaur, E. L. (1997). Casein kinase II binds to and phosphorylates cytoplasmic dynein. J. Biol. Chem. 272(9): 5887-5891.

Kasahara, H. and Izumo, S. (1999). Identification of the in vivo casein kinase II phosphorylation site within the homeodomain of the cardiac tisue-specifying homeobox gene product Csx/Nkx2.5. Mol. Cell. Biol. 19(1): 526-36.

Kato, T., et al. (2003). CK2 is a c-terminal IkappaB kinase responsible for NF-kappaB activation during the UV response. Molec. Cell 12: 829-839. 14580335

Lee, J. S., Ishimoto, A. and Yanagawa, Si. (1999). Characterization of mouse Dishevelled (Dvl) proteins in Wnt/Wingless signaling pathway. J. Biol. Chem. 274(30): 21464-70.

Lickert, H., et al. (2000). Casein kinase II phosphorylation of E-cadherin increases E-cadherin/beta-catenin interaction and strengthens cell-cell adhesion. J. Biol. Chem. 275(7): 5090-5.

Lieberman, D. N. and Mody, I. (1999). Casein kinase-II regulates NMDA channel function in hippocampal neurons. Nature Neurosci. 2(2): 125-132

Lin, J.-M., et al. (2002). A role for casein kinase 2alpha in the Drosophila circadian clock. Nature 420: 816-820. 12447397

Lin, J.-M., Schroeder, A. and Allada, R. (2005). In vivo circadian function of casein kinase 2 phosphorylation sites in Drosophila PERIOD. J. Neurosci. 25(48): 11175-83. 16319317

Lin, R., et al. (1996). Phosphorylation of IkappaBalpha in the C-terminal PEST domain by casein kinase II affects intrinsic protein stability. Mol. Cell. Biol. 16(4): 1401-1409.

Lin, W. J., Jakobi, R. and Traugh, J. A. (1994). Reconstitution of heterologous and chimeric casein kinase II with recombinant subunits from human and Drosophila: identification of species-specific differences in the beta subunit. J. Protein Chem. 13 (2): 217-225.

Liu, Z. P., Galindo, R. L. and Wasserman, S. A. (1997). A role for CKII phosphorylation of the Cactus PEST domain in dorsoventral patterning of the Drosophila embryo. Genes Dev. 11(24): 3413-3422

Marin, O., et al. (1997). Physical dissection of the structural elements responsible for regulatory properties and intersubunit interactions of protein kinase CK2 beta-subunit. Biochemistry 36(23): 7192-7198.

Mestres, P., et al. (1994). Expression of casein kinase 2 during mouse embryogenesis. Acta Anat (Basel) 149(1): 13-20.

Miyata, Y., et al. (1997). Phosphorylation of the immunosuppressant FK506-binding protein FKBP52 by casein kinase II: regulation of HSP90-binding activity of FKBP52. Proc. Natl. Acad. Sci. 94(26): 14500-14505.

Packman, L. C., et al. (1997). Casein kinase II phosphorylates Ser468 in the PEST domain of the Drosophila IkappaB homologue cactus. FEBS Lett 400 (1): 45-50.

Pepperkok, R., et al. (1994). Casein kinase II is required for transition of G0/G1, early G1, and G1/S phases of the cell cycle. J. Biol. Chem. 269(9): 6986-6991.

Pogge von Strandmann, E., Senkel, S. and Ryffel, G. U. (2001). ERH (enhancer of rudimentary homologue), a conserved factor identical between frog and human, is a transcriptional repressor. Biol. Chem. 382(9): 1379-85. 11688721

Ritt, D. A., et al. (2006). CK2 is a component of the KSR1 scaffold complex that contributes to Raf kinase activation. Curr. Biol. 17: 179-184. Medline abstract: 17174095

Saxena, A., Padmanabha, R. and Glover, C. V. (1987). Isolation and sequencing of cDNA clones encoding alpha and beta subunits of Drosophila melanogaster casein kinase II. Mol. Cell. Biol. 7 (10): 3409-3417. 88065475

Sugano, S., Andronis, C., Ong, M. S., Green, R. M. and Tobin, E. M. (1999). The protein kinase CK2 is involved in regulation of circadian rhythms in Arabidopsis. Proc. Natl. Acad. Sci. 96: 12362-12366. 10535927

Toczyski, D. P., Galgoczy, D. J. and Hartwell, L. H. (1997). CDC5 and CKII control adaptation to the yeast DNA damage checkpoint. Cell 90(6): 1097-1106.

Tran, K., Merika, M. and Thanos, D. (1997). Distinct functional properties of IkappaB alpha and IkappaB beta. Mol. Cell. Biol. 17(9): 5386-5399.

Trott, R. L., Kalive, M., Paroush, Z.. and Bidwai, A. P. (2001). Drosophila melanogaster casein kinase II interacts with and phosphorylates the basic helix-loop-helix proteins m5, m7, and m8 derived from the Enhancer of split complex. J. Biol. Chem. 276(3): 2159-67. 11208814

Valero, E., et al. (1995). Quaternary structure of casein kinase 2. Characterization of multiple oligomeric states and relation with its catalytic activity. J. Biol. Chem. 270(14): 8345-8352.

Willert, K., et al. (1997). Casein kinase 2 associates with and phosphorylates dishevelled. EMBO J. 16(11): 3089-3096.

Wisniewski, J. R., et al. (1999). Constitutive phosphorylation of the acidic tails of the high mobility group 1 proteins by casein kinase II alters their conformation, stability, and DNA binding specificity. J. Biol. Chem. 274(29): 20116-22.

Yanagawa, S.-I., Lee, J.-S. and Ishimoto, A. (1998). Identification and characterization of a novel line of Drosophila Schneider S2 cells that respond to Wingless signaling. J. Biol. Chem. 273(48): 32353-32359.

Yang, Y., Cheng, P. and Liu, Y. (2002). Regulation of the Neurospora circadian clock by casein kinase II. Genes Dev. 16: 994-1006. 11959847

Zhao, T. and Eissenberg, J. C. (1999). Phosphorylation of heterochromatin protein 1 by casein Kinase II is required for efficient heterochromatin binding in Drosophila. J. Biol. Chem. 274(21): 15095-15100

date revised: 20 June 2007

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