Disease relevance of CSNK2A1

• For a systematic investigation, the complete set of recombinant CKII subunits and of autophosphorylation mutants of CKII beta were expressed in Escherichia coli and comparative reconstitutions carried out [1].
• Recombinant baculoviruses were used to express wild-type serum response factor (SRF) and a mutant, SRF.CKIIA, which lacks all four serine residues in the major casein kinase II (CKII) site at residues 77-90 [2].
• The functional role of CKII was tested in an in vitro I kappa B alpha degradation assay with extracts from uninfected and human immunodeficiency virus (HIV)-infected U937 cells [3].
• CONCLUSION: CSNK2A1 and C1-Inh are independent predictors of survival in lung squamous cell carcinoma patients and may be useful as prognostic markers [4].
• Our data demonstrate that pMYCN is a physiological substrate for CK-II and, since CK-II activity is stimulated in response to mitogens, CK-II phosphorylation of pMYCN may, therefore, represent one signal transduction pathway used by neuroblastoma cells [5].

High impact information on CSNK2A1

• Both Myc-Max and Mad-Max heterocomplexes are favored over Max homodimers, and, unlike Max homodimers, the DNA binding activity of the heterodimers is unaffected by CKII phosphorylation [6].
• Microinjection of CKII suppresses induction of AP-1 by either phorbol ester or an inhibitory peptide [7].
• The potential role of CKII as either a regulatory or constitutive modifier of SRF in vivo will be discussed [8].
• It appears that the ability of insulin to activate CKII in skeletal muscle is not impaired in insulin-resistant Pima Indians, and that the biochemical lesion responsible for insulin resistance occurs either downstream from CKII or in a different pathway of insulin action [9].
• The role of both CKII and PP2A in controlling multiple sorting steps in the TGN/endosomal system indicates that the distribution of itinerant membrane proteins may be acutely regulated via signal transduction pathways [10].

Chemical compound and disease context of CSNK2A1

• Though structurally unrelated to chrysin, an HIV-1 inhibitory benzothiophene also bound selectively to CKII [11].
• Cotransfection experiment also demonstrated that packaging of HDV genomic RNA was not affected by the kinase inhibitor DRB or H7 and mutation at the putative CKII phosphorylation sites (serine-2, serine-123, or both), and the putative PKC site (serine-210) of HDAg did not elicit any significant effect on the HDV virion assembly [12].

Biological context of CSNK2A1

• Genomic organization and promoter identification of the human protein kinase CK2 catalytic subunit alpha (CSNK2A1) [13].
• The maximal stoichiometry of the CKII phosphorylation of plasma Vn was found to be low, which, in principle, could be due to its partial prephosphorylation in vivo [14].
• In eukaryotic cells, protein kinase CKII is required for progression through the cell division cycle [15].
• Phosphorylation of the DNA repair protein APE/REF-1 by CKII affects redox regulation of AP-1 [16].
• The human gene (CSNK2A1) coding for the casein kinase II subunit alpha is located on chromosome 20 and contains tandemly arranged Alu repeats [17].

Anatomical context of CSNK2A1

• In this report, we demonstrate that CKBBP1 is efficiently phosphorylated in vitro by purified CKII in the presence of GTP and by heparin-sensitive protein kinase in HeLa cell extract [15].
• Inhibition of CKII activity by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole blocks the binding between these two proteins and significantly reduces the percentage of cells that contain eosinophilic cytoplasmic inclusions [18].
• Moreover, phosphopeptide maps of I kappa B alpha phosphorylated in vitro by cellular extracts and in vivo in resting Jurkat T cells contained the same pattern of phosphopeptides as observed in maps of I kappa B alpha phosphorylated in vitro by purified CKII [3].
• CKII preparations partially purified from PC12 cells are able to phosphorylate recombinant L1 cytoplasmic domain (L1CD), which consists of residues 1,144-1,257 [19].
• Recombinant Vpu associated with E. coli membranes has turned out to be the best substrate for in vitro phosphorylation with CKII [20].

Associations of CSNK2A1 with chemical compounds

• Mutational analysis indicates that CKII phosphorylates threonine at residue 10 within CKBBP1 [15].
• Site-specific mutagenesis of MAZ revealed that the serine residue at position 480 was the major site of phosphorylation by CKII both in vitro and in vivo [21].
• In contrast, a peptide with an alanine instead of a serine at position 692 neither incorporates phosphate nor inhibits factor Va phosphorylation by the platelet CKII [22].
• We previously showed that CKII is co-purified with the ATF family of transcription factors using DNA-affinity latex beads [23].
• An interesting aspect of nucleolin action is that it is a target for regulation by proteolysis, methylation, ADP-ribosylation, and phosphorylation by CKII, cdc2, PKC-xi, cyclic AMP-dependent protein kinase, and ecto-protein kinase [24].

Physical interactions of CSNK2A1

• Phosphorylation of MAZ by CKII at this serine residue was required for maximum binding of MAZ to the pyrimidine-rich DNA of the nuclease-hypersensitive element (NHE) in the 5'-end promoter region of the c-myc gene [21].
• Using the yeast two-hybrid system, we have identified the highly basic, ribosomal protein L41 as a cellular protein capable of interacting with the beta subunit of CKII [25].
• Surface plasmon resonance (SPR) measurements revealed that CKII binds to immobilized HSP90 within minutes [26].
• Moreover, it was clearly shown that one of CKII subunits, the CKII alpha protein bound to glutathione-S-transferase (GST) fusion ATF1 but not GST in vitro [27].

Enzymatic interactions of CSNK2A1

• Here we report that casein kinase II (CKII) phosphorylates synphilin-1 and that the beta subunit of this enzyme complex binds to synphilin-1 [18].
• Two-dimensional phosphopeptide mapping of the sites phosphorylated by PKA, PKC, and CKII in vitro demonstrates that these enzymes are capable of phosphorylating IRF2 at multiple distinct sites [28].
• These results suggest that two serine residues of the acidic central region of the N-myc protein are phosphorylated by CKII in vivo as well as in vitro [29].
• Serine 32 and serine 36 of IkappaBalpha are directly phosphorylated by protein kinase CKII in vitro [30].
• Sequence analysis revealed that purified CKII and the kinase activity within cell extracts phosphorylated I kappa B alpha at its C terminus at S-283, S-288, S-293, and T-291 [3].

Regulatory relationships of CSNK2A1

• Moreover, the mutated MAZ was unable to enhance the expression of luciferase encoded by a c-myc promoter/luciferase reporter gene in HeLa cells in the presence of CKII [21].
• At 1:1 molar ratio, CKII beta stimulated both catalytic subunits roughly fivefold with phosvitin as a substrate [1].
• Inhibition of CKII mediated phosphorylation of APE/Ref-1 blocked mutagen-stimulated increase in AP-1 binding [16].
• Immunodepletion of CKII from these extracts abrogated both the basal and enhanced HIV-induced degradation of I kappa B alpha [3].
• CKII was not a substrate for the maturation-activated myelin basic protein kinase p44mpk from sea-star oocytes, nor for cyclic-AMP-dependent protein kinase [31].

Other interactions of CSNK2A1

• Additionally, both CKII alpha and beta subunits are present within cytoplasmic inclusions in cells that overexpress synphilin-1 [18].
• Strikingly, ERK1 failed to phosphorylate Spi-1, in vitro, whereas JNK1, like CK II, phosphorylated Spi-B and Spi-1 [32].
• It was also similar to a recombinant alpha 2 beta 2 holoenzyme whose expression had been attained in E. coli with a bicistronic construct containing the coding regions of CKII beta and CKII alpha in a tandem arrangement [1].
• We demonstrate that CKII associates with and phosphorylates the C-terminal region of CD5, a conserved domain known to be relevant for the generation of second lipid messengers, and thereby enables at least one component of its signaling function [33].
• Strong phosphorylation by CKII was detected with the fused protein of wild-type N-myc [29].

Analytical, diagnostic and therapeutic context of CSNK2A1

• Both Ser2 and Ser3 were identified as the autophosphorylation sites; replacement of one of these with Ala by oligonucleotide-mediated site-directed mutagenesis influenced only the extent of CKII beta autophosphorylation, replacement of both resulted in a loss of autophosphorylation [1].
• Immunoprecipitation studies demonstrated that CKII and I kappa B alpha physically associate in vivo [3].
• Western blot analysis demonstrates that casein kinase II (CKII), a ubiquitous serine/threonine kinase enriched in brain, is present in these immunoprecipitates [19].
• To examine the subunit structure of EF-1 and phosphorylation by protein kinase CKII, recombinant beta, gamma, and delta subunits from rabbit were expressed in E. coli and the subunits were reconstituted into partial and complete complexes and analyzed by gel filtration [34].
• We now show that during normal growth of primary cell cultures and HeLa cells CKII activity is increased concomitant with cellular growth and that the activity declines when confluency is reached [35].

References