CSNK2A2 (casein kinase 2 alpha 2)

2020-11-01   Nazanin Abazari , Alessandro Beghini 

University of Milan, Department of Health Sciences, Milan Italy Nazanin.abazari@studenti.unimi.it; alessandro.beghini@unimi.it

Identity

HGNC
LOCATION
16q21
IMAGE
Atlas Image
LEGEND
Figure 1. CSNK2A2 gene
LOCUSID
ALIAS
CK2A2,CK2alpha,CSNK2A1
FUSION GENES

Abstract

CSNK2A2 gene, 16q21, has a role in regulating the phosphorylation and circulation of old proteasomes by encoding the catalytic α subunit of casein kinase 2 (CK2α). Casein kinase 2 is a serine\/threonine protein kinase that phosphorylates acidic proteins. It can regulate Wnt signalling by phosphorylating CTNNB1 and the transcription factor LEF1 and for this reason, it is involved in some cellular key processes such as cell cycle progression, inhibition of apoptosis, DNA damage repair, differentiation and transcription but also viral infection. CSNK2A2 is a cancer-related gene and its upregulation has been detected is many cancers such as glioblastoma multiforme, colorectal cancer, breast cancer and ovarian cancer, and also in some diseases such as diabetes, theileriasis in cattle and distal muscular dystrophy with anterior tibial onset in mice are associated with CSNK2A2.

DNA/RNA

Description

DNA size: 40200 bp, DNA linear, on reverse strand. This gene has 6 transcripts (splice variants), 412 orthologues, 2 paralogues and is a member of 1 Ensembl protein family.

Transcription

CSNK2A2-201 ENST00000262506.8: mRNA 1887 bp, protein 350 aa
CSNK2A2-202 ENST00000562367.1: mRNA 687 bp, No protein
CSNK2A2-203 ENST00000563307.1: mRNA 4978 bp, protein 152 aa
CSNK2A2-204 ENST00000565188.1: mRNA 547 bp, protein 135 aa
CSNK2A2-205 ENST00000566813.5: mRNA 1569 bp, No protein
CSNK2A2-206 ENST00000567730.6: mRNA 947 bp, protein 230 aa (www.ensembl.org).

Pseudogene

A related transcribed pseudogene is found on chromosome 11.

Proteins

Atlas Image
Figure 2. CSNK2A2 (ck2) protein

Description

CK2 (casein kinase 2) is an evolutionarily protected protein kinase, and the deletion of both of its catalytic subunits is lethal. (Padmanabha et al., 1990).
The crystal structure of a fully active form (Tetramer) of human CK2 consisting of two C-terminally truncated (Alpha) catalytic and two regulatory (Beta) subunits (Protein Data Bank code: 1JWH). This protein is composed of 350 amino acids, with Molecular mass of 41213 Da. For two α subunits, α being 42 kDa and α being 38 kDa, and two β subunits, each weighing in at 28 kDa. The β subunits form homodimers which are building blocks to generate heterotetramers with the catalytic subunits (α or α) in which these two catalytic subunits in the holoenzyme make no contacts with each other (Niefind, Guerra et al. 2001). CK2 proteins can function as monomeric kinases or within a tetrameric complex of two CK2 kinase units and two units of the regulatory protein CK2b. ((Ortega, Seidner et al. 2014).
Quaternary structure is generally characterized by tight regulation. The enzyme acts independently of classical activating second messengers. (Ackermann, Neidhart et al. 2005). Unlike most other proteins, CK2 shows the rare ability dual-co-substrate specificity to use either ATP or GTP as phosphoryl donor. (Niefind et al., 1999).
CSNK2A2 encodes alpha prime polypeptide (the catalytic subunit of the protein kinase enzyme). The α subunits do not require the β regulatory subunits to function, this allows dimers to form of the catalytic domains independent of β subunit transcription. Catalytic subunit of kinase complex phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine such as casein (Pinna 2002). In mouse transgenic models CK2α is an oncogene and CK2α overexpression in mammary gland and lymphoid compartment leads to tumor formation (Seldin 1995).
CSNK2A2 protein also has interactions with other proteins such as CSNK2B, CSNK2A1, ENSG00000263020, JUN , TP53, SUPT16H, SSRP1, DVL3, DVL1, NFKBIA. https://www.sinobiological.com/resource/ck2-alpha-csnk2a1/proteins
Atlas Image
Figure 3. Sequence alignment

Expression

In human, CSNK2A2 has a broad expression in testis (RPKM 55.0) and skin (RPKM 19.3) but also it is expressed in 24 other tissues including bone marrow, whole blood, lymph node, thymus, cerebellum, brain, retina, spinal cord, heart, smooth muscle, skeletal muscle, small intestine, colon, adipocyte, kidney, liver, lung, pancreas, thyroid, salivary gland, adrenal gland, ovary, uterus, placenta, cervix and prostate (Ortega, Seidner et al. 2014). https://www.genecards.org/cgi-bin/carddisp.pl?gene=CSNK2A2#expression.
A significant increase in expression of eight Wnt signaling pathway proteins including CSNK2A2, was detected in glioblastoma multiforme (GBM) (Shevchenko, Arnotskaya et al. 2020).
Experimental studies suggest that irregular expression of the alpha CK2 subunit transmits a oncogenic potential in the cells such that in cooperation with certain oncogenes it causes a profound increase in tumor phenotype. (Tawfic, Yu et al. 2001).
In addition, increased CSNK2A2 expression has been observed in breast cancer tissue and breast cancer cell lines, colon cancer progression as well as villous colon adenomas (Romieu-Mourez, Landesman-Bollag et al. 2001, Nibbe, Markowitz et al. 2009, Nguyen, Albers et al. 2010, Wang, Chang et al. 2016). Moreover, data on transcript expression of the specified gene (CK2) in cancer versus normal tissue revealed widespread upregulation in the expression of CK2 genes in primary tumor tissues (Ortega, Seidner et al. 2014).
Atlas Image
Figure4. CSNK2A2 (ck2) mRNA Expression in different tumor types GTXportal.org/home/gene/.

Localisation

CSNK2A2 is localized in the nucleus and cytosol. Nuclear matrix and chromatin described to be the key sites for signaling of the CK2 activity in relation to cell growth (Tawfic, Yu et al. 2001).
Atlas Image
Figure 5. CSNK2A2 (ck2) in wnt signaling

Function

CSNK2A2 is responsible for phosphorylation of substrates containing acidic residues in various pathways within a cell; ATP or GTP can be used as phosphate source. Indeed, it can regulate numerous cellular processes, such as cell cycle progression, apoptosis, and transcription, as well as viral infection.
During mitosis CK2s anti-apoptotic function is in the continuation of the cell cycle; from G1 to S phase and G2 to M phase checkpoints, it functions as a component of the TP53-dependent spindle assembly checkpoint (SAC) that maintains cyclin-B- CDK1 activity and G2 arrest in response to spindle damage.
Comparison the induced expression of catalytically inactive CK2a in human osteosarcoma U2-OS cells suggested that CK2α may have unique functions associated with the control of proliferation or viability.
CSNK2A2 is also required for TP53-mediated apoptosis, phosphorylating Ser-392 of TP53 following UV irradiation.
CSNK2A2 also regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV. Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, SRF, MAX, JUN, FOS, MYC and MYB. Phosphorylates HSP90AA1 (Hsp90) and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function.
It acts as an ectokinase that phosphorylates several extracellular proteins. During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV (Keller, Zeng et al. 2001, Sayed, Pelech et al. 2001, Shin, Lee et al. 2005).
The Wnt pathway connection:
CSNK2A2 acts as a multi-site regulator of the Wnt pathway, and it is well known for phosphorylating CTNNB1 (β-catenin ) and the transcription factor LEF1.
Wnt signaling is initiated by binding of the secreted Wnt ligand to the members of the Frizzled receptor family. The level of β-catenin in the cytosol, is a key element in the Wnt pathway which triggers the activation of Wnt responsive genes. In the absence of Wnt stimulation, β-catenin is degraded by the proteasome (which depends upon β-catenin phosphorylation in a multi-protein complex by a hierarchical mechanism involving both CSNK1A1 (CK1) and GSK3). This phosphorylation is crucial for binding of β-catenin to the F-box protein βTrCP, which imparts specficity on the ubiquitination apparatus.
Wnt signaling inhibits GSK3 and prevents the ubiquitination and degradation of β-catenin, which leads to the accumulation of β-catenin in the cytosol and the activation of Wnt responsive genes, some of which are proto-oncogenes.
It is hypothesized that CK2 has dual role in the Wnt signaling pathway. First it can directly phosphorylate β-catenin and prevents its degradation by counteracting the effect of GSK3 phosphorylation within the negative regulatory complex (Son et al., 2000). Inhibition of CK2 decreases β-catenin level and blocks proliferation of Wnt-transfected cells. Suggesting that β-catenin phosphorylated by CK2 escapes ubiquitination and degradation, leading to an increased level of β-catenin available to activate Wnt-responsive genes.
On the other hand, CK2, by phosphorylating CDC34 (the E2 ubiquitin-conjugating enzyme UBC3), promotes its binding to the proteasome receptor β-TrCP, ultimately assisting the degradation of β-catenin (Semplici et al., 2002).
The apoptosis pathway connection:
Under survival conditions, CK2 phosphorylates proteins such as ARC and BID. When ARC is phosphorylated, it is targeted to mitochondria, where it inhibits CASP8 (caspase 8). Bid is resistant to cleavage by caspase 8, when it is phosphorylated by CK2. Under apoptotic conditions, CK2 phosphorylation sites on proteins such as BID and ARC are not phosphorylated, indeed ARC is not targeted to mitochondria and does not inhibit caspase 8. In the absence of phosphorylation, Bid is susceptible to cleavage by caspase 8.
The subsequent translocation of BID to the mitochondria is followed by release of cytochrome C that leads to the amplification of caspase activation (proteins, including MAX and HS1, become susceptible to caspase-mediated cleavage when they are not phosphorylated by CK2) (Litchfield 2003).
CSNK2A2 can also negatively regulate apoptosis by phosphorylating the caspases ( CASP9 and CASP2) and the apoptotic regulator NOL3. This phosphorylation, protects CASP9 from cleavage and activation by CASP8, so can inhibits the CASP2 dimerization and CASP8 activation.
Atlas Image
Figure 6. CSNK2A2 (ck2) and apoptosis

Homology

The CSNK2A2 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, S.cerevisiae, K.lactis, E.gossypii, A.thaliana, and rice.

Mutations

Note

First human condition associated with germline mutations in any of the CK2 subunits has been described by Volkan Okur (Volkan Okur, 2016 Jul) with a clinical phenotype of neurodevelopmental disabilities and dysmorphic features. Patients from five independent families with overlapping neurodevelopmental disorders and dysmorphic features were found to have likely damaging de novo splice site or missense variants in highly conserved regions of CSNK2A1. They found one splice site variant (c.824 + 2T>C) and four missense variants (p.R47Q, p.Y50S, p.D175G, p.K198R) in this gene.
Atlas Image
Figure 7. 3D structure of human CSNK2A2 and mutation sites
Atlas Image
Figure 8. Domains of CSNK2A1 and locations of de novo variants.
Atlas Image
Figure 9. Predicted pathogenicity of novel de novo CSNK2A1 variants

Somatic

Somatic mutations in CSNK2A1 have been implicated in various cancers by regulating downstream cancer-associated genes such as JAK/STAT, NF-kB, PI3K/AKT (Zheng et al. 2013).

Implicated in

Entity name
Diabetes
Note
Researchers investigated the relationship of relative leukocyte telomere length (RTL) with cardiometabolic risk. Genome-wide association study (GWAS) and meta-analysis identified two variants (rs7196068 and rs74019828) in CSNK2A2 which are associated with leukocyte telomere length in a Punjabi Sikh diabetic cohort.
CSNK2A2 is affiliated with the members of the shelterin complex involved in chromosome-end protection, telomere regulation, and maintenance. Interestingly, the telomeric repeat binding factor 1 ( TERF1) serves as a substrate for CSNK2A2, which phosphorylates and initiates its binding to telomeres. Partial knock-down of CSNK2A2 resulted in removal of TERF1 from telomeres and degradation of TERF1.
CSNK2A2 also influences Wnt signaling via beta-catenin phosphorylation and the PI3-K signaling pathway via the phosphorylation of Akt (Saxena, Bjonnes et al. 2014).
Entity name
Epithelial ovarian cancer (EOC)
Note
Ovarian cancer is the leading cause of death for gynecologic cancers, ranking fifth overall for cancer-related death among women. The function of protein kinase CK2α (CK2α) in EOC is still unknown. Study on the EOC cell lines (like A2780, HO8910, COV644, OVCAR3, SKOV3) and the primary normal ovarian surface epithelial (NOSE) cells revealed that CK2α protein expression was increased in A2780, HO8910, OVCAR3, and SKOV3 ovarian cancer cell lines compared to the NOSE cells. In addition, CK2α knockdown by specific siRNAs, inhibited migration, and invasion ability of OVCAR3 and SKOV3 cells. Study of Zebiao Ma suggests that, CK2α may play a role in tumor aggressive behavior of EOC and could be used as a marker for predicting prognosis of EOC patient, plus high CK2α expression might predict poor patient survival (Ma, Wang et al. 2017)
Entity name
Triple negative breast cancer (TNBC)
Note
Increased CK2 protein expression and activity is observed in a broad range of cancers including breast cancer. Aggressive breast cancers like triple-negative breast cancer (TNBC) refers to any breast cancer that does not express the genes for estrogen receptors ESR1 and ESR2), progesterone receptor (PGR) and epidermal growth factor receptor 2 ( ERBB2 (HER2/neu)). Lacking HER2 overexpression, makes it more difficult to be treated, since most hormone therapies target one of these three receptors, therefore this feature of TNBC have improved mortality. Casein kinase 2 (CK2) is a survival protein kinase that suppresses cancer cell death. RNA expression levels analysis revealed strong CDK11 and CK2 mRNA as well as protein expression in most human breast cancer cells. Down-regulation of CDK11 and/or CK2 in breast cancer cells caused significant loss of cell viability and clonal survival, suggesting that CDK11 and CK2 expression are individually essential for breast cancer cell survival including TNBC and they serve as promising new targets for therapeutic development in breast cancer (Kren, Unger et al. 2015).
Entity name
Colorectal cancer (CRC)
Note
It has been identified that several proteins (CSNK2A2, PLK1, and IGFBP3) are associated with the progression of colorectal cancer (CRC). CSNK2A2 in CRC, suppresses apoptosis by desensitizing cells to TRAIL in a caspase-dependent manner but independent of NF-kβ. It has also been shown to promote survival of colon cancer cells by increasing the expression of survivin via the canonical transcription pathway hyperactive in CRC ( LEF1 (lymphoid enhancer binding factor) )(Nibbe, Markowitz et al. 2009).
Entity name
Glioblastoma multiforme (GBM)
Note
In a study, researchers compared the expression levels of signaling pathway proteins in CD133(+) CSCs and CD133 (-) differentiated glioblastoma cells (DGCs). This revealed a significant increase in expression of eight Wnt signalling pathway proteins ( APC, CSNK1E, CSNK1A1, CSNK2A2, CSNK2B, CTNNB1, DVL1, CHTF18 (RUVBL)) in cancer stem cells (CSCs) of Glioblastoma multiforme (GBM). Two catalytic subunits (CSNK2A2 and CSNK2B) has been identified with higher expression levels (3.01 - 3.04 fold) in CSCs as compared with DGCs (Shevchenko, Arnotskaya et al. 2020).

Bibliography

Pubmed IDLast YearTitleAuthors
163355322005The catalytic subunit alpha' gene of human protein kinase CK2 (CSNK2A2): genomic organization, promoter identification and determination of Ets1 as a key regulator.Ackermann K et al
112394572001A DNA damage-induced p53 serine 392 kinase complex contains CK2, hSpt16, and SSRP1.Keller DM et al
258373262015Preclinical evaluation of cyclin dependent kinase 11 and casein kinase 2 survival kinases as RNA interference targets for triple negative breast cancer therapy.Kren BT et al
123962312003Protein kinase CK2: structure, regulation and role in cellular decisions of life and death.Litchfield DW et al
283552892017Increased expression of protein kinase CK2α correlates with poor patient prognosis in epithelial ovarian cancer.Ma Z et al
205144312010Differentiation of tubular and villous adenomas based on Wnt pathway-related gene expression profiles.Nguyen AV et al
190982852009Discovery and scoring of protein interaction subnetworks discriminative of late stage human colon cancer.Nibbe RK et al
115744632001Crystal structure of human protein kinase CK2: insights into basic properties of the CK2 holoenzyme.Niefind K et al
255417192014Mining CK2 in cancer.Ortega CE et al
122441252002Protein kinase CK2: a challenge to canons.Pinna LA et al
113258572001Roles of IKK kinases and protein kinase CK2 in activation of nuclear factor-kappaB in breast cancer.Romieu-Mourez R et al
247953492014Genome-wide association study identifies variants in casein kinase II (CSNK2A2) to be associated with leukocyte telomere length in a Punjabi Sikh diabetic cohort.Saxena R et al
117048242001Protein kinase CK2 is involved in G2 arrest and apoptosis following spindle damage in epithelial cells.Sayed M et al
85733101995New models of lymphoma in transgenic mice.Seldin DC et al
324486072020Proteins of Wnt signaling pathway in cancer stem cells of human glioblastoma.Shevchenko V et al
161930642005Caspase-2 primes cancer cells for TRAIL-mediated apoptosis by processing procaspase-8.Shin S et al
113327132001Protein kinase CK2 signal in neoplasia.Tawfic S et al
268737292016High Expression of miR-532-5p, a Tumor Suppressor, Leads to Better Prognosis in Ovarian Cancer Both In Vivo and In Vitro.Wang F et al

Other Information

Locus ID:

NCBI: 1459
MIM: 115442
HGNC: 2459
Ensembl: ENSG00000070770

Variants:

dbSNP: 1459
ClinVar: 1459
TCGA: ENSG00000070770
COSMIC: CSNK2A2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000070770ENST00000262506P19784
ENSG00000070770ENST00000563307H3BV19
ENSG00000070770ENST00000565188H3BNI9
ENSG00000070770ENST00000567730H3BSA1

Expression (GTEx)

0
10
20
30
40
50
60
70
80
90
100

Pathways

PathwaySourceExternal ID
Wnt signaling pathwayKEGGko04310
Adherens junctionKEGGko04520
Wnt signaling pathwayKEGGhsa04310
Adherens junctionKEGGhsa04520
Ribosome biogenesis in eukaryotesKEGGko03008
Ribosome biogenesis in eukaryotesKEGGhsa03008
MeaslesKEGGko05162
MeaslesKEGGhsa05162
Herpes simplex infectionKEGGko05168
Herpes simplex infectionKEGGhsa05168
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
NF-kappa B signaling pathwayKEGGhsa04064
NF-kappa B signaling pathwayKEGGko04064
Metabolism of proteinsREACTOMER-HSA-392499
Protein foldingREACTOMER-HSA-391251
Chaperonin-mediated protein foldingREACTOMER-HSA-390466
Signal TransductionREACTOMER-HSA-162582
Signaling by WntREACTOMER-HSA-195721
TCF dependent signaling in response to WNTREACTOMER-HSA-201681
WNT mediated activation of DVLREACTOMER-HSA-201688
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Cell CycleREACTOMER-HSA-1640170
Cell Cycle, MitoticREACTOMER-HSA-69278
M PhaseREACTOMER-HSA-68886
Mitotic PrometaphaseREACTOMER-HSA-68877
Condensation of Prometaphase ChromosomesREACTOMER-HSA-2514853
MetabolismREACTOMER-HSA-1430728
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Phospholipid metabolismREACTOMER-HSA-1483257
Glycerophospholipid biosynthesisREACTOMER-HSA-1483206
Synthesis of PCREACTOMER-HSA-1483191
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
L1CAM interactionsREACTOMER-HSA-373760
Signal transduction by L1REACTOMER-HSA-445144
Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta foldingREACTOMER-HSA-6814122
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Activity through PhosphorylationREACTOMER-HSA-6804756
Mitophagy - animalKEGGko04137
Mitophagy - animalKEGGhsa04137

References

Pubmed IDYearTitleCitations
179033082007Genome-wide association of sleep and circadian phenotypes.87
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
210934422011Structural basis of CX-4945 binding to human protein kinase CK2.27
264309622015Protein kinase CK2α catalytic subunit is overexpressed and serves as an unfavorable prognostic marker in primary hepatocellular carcinoma.19
279202542017Casein Kinase 2 Is Linked to Stress Granule Dynamics through Phosphorylation of the Stress Granule Nucleating Protein G3BP1.19
119720582002Association and regulation of casein kinase 2 activity by adenomatous polyposis coli protein.17
120376802002CK2-dependent phosphorylation of the E2 ubiquitin conjugating enzyme UBC3B induces its interaction with beta-TrCP and enhances beta-catenin degradation.15
247953492014Genome-wide association study identifies variants in casein kinase II (CSNK2A2) to be associated with leukocyte telomere length in a Punjabi Sikh diabetic cohort.15
257882692015Protein kinase CK2 is widely expressed in follicular, Burkitt and diffuse large B-cell lymphomas and propels malignant B-cell growth.15

Citation

Nazanin Abazari ; Alessandro Beghini

CSNK2A2 (casein kinase 2 alpha 2)

Atlas Genet Cytogenet Oncol Haematol. 2020-11-01

Online version: http://atlasgeneticsoncology.org/gene/40171/csnk2a2