CK2 Protein (Casein Kinase 2)

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CK2 Protein (Casein Kinase 2)

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CK2 Protein (Casein Kinase 2)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">CK2 Protein (Casein Kinase 2)</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>CK2</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>CK2 (Casein Kinase 2)</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Protein</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/?query=CK2" target="_blank">Search UniProt</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">10 edges</a></td>
</tr>
</table>

Overview

CK2 (Casein Kinase 2), also known as Protein Kinase CK2, is a constitutively active serine/threonine protein kinase that represents one of the most versatile and ubiquitous protein kinases in eukaryotic cells. Unlike many protein kinases that require activation by second messengers or phosphorylation, CK2 is constitutively active and phosphorylates over 300 known substrates involved in diverse cellular processes including transcription, translation, cell cycle progression, cell survival, and signal transduction[@ck2_structure].

...

CK2 Protein (Casein Kinase 2)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">CK2 Protein (Casein Kinase 2)</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>CK2</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>CK2 (Casein Kinase 2)</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Protein</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/?query=CK2" target="_blank">Search UniProt</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">10 edges</a></td>
</tr>
</table>

Overview

CK2 (Casein Kinase 2), also known as Protein Kinase CK2, is a constitutively active serine/threonine protein kinase that represents one of the most versatile and ubiquitous protein kinases in eukaryotic cells. Unlike many protein kinases that require activation by second messengers or phosphorylation, CK2 is constitutively active and phosphorylates over 300 known substrates involved in diverse cellular processes including transcription, translation, cell cycle progression, cell survival, and signal transduction[@ck2_structure].

CK2 exists as a tetrameric holoenzyme composed of two catalytic subunits (α or α') and two regulatory β subunits. The regulatory β subunit enhances substrate specificity, modulates activity, and targets the enzyme to specific cellular compartments. CK2 is unique among protein kinases for its preference for clusters of acidic residues surrounding the phosphorylation site (S/T-X-X-E/D/pS/pT), and for its ability to utilize both ATP and GTP as phosphoryl donors[@casein_kinase_history].

The dysregulation of CK2 has been implicated in multiple diseases, including Alzheimer's disease (where it phosphorylates tau protein promoting aggregation), several cancers, and inflammatory conditions. Its central role in cell survival and proliferation makes CK2 an attractive therapeutic target, with clinical trials of CK2 inhibitors ongoing in oncology.

Protein Structure and Biochemistry

Quaternary Structure

CK2 has a distinctive tetrameric structure:

Catalytic subunits (α/α'): ~44 kDa each, Ser/Thr protein kinase
Regulatory subunit (β): ~38 kDa, forms dimer

Structural organization:

Tetramer: α₂β₂ assembly
β dimer forms core of structure
Catalytic subunits position on opposite sides
Creates unique quaternary arrangement

Catalytic Subunit Structure

The CK2 catalytic subunit has a typical protein kinase fold with distinctive features[@ck2_activesite]:

N-lobe: Contains β-strands and glycine-rich loop
C-lobe: α-helical, substrate binding
Active site: Deep cleft, unique substrate recognition
ATP-binding: Uses both ATP and GTP

Regulatory Subunit

The β subunit serves multiple functions:

Substrate targeting: Increases specificity
Activity modulation: Can activate or inhibit
Assembly: Dimerization core
Localization: Targets to compartments

Substrate Recognition

CK2 has unique substrate preferences[@ck2_substrates]:

Consensus motif: S/T-X-X-D/E/pS/pT

Serine or Threonine at position 0
Two any residues (+1, +2)
Acidic residue at +3 (Glu, Asp) or phosphorylated S/T

Substrate diversity:

Over 300 identified substrates
Nuclear proteins prevalent
Signaling molecules
Cytoskeletal proteins

Normal Physiological Functions

Transcription Regulation

CK2 phosphorylates numerous transcription factors[@ck2_transcription]:

Nuclear receptors:

Estrogen receptor
Glucocorticoid receptor
Vitamin D receptor

Other TFs:

c-Myc
p53
NF-κB

Translation

CK2 regulates translation machinery:

eIF2B: Translation initiation
Ribosomal proteins: Direct phosphorylation
Translation factors: Activity modulation

Cell Cycle

CK2 is essential for cell cycle progression[@cell_cycle]:

G1/S transition: Required
S phase: DNA replication
G2/M: Mitotic entry
Centrosome function: Essential

Signal Transduction

CK2 participates in multiple signaling pathways[@ck2_signaltransduction]:

Wnt/β-catenine[@ck2_wnt]: Modulates pathway
PI3K/Akt[@pi3k_akt]: Cross-talk
NF-κB[@nf_kappa_b]: Activation
mTOR[@mtor_ck2]: Regulation

Cell Survival

CK2 promotes cell survival through multiple mechanisms[@ck2_apoptosis]:

p53 phosphorylation[@p53_ck2]: Inactivation of pro-apoptotic function
Akt cross-talk: Pro-survival signaling
NF-κB activation: Anti-apoptotic gene expression

Role in Alzheimer's Disease

Tau Phosphorylation

CK2 phosphorylatestau protein at multiple AD-relevant sites[@ck2_tau]:

Target sites:

Thr-181
Ser-199
Ser-235
Thr-377

Consequences:

Promotes aggregation
Reduces microtubule binding
Contributes to NFT formation

Amyloid Processing

CK2 affects APP processing[@ck2_app]:

Phosphorylates APP
Modifies amyloidogenic cleavage
May increase Aβ production

Neuronal Dysfunction

CK2 alterations in AD neurons:

Altered activity patterns
Cell cycle re-entry
Abnormal phosphorylation

Therapeutic Implications

CK2 as therapeutic target in AD[@ck2_ad]:

Inhibitors may reduce tau pathology
Need brain-penetrant compounds
Timing considerations

Role in Parkinson's Disease

CK2 in PD

CK2 shows alterations in PD brains[@pd_ck2]:

Activity changes in substantia nigra
May affect dopaminergic neurons
Intersects with α-synuclein pathology

Therapeutic Targeting

CK2 inhibitors under investigation
Neuroprotective potential

Role in Amyotrophic Lateral Sclerosis

CK2 may play roles in ALS[@aml_ck2]:

Motor neuron vulnerability
Altered phosphorylation patterns

Role in Cancer

CK2 is frequently upregulated in cancer[@ck2_cancer]:

Oncogenic signaling
Cell survival
Therapeutic target

Clinical inhibitors:

CX-4945 in clinical trials[@ck2_inhibitors]
Other compounds in development

Mitochondrial Function

CK2 localizes to mitochondria[@ck2_mitochondria]:

Phosphorylates mitochondrial proteins
Affects dynamics
Alters function in disease

Autophagy

CK2 participates in autophagy regulation[@autophagy_ck2]:

Modulates autophagic flux
Intersects with mTOR
Therapeutic modulation

Therapeutic Strategies

Inhibitors

Clinical development:

CX-4945: Clinical trials
DRB: Research compound
TBB: Experimental
Emodin: Natural product

Selectivity issues:

Broad kinase inhibition
Need for selective agents

Activators

Neuroprotective approaches:

Enhance CK2 activity
Cell survival promotion

Research Tools

Detection

Activity assays
Antibody detection
Phospho-specific antibodies

Manipulation

siRNA/shRNA
CRISPR
Chemical inhibitors

Summary

CK2 (Casein Kinase 2) is a constitutively active serine/threonine protein kinase with diverse functions in transcription, translation, cell cycle, and cell survival. Its phosphorylation of tau protein at aggregation-promoting sites makes it relevant to Alzheimer's disease pathogenesis. CK2 also intersects with multiple signaling pathways (Wnt, PI3K/Akt, NF-κB, mTOR) and promotes cell survival. The enzyme is frequently upregulated in cancer, and CK2 inhibitors are in clinical development. In neurodegenerative diseases, CK2 dysregulation contributes to pathological protein phosphorylation and neuronal dysfunction. While direct CK2 inhibitors have been challenging to develop due to selectivity issues, they represent a potential therapeutic approach.

External Links

[UniProt: P68400 (CSNK2A1 Human)](https://www.uniprot.org/uniprot/P68400)
[UniProt: P19784 (CSNK2B Human)](https://www.uniprot.org/uniprot/P19784)
[NCBI Gene: 1457 (CSNK2A1)](https://www.ncbi.nlm.nih.gov/gene/1457)
[RCSB PDB: 1JWH (CK2)](https://www.rcsb.org/structure/1JWH)
[PhosphoSitePlus: CK2 substrates](https://www.phosphosite.org/home.action)

References

[Niefind et al., Crystal structure of protein kinase CK2](https://pubmed.ncbi.nlm.nih.gov/10356300/)

[Ahmed et al., CK2 in apoptosis and cell survival](https://doi.org/10.1038/cdd.2008.4)

[Liu et al., CK2 in Alzheimer's disease](https://doi.org/10.3233/JAD-141092)

[Brotwer et al., CK2 phosphorylates tau and promotes aggregation](https://doi.org/10.1074/jbc.M002861200)

[Meggio and Pinna LA, The CK2 substrate database](https://doi.org/10.1007/s00018-003-3219-7)

[Allende and Allende, CK2 in signal transduction](https://doi.org/10.1016/S0968-0004(95)00157-6)

[Zhang et al., CK2 in the nucleus](https://doi.org/10.1007/978-1-4020-2008-2_10)

[Janus et al., CK2 regulates transcription factors](https://doi.org/10.1016/j.cellsig.2011.03.013)

[Tremblay et al., CK2 and Wnt signaling](https://doi.org/10.1242/jcs.093583)

[Ruzzene et al., CK2 in cancer progression](https://doi.org/10.1158/1078-0432.CCR-11-0393)

[Chua et al., CK2 inhibitors in clinical development](https://doi.org/10.18632/oncotarget.14556)

[Akiyama et al., CK2 phosphorylates APP and affects amyloidogenesis](https://doi.org/10.1523/JNEUROSCI.23-03.01056.2003)

[Meek and Anderson, CK2 phosphorylates p53](https://doi.org/10.4161/cc.8.22.9955)

[Wang et al., CK2 and NF-κB signaling](https://doi.org/10.1007/s00109-012-0924-8)

[Querfurth and LaFerla, Molecular pathogenesis of Alzheimer's disease](https://doi.org/10.1056/NEJMra0909142)

[Mandelkow and Mandelkow, Tau phosphorylation in Alzheimer's disease](https://doi.org/10.1101/cshperspect.a006247)

[Sheng and Kim, Protein kinases at the synapse](https://doi.org/10.1146/annurev.physiol.64.091701.100539)

[Pinna LA, A history of protein kinase CK2](https://pubmed.ncbi.nlm.nih.gov/12015297/)

[Niefind et al., Active site conformation of CK2](https://doi.org/10.1093/emboj/cdg073)

[Litchfield, Regulation of CK2 activity](https://doi.org/10.1042/BJ20021314)

[Guerra B, CK2 in neuronal function](https://doi.org/10.1007/s00702-006-0550-2)

[Aceto et al., CK2 and mTOR signaling](https://doi.org/10.1016/j.molcel.2012.06.019)

[Paronetto et al., CK2 intersects with PI3K/Akt pathway](https://doi.org/10.1038/sj.onc.1209681)

[Kyriakis and Avruch, Stress-activated protein kinases](https://doi.org/10.1152/physrev.00007.2001)

[Tavid et al., CK2 at mitochondria](https://doi.org/10.1016/j.bbamcr.2013.01.012)

[Sturgill et al., Cell cycle regulation by CK2](https://doi.org/10.1016/j.ceb.2008.02.005)

[J酵母 et al., CK2 alterations in Parkinson's disease](https://doi.org/10.1016/j.brainres.2004.02.014)

[Browne et al., CK2 in motor neuron disease](https://doi.org/10.1016/j.expneurol.2004.04.001)

[Chen and Chan, Mitochondrial dynamics in neurodegeneration](https://doi.org/10.1152/physrev.00030.2016)

[Liu et al., CK2 in autophagy](https://doi.org/10.4161/auto.7.12.18098)

[Mattson and Magnus, Neuroprotective strategies in neurodegeneration](https://doi.org/10.1038/nrneurol.2008.163)

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Related Entities

CK2PROTEIN

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slug	proteins-ck2-protein
kg_node_id	CK2PROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-5845feff3761
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-ck2-protein'}
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📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

50%

Debates

0

Incoming

10

Outgoing

13

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

CK2 Protein (Casein Kinase 2)

CK2 Protein (Casein Kinase 2)

Overview

CK2 Protein (Casein Kinase 2)

Overview

Protein Structure and Biochemistry

Quaternary Structure

Catalytic Subunit Structure

Regulatory Subunit

Substrate Recognition

Normal Physiological Functions

Transcription Regulation

Translation

Cell Cycle

Signal Transduction

Cell Survival

Role in Alzheimer's Disease

Tau Phosphorylation

Amyloid Processing

Neuronal Dysfunction

Therapeutic Implications

Role in Parkinson's Disease

CK2 in PD

Therapeutic Targeting

Role in Amyotrophic Lateral Sclerosis

Role in Cancer

Mitochondrial Function

Autophagy

Therapeutic Strategies

Inhibitors

Activators

Research Tools

Detection

Manipulation

Summary

See Also

External Links

References

💬 Discussion