Casein kinase 2

casein kinase 2,
alpha prime polypeptide
casein kinase 2,; alpha prime polypeptide
Identifiers
Symbol	CSNK2A2
NCBI gene	1459
HGNC	2459
OMIM	115442
RefSeq	NM_001896
UniProt	P19784
Other data
EC number	2.7.11.1
Locus	Chr. 16 [1]
Structures
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Structures	Swiss-model
Domains	InterPro

Search for
Structures	Swiss-model
Domains	InterPro

casein kinase 2,
alpha 1 polypeptide
casein kinase 2,; alpha 1 polypeptide
Identifiers
Symbol	CSNK2A1
NCBI gene	1457
HGNC	2457
OMIM	115440
RefSeq	NM_001895
UniProt	P68400
Other data
EC number	2.7.11.1
Locus	Chr. 20 p13
Structures
Search for
Structures	Swiss-model
Domains	InterPro

Casein kinase 2 (EC 2.7.11.1)(CK2/CSNK2) is a serine/threonine-selective protein kinase that has been implicated in cell cycle control, DNA repair, regulation of the circadian rhythm, and other cellular processes. De-regulation of CK2 has been linked to tumorigenesis as a potential protection mechanism for mutated cells. Proper CK2 function is necessary for survival of cells as no knockout models have been successfully generated.^[1]

Structure

Ribbon structure of CK2 tetramer containing two αあるふぁ and two βべーた subunits

CK2 typically appears as a tetramer of two αあるふぁ subunits; αあるふぁ being 42 kDa and αあるふぁ’ being 38 kDa, and two βべーた subunits, each weighing in at 28 kDa.^[1] The βべーた regulatory domain only has one isoform^[2] and therefore within the tetramer will have two βべーた subunits. The catalytic αあるふぁ domains appear as an αあるふぁ or αあるふぁ’ variant and can either be formed in a homodimer (αあるふぁ & αあるふぁ, or αあるふぁ’ & αあるふぁ’) formation or heterodimer formation (αあるふぁ & αあるふぁ’).^[2] It is worth noting that other βべーた isoforms have been found in other organisms but not in humans.^[2]

The αあるふぁ subunits do not require the βべーた regulatory subunits to function, this allows dimers to form of the catalytic domains independent of βべーた subunit transcription. The presence of these αあるふぁ subunits does have an effect on the phosphorylation targets of CK2.^[3] A functional difference between αあるふぁ and αあるふぁ’ has been found but the exact nature of differences isn't fully understood yet. An example is that Caspase 3 is preferentially phosphorylated by αあるふぁ’ based tetramers over αあるふぁ based tetramers.^[3]

Function

CK2 is a protein kinase responsible for phosphorylation of substrates in various pathways within a cell; ATP or GTP can be used as phosphate source.^[1] CK2 has a dual functionality with involvement in cell growth/proliferation and suppression of apoptosis.^[1] CK2s anti-apoptotic function is in the continuation of the cell cycle; from G1 to S phase and G2 to M phase checkpoints.^[2] This function is achieved by protecting proteins from caspase-mediated apoptosis via phosphorylation of sites adjacent to the caspase cleavage site, blocking the activity of caspase proteins. CK2 also protects from drug-induced apoptosis via similar methods but it is not as well understood.^[2] Knockdown studies of both αあるふぁ and αあるふぁ’ sub-units have been used to verify this anti-apoptotic function.

Important phosphorylation events also regulated by CK2 are found in DNA damage repair pathways, and multiple stress-signaling pathways. Examples are phosphorylation of p53 or MAPK,^[2] which both regulate many interactions within their respective cellular pathways.

Another indication of separate function of αあるふぁ subunits is that mice that lack CK2αあるふぁ’ have a defect in the morphology of developing sperm.^[4]

Regulation

Although the targets of CK2 are predominantly nucleus-based the protein itself is localized to both the nucleus and cytoplasm.^[1] Casein kinase 2 activity has been reported to be activated following Wnt signaling pathway activation.^[5] A Pertussis toxin-sensitive G protein and Dishevelled appear to be an intermediary between Wnt-mediated activation of the Frizzled receptor and activation of CK2. Further studies need to be done on the regulation of this protein due to the complexity of CK2 function and localization.

Phosphorylation of CK2αあるふぁ T344 has been shown to inhibit its proteasomal degradation and support binding to Pin1. O-GlcNAcylation at S347 antagonizes this phosphorylation and accelerates CK2αあるふぁ degradation.^[6] O-GlcNAcylation of CK2αあるふぁ has also been shown to alter the phosphoproteome, notably including many chromatin regulators such as HDAC1, HDAC2, and HCFC1.^[7]

Role in tumorigenesis

Among the array of substrates that can be altered by CK2 many of them have been found in increased prevalence in cancers of the breast, lung, colon, and prostate.^[3] An increased concentration of substrates in cancerous cells infers a likely survival benefit to the cell, and activation of many of these substrates requires CK2. As well the anti-apoptotic function of CK2 allows the cancerous cell to escapes cell death and continue proliferating. Having roles in cell cycle regulation may also indicate CK2's role in allowing cell cycle progression when normally it should have been ceased. This also promotes CK2 as a possible therapeutic target for cancer drugs. When added with other potent anti-cancer therapies, a CK2 inhibitor may increase the effectiveness of the other therapy by allowing drug-induced apoptosis to occur at a normal rate.^[3]

Role in viral infection

In SARS-CoV-2 (COVID-19) infected Caco-2 cells, the phosphorylase activity of CK2 is increased resulting in phosphorylation of several cytoskeletal proteins. These infected cells also display CK2-containing filopodia protrusions associated with budding viral particles. Hence the protrusions may assist the virus in infecting adjacent cells. In these same cells, the CK2 inhibitor silmitasertib displayed potent antiviral activity.^[8] Senhwa Biosciences and the US National Institutes of Health have announced that they will evaluate the efficacy of silmitasertib in treating COVID-19 infections.^[9]