Protein kinase CK2: a potential therapeutic target for diverse human diseases

Abstract

CK2 is a constitutively active Ser/Thr protein kinase, which phosphorylates hundreds of substrates, controls several signaling pathways, and is implicated in a plethora of human diseases. Its best documented role is in cancer, where it regulates practically all malignant hallmarks. Other well-known functions of CK2 are in human infections; in particular, several viruses exploit host cell CK2 for their life cycle. Very recently, also SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has been found to enhance CK2 activity and to induce the phosphorylation of several CK2 substrates (either viral and host proteins). CK2 is also considered an emerging target for neurological diseases, inflammation and autoimmune disorders, diverse ophthalmic pathologies, diabetes, and obesity. In addition, CK2 activity has been associated with cardiovascular diseases, as cardiac ischemia-reperfusion injury, atherosclerosis, and cardiac hypertrophy. The hypothesis of considering CK2 inhibition for cystic fibrosis therapies has been also entertained for many years. Moreover, psychiatric disorders and syndromes due to CK2 mutations have been recently identified. On these bases, CK2 is emerging as an increasingly attractive target in various fields of human medicine, with the advantage that several very specific and effective inhibitors are already available. Here, we review the literature on CK2 implication in different human pathologies and evaluate its potential as a pharmacological target in the light of the most recent findings.

Fig. 1

Depiction of the most relevant CK2 interventions on cellular signaling pathways. Double arrows indicate a dynamic equilibrium that moves toward the longest arrow direction; inhibitions are indicated by bar-headed arrows. a PI3K/Akt pathway: CK2 is known to directly potentiate Akt functions, but it also inhibits PTEN, thus preventing its downregulating functions. b IKK/NFκB pathway: CK2 induces IκBα degradation thus reducing its inhibitory action, and stimulates IKK and the p65 subunit of NFkB. c JAK2/STAT3 pathway: CK2 directly activates JAK2 and STAT3 and, in turn, CK2 expression is under the control of STAT3. d Wnt/β-catenin pathway: CK2 activates Dvl, thus inhibiting the GSK3-mediated degradation of β-catenin, and phosphorylates β-catenin, promoting its stability; moreover, its phosphorylation of TCF/LEF stimulates the β-catenin/LEF complex formation and transcriptional activity. e DNA damage response: CK2 phosphorylates the indicated proteins to improve their DNA repair activity. f Androgen receptor (AR) pathway: CK2 activity increases AR protein stability, leading to promote the AR-dependent transcriptional activity

Fig. 2

CK2 roles in cancer. Signaling pathways by which CK2 exerts its specific functions in cancer cells are depicted. For each pathway, CK2 targets are shown only in case their effects in tumorigenesis have been dissected (not showing CK2 substrates whose phosphorylation does not produce a well-defined effect). Double arrows indicate a dynamic equilibrium that moves toward the longest arrow direction; inhibitions are indicated by bar-headed arrows. a Major mechanisms by which CK2 prevents caspase activation. CK2 phosphorylation of BID prevents its cleavage to the truncated form (tBID) and its consequent migration to the mitochondria; this event blocks the apoptotic cascade dependent on the cytosolic release of proapoptotic factors cytochrome c (Cyt c), an activator of caspase 9 via APAF-1 (apoptotic protease activating factor-1), and Smac/DIABLO, a repressor of IAP (inhibitor of apoptosis) proteins. Furthermore, CK2 directly phosphorylates and prevents the activation of caspase-3, and promotes the action of the caspase inhibitor ARC, which blocks caspase 8. b CK2 effects on multidrug resistance (MDR). CK2 reduces the cancer cell response to chemotherapeutic drugs by promoting the expression of the three major drug extrusion pumps, namely MRP1, P-gp, and BCRP. MRP1 and P-gp are also directly activated by CK2. c Major actions of CK2 on the unfolded protein response pathway. CK2 acts on different branches of the unfolded protein response, with the effect of preventing the final apoptotic outcome (by blocking the PERK signaling) and driving towards the survival response (by supporting the IRE1 signaling). d CK2 regulation of chaperone proteins. CK2 directly controls the activity of HSP70 and CDC37 (HSP90 co-chaperone), and protects HSP27 from degradation. These chaperones, in turn, stabilize and maintain the activity of oncogenic proteins, especially protein kinases (oncokinases). e Major mechanisms of CK2 control on tumor suppressor proteins. CK2 promotes p53 degradation through the phosphorylation of the ubiquitin-specific peptidase 7 (USP7S); this in turn stabilizes MDM2 with the final effect of targeting p53 to the proteasome. IKAROS is directly phosphorylated by CK2, reducing its DNA-binding affinity and promoting its degradation. CK2 also directly phosphorylates PML; this drives its proteasome-mediated degradation, and finally reduces its function of promoting senescence and apoptosis

Fig. 3

CK2 targets in neurodegenerative diseases. Red shapes denote targets that mediate CK2 pathological functions, blue shapes are proteins by which CK2 may exert a protective function against the disease, gray shapes indicate that the CK2-dependent phosphorylation has no disease-related effect. a Parkinson’s disease (PD): CK2 promotes α-synuclein aggregation in Lewis bodies (LB) by phosphorylating its Ser129, but this site is also target of other protein kinases. b Alzheimer’s disease (AD): CK2 is responsible for the 5-HT₄ receptor-stimulated induction of α-secretase activity, which in turn reduces the Aβ (amyloid β-peptide) production, through the non-amyloidogenic pathway of amyloid precursor protein (APP) processing. However, CK2 induces tau hyperphosphorylation, through the phosphorylation of SET, an inhibitor of the PP2A phosphatase, and its consequent cytosolic localization and binding to PP2A. Moreover, CK2 phosphorylates KLC 1, causing FAT impairment. Another AD-related CK2 target is PS-2, whose phosphorylation, however, does not affect the APP processing. c Huntington’s disease (HD): the HTT sites Ser13 and Ser16, found hypo-phosphorylated in the polyQ-HTT mutant, are increased by CK2 through a direct or indirect mechanism (dashed arrows), and this reduces cellular toxicity. d Spinocerebellar ataxia type 3 (SCA3): CK2 associates to and phosphorylates ataxin-3, thus promoting its nuclear localization and stabilization, and enhancing the formation of inclusions. e Amyotrophic lateral sclerosis (ALS): CK2 is a potential kinase of TDP43, the major component of protein aggregates in motor neurons, whose phosphorylation decreases its propensity to aggregate. Moreover, CK2 phosphorylates cyclin F, thus negatively controlling the E3 ligase activity of the SKP1/cullin1/F‐box (SCF)‐E3 ligase complex, and finally reducing the aberrant proteins ubiquitination typically observed in ALS

Fig. 4

CK2-related human pathologies. Human organs/tissues are schematically represented as the main sites of diseases, where CK2 has been found implicated. Solid tumors are not included in this scheme. The following abbreviations are used: PD Parkinson’s disease, AD Alzheimer’s disease, HD Huntington’s disease, ADHD attention deficit/hyperactivity disorder, MDD major depressive disorder, OCNDS Okur–Chung neurodevelopment syndrome, HTNV Hantaan virus, RSV respiratory syncytial virus, COVID-19 coronavirus Sars-CoV-2 disease, EMCV encephalomyocarditis virus, T1DM type 1 diabetes mellitus, T2DM type 2 diabetes mellitus, T-ALL T-cell acute lymphoblastic leukemia, B-ALL B-cell acute lymphoblastic leukemia, AML acute myeloid leukemia, CLL chronic lymphocytic leukemia, CML chronic myelogenous leukemia; MM multiple myeloma, MSL multiple symmetric lipomatosis, ALS amyotrophic lateral sclerosis