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

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.

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Fig: 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. fAndrogen receptor (AR) pathway: CK2 activity increases AR protein stability, leading to promote the AR-dependent transcriptional activity

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.

Borgo, C., D’Amore, C., Sarno, S. et al. Protein kinase CK2: a potential therapeutic target for diverse human diseases. Sig Transduct Target Ther 6, 183 (2021). https://doi.org/10.1038/s41392-021-00567-7

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