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.
Introduction
CK2 general features
CK2 (previously called casein kinase 2 or CK-II) is one of the first identified protein kinases.1 It phosphorylates hundreds of physiological substrates,2 and is one of the major contributors to the generation of the human phospho-proteome.3
Structurally, mammalian CK2 is a tetrameric enzyme, composed of two catalytic and two regulatory subunits. The catalytic ones might be represented either by α or α′, very similar but encoded by two different genes, CSNK2A1 and CSNK2A2, respectively, while only one human CK2 regulatory subunit exists, β, encoded by the CSNK2B gene. The regulatory functions of β are limited to preserving the enzyme stability and driving the selection of substrates.4 In fact, CK2 is constitutively active, and catalytically competent also in its monomeric form.4
CK2 functions and involvement in signal transduction
In signal transduction, CK2 is defined as a “lateral player”.5,6 In fact, being constitutively active, it does not respond to a figuratively “vertical” stimulus coming from outside the cell. It is instead already present and ready to play its “horizontal” function on pathways that are otherwise activated. Among the many CK2 substrates, components of diverse signaling pathways are present, implying that CK2 controls important cellular processes, frequently producing abnormal responses and contributing to pathological phenotypes. Its intervention that might cause dysregulation relevant for human diseases has been dissected in several signaling pathways. The ones with the most well-defined role of CK2 are shown in Fig. 1. Figure 1a schematically describes the multilevel intervention of CK2 on the PI3K (phosphoinositide 3-kinase)/Akt pathway:7,8 CK2 directly phosphorylates Akt1 at Ser129, thus promoting its activity and stabilizing the phosphorylation of the PDK1 (phosphoinositide-dependent kinase 1)-dependent activation site Thr308. Moreover, CK2 phosphorylates PTEN, with the effect of inhibiting its phosphatase activity and preventing the downregulation of PI3K-dependent signaling. The participation of CK2 in the IKK (IκB kinase)/NFκB pathway9 (Fig. 1b) is based on several targets, including IκBα (inhibitor of NFκB), whose phosphorylation is increased by CK2 both directly and through the activation of IKK. The phosphorylation of IκBα promotes its degradation, and the consequent NFκB release from the inhibitory complex with its final nuclear translocation. In addition, Ser529 of the NFκB p65 subunit is also phosphorylated by CK2, with the effect of increasing NFκB p65 transcriptional activity.10 On JAK2/STAT3 pathway (Fig. 1c), CK2 targets both STAT311 and JAK2,12 resulting in a final amplification of cytokine signals. Interestingly, CK2 itself has been found under the control of STAT3.13 The Wnt/β-catenin pathway (Fig. 1d) is another signaling with a multisite regulation by CK2,9 which intervenes at the level of dishevelled (Dvl; thus reducing its GSK3-mediated degradation of β-catenin), β-catenin (to promote its nuclear translocation and transcriptional activity), and the transcription factor TCF/LEF. CK2 is known to increase the DNA repair in response to damage signals14 (Fig. 1e); the mechanism implies the phosphorylation of several proteins, such as XRCC4 (crucial for the nonhomologous end-joining, NHEJ, the major DNA double-strand break repair pathway), and XRCC1 (promoting DNA single-strand break repair); in general, the effect of the CK2-dependent phosphorylation is an increased association to DNA–repair protein complexes. On the signaling elicited by the androgen receptor (AR) stimulation (Fig. 1f), CK2 activity has been shown essential for the stability of the receptor protein, and therefore to support the AR transcriptional action.15,16 Some roles of CK2 have been reported also in other signaling pathways, such as Hedgehog,17 TNF-α,18 Notch1,19 and Tyr-kinase receptors.18,20 The degree by which CK2 potentiates each signal depends of course on its expression/activity level, becoming prominent in cancer cells, where CK2 is usually overexpressed3,6 (see below).