The Role of Protein Kinase CK2 in Development and Disease Progression: A Critical Review

Abstract

Protein kinase CK2 (CK2) is a ubiquitous holoenzyme involved in a wide array of developmental processes. The involvement of CK2 in events such as neurogenesis, cardiogenesis, skeletogenesis, and spermatogenesis is essential for the viability of almost all organisms, and its role has been conserved throughout evolution. Further into adulthood, CK2 continues to function as a key regulator of pathways affecting crucial processes such as osteogenesis, adipogenesis, chondrogenesis, neuron differentiation, and the immune response. Due to its vast role in a multitude of pathways, aberrant functioning of this kinase leads to embryonic lethality and numerous diseases and disorders, including cancer and neurological disorders. As a result, CK2 is a popular target for interventions aiming to treat the aforementioned diseases. Specifically, two CK2 inhibitors, namely CX-4945 and CIBG-300, are in the early stages of clinical testing and exhibit promise for treating cancer and other disorders. Further, other researchers around the world are focusing on CK2 to treat bone disorders. This review summarizes the current understanding of CK2 in development, the structure of CK2, the targets and signaling pathways of CK2, the implication of CK2 in disease progression, and the recent therapeutics developed to inhibit the dysregulation of CK2 function in various diseases.

Keywords: CIBG-300; CX-4945; cancer; casein kinase II; development.

Figure 1

CK2 is expressed at embryonic day 11 and is critical for many developmental processes. Specifically, CK2 is necessary for limiting neurogenesis and preventing the excessive differentiation of neurons. In addition, CK2 expression promotes long-term memory storage. Further, this protein is essential for skeletogenesis, chondrogenesis, adipogenesis, and proper limb formation. CK2 contributes to spermatogenesis, and the inhibition of its expression leads to infertility. Finally, CK2 is important for B cell differentiation and development, myotube formation, the regulation of the epithelial-to-mesenchymal transition (EMT), and the establishment of circulation between the fetus and the mother during the third trimester.

Figure 2

There are three classifications of CK2 substrates. Class I substrates are identified as proteins that are equally phosphorylated by the holoenzyme and individually by the catalytic subunits. Class II substrates are specifically phosphorylated by the catalytic submits of CK2 but not by the holoenzyme. Class III substrates are preferentially targeted and phosphorylated by the holoenzyme but not by the catalytic subunits of CK2.

Figure 3

The localization of CK2 changes when cells are exposed to ionizing radiation (IR). Specifically, CK2α is translocated from the cytoplasm to the nucleus in multiple cell lines, including A549, H460, PC9, and M059K. Further, upon radiation exposure, the overall kinase activity of CK2 increases, emphasizing its role in the DNA-damage-repair response, as it colocalizes with DNA in the nucleus of cells.

Figure 4

The localization of the catalytic subunits of CK2 is altered during hypoxia. Specifically, these subunits are translocated to the nucleus transiently to aid the cellular response to hypoxia.

Figure 5

Simplified schematic demonstrating three therapeutics targeting the activity of CK2. (A). CX-4945 is a competitive ATP inhibitor that binds preferentially to ATP-pocket domains. Here, it binds to both CK2α and CK2α’, thereby preventing ATP from binding and activating CK2. CX-4945 has prevented tumor progression by inhibiting signaling pathways such as Smad and PI3K/AKT. (B). CIBG-300 functions by binding to conserved phosphorylation sequences on the substrates of CK2, such as Akt. This association prevents the phosphorylation of these substrates by CK2, leading to decreased cell signaling, proliferation, and survival. (C). CK2.3 is uptaken by cells and binds to CK2, therefore preventing its association with BMPRIa. As a result, BMPRII can phosphorylate BMPRIa, leading to the downstream activation of signaling pathways that induce mineralization and cell survival.